Respiratory Care: Principles and Practice [4 ed.] 9781284155228, 1284155226, 9781284155266, 9781284205237

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Normal Values Vital Signs Respiratory rate: 12–20 breaths/min in adults; 60–75 breaths/min in infants Heart rate: 60–100 beats/min in adults; 120–170 beats/min in infants Blood pressure: 120/80 mm Hg; lower for infants and children Body temperature: 37° C; 98.6° F

Arterial Blood Gases pH: 7.35–7.45 Paco2: 35–45 mm Hg : 22–24 mmol/L Pao2: 80–100 mm Hg (breathing room air at sea level) Sao2: 95–98% (breathing room air at sea level) P(A – a)O2: < 25 mm Hg

Venous Blood Gases pH: 7.31–7.41 P co2: 40–50 mm Hg P o2: 35–45 mm Hg S o2: 65–75% C(a– )o2: 5 mL/dL

Hemodynamics Systolic blood pressure: 90–140 mm Hg Diastolic blood pressure: 60–90 mm Hg Mean arterial pressure: 65–105 mm Hg Pulmonary artery systolic pressure: 15–30 mm Hg Pulmonary artery diastolic pressure: 4–12 mm Hg

Mean pulmonary artery pressure: 9–16 mm Hg Right ventricular systolic pressure: 15–30 mm Hg Right ventricular end-diastolic pressure: 0–8 mm Hg Central venous pressure: 0–8 mm Hg Pulmonary artery wedge pressure: 2–12 mm Hg Cardiac output: 5–8 L/min Cardiac index: 2.5–3.5 L/min/m2 Stroke volume: 60–100 mL/beat Systemic vascular resistance: 900–1400 dyne × s × cm–5 Pulmonary vascular resistance: 150–250 dyne × s × cm–5 Urine output: 1 mL/kg/hr

Blood Chemistry Na+: 135–145 mmol/L K+: 3.5–5.5 mmol/L Cl–: 98–107 mmol/L : 22–32 mmol/L Ionized Ca+2: 1.2–1.3 mmol/L Mg+2: 0.7–1.1 mmol/L : 0.9–1.5 mmol/L Lactate: < 2 mmol/L Total protein: 60–80 g/L Albumin: 35–55 g/L Blood urea nitrogen: 7–21 mg/dL Creatinine: 0.7–1.4 mg/dL Anion gap: 8–16 mmol/L Total bilirubin: < 1.1 mg/dL Glucose: 70–110 mg/dL Osmolality: 280–300 mOsmol/kg Troponin T: < 0.03 ng/mL NT-proBNP: < 50 yrs, 0–450 pg/mL; 50–75 yrs, 0–900 pg/mL; > 75 yrs, 0–1,500 pg/mL D-dimer: < 500 ng/mL C-reactive protein: < 8 mg/L

Hematology

Hemoglobin: 13.5–15.5 g/dL for men; 12.5–14.5 g/dL for women Hematocrit: 42–52% for men; 37–48% for women White blood cell count: 4,000–11,000/mm3 Platelets: 150,000–400,00/mm3

Respiratory Physiology Tidal volume: 6–7 mL/kg predicted body weight Anatomic dead space: 150 mL in adults (2.2 mL/kg) Minute ventilation: 6–8 L/min VD/VT: 0.3–0.4 Shunt: 2–5% / : 0.8 R: 0.8 o2: 250 mL/min in adults; 3.5 mL/kg/min co2: 200 mL/min in adults; 2.8 mL/kg/min Lung compliance: 200 mL/cm H2O Chest wall compliance: 200 mL/cm H2O Respiratory system compliance: 100 mL/cm H2O Work of breathing: 0.35 joules/L

FOURTH EDITION

Respiratory Care PRINCIPLES AND PRACTICE Dean R. Hess, PhD, RRT, FAARC Respiratory Care, Massachusetts General Hospital Managing Editor, RESPIRATORY CARE Lecturer, Northeastern University Neil R. MacIntyre, MD, FAARC Professor of Medicine Medical Director of Respiratory Care Services, Duke University Medical Center William F. Galvin, MSEd, RRT, CPFT, AE-C, FAARC Assistant Professor Frances M. Maguire School of Nursing and Health Professions Program Director, Respiratory Care Administrative and Teaching Faculty, TIPS Program Gwynedd Mercy University

Shelley C. Mishoe, PhD, RRT, FAARC Professor, School of Community and Environmental Health Old Dominion University Associate Provost, Dean, Chair, Professor Emeritus Augusta University

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Brief Contents © Andriy Rabchun/Shutterstock

Preface Features About the Editors Contributing Authors Reviewers PART 1

Respiratory Assessment

Chapter 1

History and Physical Examination

Chapter 2

Respiratory Monitoring

Chapter 3

Hemodynamic Monitoring

Chapter 4

Arterial Blood Gas Sampling, Analysis, and Interpretation

Chapter 5

Blood Chemistries and Hematology

Chapter 6

Cardiac Assessment

Chapter 7

Imaging the Thorax

Chapter 8

Pulmonary Function Testing

Chapter 9

Interventional Pulmonary Procedures

Chapter 10

Polysomnography

Chapter 11

Nutrition Assessment and Support

Chapter 12

Cardiopulmonary Exercise Assessment

PART 2

Respiratory Therapeutics

Chapter 13

Therapeutic Gases: Manufacture, Storage, and Delivery

Chapter 14

Therapeutic Gases: Management and Administration

Chapter 15

Humidity and Aerosol Therapy

Chapter 16

Airway Clearance and Lung Expansion Therapy

Chapter 17

Airway Management

Chapter 18

Cardiopulmonary Resuscitation

Chapter 19

Mechanical Ventilators: Classification and Principles of Operation

Chapter 20

Mechanical Ventilation

Chapter 21

Noninvasive Respiratory Support

Chapter 22

Neonatal and Pediatric Respiratory Care

Chapter 23

Extracorporeal Life Support for Respiratory Failure

Chapter 24

Pulmonary Rehabilitation

Chapter 25

Home Respiratory Care

Chapter 26

Disaster Management

Chapter 27

Respiratory Care of the Elderly

Chapter 28

Patient Safety

PART 3

Respiratory Diseases

Chapter 29

Principles of Disease Management

Chapter 30

Patient Education

Chapter 31

Infection Control Principles

Chapter 32

Asthma

Chapter 33

Chronic Obstructive Pulmonary Disease

Chapter 34

Interstitial Lung Disease

Chapter 35

Pulmonary Vascular Disease

Chapter 36

Pneumonia

Chapter 37

Cystic Fibrosis

Chapter 38

Acute Respiratory Distress Syndrome

Chapter 39

Postoperative Respiratory Care

Chapter 40

Heart Failure

Chapter 41

Trauma

Chapter 42

Burn and Inhalation Injury

Chapter 43

Sepsis

Chapter 44

Neuromuscular Dysfunction

Chapter 45

Sleep-Disordered Breathing

Chapter 46

Perioperative Management of Lung Transplant Recipients

Chapter 47

Lung Cancer

Chapter 48

Neonatal and Pediatric Respiratory Disorders

PART 4

Applied Sciences for Respiratory Care

Chapter 49

Respiratory Anatomy

Chapter 50

Ventilation and Oxygenation

Chapter 51

Respiratory Mechanics

Chapter 52

Control of Breathing

Chapter 53

Cardiovascular, Renal, and Neural Anatomy and Physiology

Chapter 54

Physical Principles

Chapter 55

Chemistry for Respiratory Care

Chapter 56

Respiratory Microbiology

Chapter 57

Respiratory Drugs

PART 5

The Respiratory Care Profession

Chapter 58

History of the Respiratory Care Profession

Chapter 59

Professional Organizations

Chapter 60

Ethics of Healthcare Delivery

Chapter 61

Healthcare Economics

Chapter 62

Respiratory Care Research and Evidence-Based Practice

Glossary Index

Contents © Andriy Rabchun/Shutterstock

Preface Features About the Editors Contributing Authors Reviewers PART 1 Chapter 1

Respiratory Assessment History and Physical Examination Priscilla R. Simmons Introduction Creating a Therapeutic Climate Components of the Health History Chief Complaint History of Present Illness Occupational and Environmental History Geographic Exposure Activities of Daily Living Smoking History Cough and Sputum Production Family History Medical History Review of Systems

Vital Signs Techniques of Assessment Inspection Palpation Percussion Auscultation Physical Examination of the Lungs and Thorax Inspection Palpation Percussion Auscultation Signs of Respiratory Distress Assessment of Other Body Systems The Heart and Blood Vessels The Neurologic System Key Points Suggested Reading Chapter 2

Respiratory Monitoring Dean R. Hess Introduction Pulse Oximetry Approaches to Deal with Errors Caused by Motion and Low Perfusion Pulse Oximetry to Measure Hemoglobin, Carboxyhemoglobin, and Methemoglobin Use of the Plethysmographic Waveform Capnography Time-Based Capnography End-Tidal PCO2 Volume-Based Capnography

Transcutaneous Monitoring Respiratory Rate and Pattern Brain Tissue PO2 Near-Infrared Spectroscopy Key Points References Chapter 3

Hemodynamic Monitoring Dean R. Hess Introduction Cardiac Rate and Rhythm Arterial Blood Pressure Respiratory Variation in Pulse Amplitude Noninvasive Cardiac Output Central Venous Pressure Monitoring Pulmonary Artery Catheters Catheter Setup Pressure Waveforms Pitfalls in Interpreting Waveforms Cardiac Output Measurement Continuous Oximetric Monitoring Vascular Resistance Clinical Use of Hemodynamic Measurements Key Points References

Chapter 4

Arterial Blood Gas Sampling, Analysis, and Interpretation Shelley C. Mishoe Introduction Blood Gas Analyzers

pH Electrode PCO2 Electrode PO2 Electrode Oximeter Point-of-Care Testing Blood Gas Sampling and Analysis Sites of Arterial Puncture Allen Test Radial Arterial Puncture Punctures of Other Arterial Sites Radial Arterial Cannulation Venous Blood Gases Capillary Blood Gases Preanalytic Errors Sample Analysis Calibration Quality Control and Proficiency Testing Temperature Adjustment Physiology of Acid–Base Balance Concept of pH Buffer Solutions Henderson-Hasselbalch Equation Clinical Application of the Henderson-Hasselbalch Equation Base Excess Anion Gap Strong Ion Difference Albumin-Corrected Anion Gap Regulation of pH Erythrocytes and Acid–Base Control

The Lungs and Acid–Base Control The Kidneys and Acid–Base Control Acid–Base Disorders Respiratory Acidosis Respiratory Alkalosis Metabolic Acidosis Metabolic Alkalosis Arterial Blood Gas Interpretation Normal Arterial Blood Gas Values Seven-Step Approach to ABG Interpretation Case Studies Case 1. Acute Respiratory Acidosis Case 2. Partially Compensated Metabolic Acidosis Case 3. Partially Compensated Respiratory Acidosis Key Points References Chapter 5

Blood Chemistries and Hematology Jessie G. Harvey Rajesh Bhagat Neil R. MacIntyre Introduction Serum Electrolytes Body Water Sodium Potassium Chloride Total Serum Carbon Dioxide Unmeasured Anions Calcium

Magnesium Phosphorus Lactate Serum Chemistries Associated with Renal Function Blood Urea Nitrogen Creatinine Serum Enzyme Activity Cardiac Enzymes and Proteins Cardiac Enzymes Troponins Brain Natriuretic Peptide Miscellaneous Serum Chemistries C-Reactive Protein Bilirubin Proteins Glucose Procalcitonin Coagulation Tests Prothrombin Time Activated Partial Thromboplastin Time Thrombin Time Hematology Hemoglobin and Hematocrit Platelets Total and Differential Leukocyte Count Laboratory Standards and Quality Control Key Points References Chapter 6

Cardiac Assessment

Jaspal Singh William E. Downey Introduction Evaluation of Ventricular Function Case 1. Congestive Heart Failure Left Ventricular Dysfunction Case 2. Right Ventricular Failure Right Ventricular Function Valvular Function Case 3. Valvular Disease Evaluation of Valvular Function Coronary Artery Disease Case 4. Coronary Artery Disease Evaluation of the Coronary Circulation Specific Tests to Assess Coronary Circulation Anatomic Tests Arrhythmias Case 5. Cardiac Arrhythmia ECG in Pulmonary Disease Refractory Hypoxemia Case 6. Intracardiac Shunt Bubble Echocardiogram Key Points References Appendix 6-1 Locations for Chest Electrodes Lead I Lead II Lead III Lead MCL1 (Modified Chest Lead)

Dysrhythmia Recognition Normal Sinus Rhythm (NSR) Sinus Bradycardia Sinus Tachycardia Sinus Arrhythmia Premature Atrial Contractions (PACs) Supraventricular Tachycardia Atrial Flutter Atrial Fibrillation Premature Junctional Contractions (PJCs) Accelerated Junctional Rhythm Junctional Tachycardia Premature Ventricular Contractions (PVCs) Ventricular Escape Rhythm (Idioventricular Rhythm [IVR]) Accelerated Idioventricular Rhythm (AIVR) Ventricular Tachycardia (Monomorphic VT) Torsades de Pointes Ventricular Fibrillation Asystole (Ventricular Asystole, Ventricular Standstill) First-Degree AV Block Second-Degree AV Block, Type I (Wenckebach, Mobitz I) Second-Degree AV Block, Type II (Mobitz II) Second-Degree AV Block, 2:1 Conduction Complete (Third-Degree) AV Block Chapter 7

Imaging the Thorax Dean R. Hess Introduction Density and Contrast The Normal Chest Radiograph

Technical Factors Examination of the Chest Radiograph Abnormalities Seen on Chest Radiographs Chronic Obstructive Pulmonary Disease Pneumonia Atelectasis Left Heart Failure Pneumothorax and Air Leaks Pleural Effusion Evaluation of Tubes and Catheters Pulmonary Embolism Acute Respiratory Distress Syndrome Chest Trauma Computed Tomography Ultrasonography Magnetic Resonance Imaging Positron Emission Tomography Electrical Impedance Tomography Key Points References Chapter 8

Pulmonary Function Testing Jeffrey M. Haynes Introduction Goals of Pulmonary Function Testing Infection Control Spirometry Equipment Pretest Procedures Spirometry Tests

Forced Vital Capacity Flow-Volume Loops and Volume-Time Graphs Slow Vital Capacity Maximum Voluntary Ventilation Quality Assurance of Spirometry Testing Bronchodilator Testing Spirometry Interpretation Lung Volumes and Capacities Measurement of Lung Volumes Nitrogen Washout Test Helium Dilution Test Body Plethysmography Test Interpretation of Lung Volumes Diffusing Capacity Interpretation of DLCO Specialized Pulmonary Function Tests Bronchial Challenge Tests Methacholine Challenge Mannitol Challenge Exercise Challenge Airways Resistance Airways Resistance via Body Plethysmography Impulse Oscillometry (Forced Oscillation Technique) Respiratory Muscle Strength Exhaled Nitric Oxide Single Breath Nitrogen Washout (SBN2) Exercise Laryngoscopy Key Points References

Chapter 9

Interventional Pulmonary Procedures Ellen E. Volker Amy E. Treece Momen M. Wahidi Scott L. Shofer Introduction Diagnostic Bronchoscopy Overview of Bronchoscopy The Flexible Bronchoscope Flexible Fiberoptic Bronchoscopy Patient Selection Asthma and Bronchospasm Cardiovascular Risk Head Trauma and Elevated Intracranial Pressure Hypoxemia and High Oxygen Requirement Anticoagulant and Antiplatelet Therapy Thrombocytopenia Uremia and Renal Dysfunction Patient Preparation Informed Consent Procedure Risks and Complications Minimizing Complications Postprocedure Care and Education Patient Sedation Flexible Fiberoptic Bronchoscopy Techniques Airway Examination Bronchoalveolar Lavage Bronchoscopic Washing Bronchoscopic Brushing Endobronchial Biopsy

Transbronchial Biopsy Transbronchial Needle Aspiration Complications of Bronchoscopy Pneumothorax Bleeding Complications Indications for Bronchoscopy Acute Lung Collapse, Atelectasis, and Secretion Management Hemoptysis Cough Suspected Malignancy Infection Suspected Foreign Body Aspiration Interstitial Lung Disease Lung Transplant Trauma Therapeutic Bronchoscopy Rigid Bronchoscopy Indications Equipment Insertion Anesthesia and Ventilation Therapeutic Procedures Airway Stenting Silicone Stents Self-Expanding Metallic Stents Hybrid Stents Efficacy and Complications of Stent Placement Pleural Disease Indications for Thoracentesis

Thoracentesis Procedure Interpretation of Results Management of Recurrent Pleural Effusions Endobronchial Valves Key Points References Chapter 10

Polysomnography Bashir A. Chaudhary Shelley C. Mishoe Introduction Normal Sleep and Sleep Stages Polysomnography Components Electroencephalography Electrooculography Electromyography Respiratory Measurement Scoring Criteria Sleep Stages Major Body Movements Sleep-Disordered Breathing Arousals Cardiac Rules Periodic Limb Movements of Sleep Polysomnography Report Key Points References

Chapter 11

Nutrition Assessment and Support Dean R. Hess Introduction

Effects of Nutrition on Respiratory Function and Critical Illness Minute Ventilation Muscle Weakness Surfactant Production Obesity Immune Function Hypoalbuminemia Stress Response to Critical Illness Refeeding Syndrome Acute and Chronic Inflammation Nutrition Assessment Calculation and Measurement of Energy Requirements Equations Versus Measurements Calorimetry Indirect Calorimetry Modified Weir Equation Method Caloric Equivalent Method Fick Method Protein Requirements Nutritional Support Guidelines Nutrition Delivery Nutritional Support in Mechanically Ventilated Patients Nutritional Support in Chronic Respiratory Disease Key Points References Chapter 12

Cardiopulmonary Exercise Assessment Neil R. MacIntyre Introduction Normal Cardiopulmonary Response to Exercise

Oxygen Consumption and Carbon Dioxide Production Ventilatory Responses Gas Exchange Responses to Exercise Cardiovascular Responses to Exercise Oxygen Delivery Oxygen Extraction Incremental Exercise Testing Symptom-Limited Work Rate Symptoms at Maximal Exercise Oxygen Consumption and Carbon Dioxide Production Exercise Ventilation Arterial Blood Gas Measurements Ratio of Dead Space to Tidal Volume Cardiovascular Assessment Interpreting the Results of Incremental Cardiopulmonary Exercise Testing Timed Walk Tests Indications for Cardiopulmonary Exercise Testing Safety Issues Key Points References PART 2 Chapter 13

Respiratory Therapeutics Therapeutic Gases: Manufacture, Storage, and Delivery John E. Boatright Molly Quinn Jensen Introduction Chemical and Physical Properties of Therapeutic Gases Flammability Life Support

Atmospheric Concentration (by Volume) Atmospheric Pressure Viscosity Density Relative Density Boiling Point Critical Temperature Critical Pressure Triple Point Solubility in Water Physical State in Cylinder Air Therapeutic Uses Manufacture Cylinders Piped Air Systems Portable Compressors Oxygen Physical Characteristics Support of Combustion Manufacture and Distribution of Oxygen Photosynthesis Isolating Metallic Oxides Electrolysis of Water Fractional Distillation of Liquefied Air Molecular Filtration Distribution Carbon Dioxide Physical Characteristics Therapeutic Uses

Manufacture and Distribution Helium Physical Characteristics Therapeutic Uses Manufacture and Distribution Nitric Oxide Physical Characteristics Therapeutic Uses Manufacture and Distribution Nitrogen Physical Characteristics Therapeutic Uses Manufacture and Distribution Storage and Distribution of Medical Gases Medical Gas Cylinders Cylinder Markings Cylinder Testing Cylinder Color-Coding and Labeling Cylinder Valves Safe Storage and Handling of Cylinders Regulators Safety-Indexed Connection Systems American Standard Safety System Pin Index Safety System Diameter Index Safety System Calculating Duration of Flow from a Gas Cylinder Central Medical Gas Distribution Systems for Gas Storage and Distribution Liquid Oxygen Systems for Home and Transport Alternating Supply Systems

Gas Piping Systems Valves Zone Valves Gauges and Alarms Station Outlets Central Compressed Medical Air Distribution Key Points References Chapter 14

Therapeutic Gases: Management and Administration John E. Boatright Molly Quinn Jensen Introduction The Rationale for Supplemental Oxygen Indications for Oxygen Therapy Limitations of Supplemental Oxygen Complications and Hazards of Oxygen Therapy Oxygen Toxicity Hyperoxemia Nitrogen Washout Atelectasis Oxygen-Induced Hypoventilation Retinopathy of Prematurity Closure of the Ductus Arteriosus Support of Combustion Dosage Regulation and Administration Devices Flow Restrictor Bourdon Gauge Flow Meters Thorpe Tube Flow Meters Oxygen Administration Devices Low-Flow (Variable-Performance) Devices

High-Flow (Fixed-Performance) Devices Oxygen Enclosures Hyperbaric Oxygen Therapy Monitoring the Physiologic Effects of Oxygen Blood Gases and Oximetry Oxygen Analysis Clinical Application of Oxygen Therapy Helium–Oxygen Therapy Carbon Dioxide Therapy Nitric Oxide Therapy Key Points References Chapter 15

Humidity and Aerosol Therapy Dean R. Hess Introduction Humidity Normal Heat and Moisture Exchange Goals of Humidity Therapy Devices Used for Humidification Active Humidifiers Passive Humidifiers Bland Aerosol Therapy Humidification to Tracheostomy Device Selection for Humidity Therapy Aerosol Drug Administration Basic Concepts of Aerosol Therapy Aerosol Deposition, Targeting, and Translocation Factors Affecting Drug Dose Distribution Aerosol Generators

Jet Nebulizers Mesh Nebulizers Soft Mist Inhaler Ultrasonic Nebulizers Pressurized Metered-Dose Inhalers Spacers and Valved Holding Chambers Dry Powder Inhalers Aerosol Delivery During Invasive Mechanical Ventilation Aerosol Delivery During Noninvasive Ventilation Aerosol Delivery by Tracheostomy Aerosol Delivery by High-Flow Nasal Cannula Selection of an Aerosol Delivery Device Aerosol Delivery for Systemic Disease Key Points References Chapter 16

Airway Clearance and Lung Expansion Therapy Dean R. Hess Introduction Normal Mechanisms of Mucociliary Transport Airway Clearance Deep Breathing and Coughing Forced Expiratory Technique Manually Assisted Cough Active Cycle of Breathing Autogenic Drainage Mechanical Insufflation–Exsufflation Aerosol Therapy Conventional Chest Physiotherapy Positive Expiratory Pressure

Oscillatory (or Vibratory) Positive Expiratory Pressure High-Frequency Chest Wall Compression Intrapulmonary Percussive Ventilation High-Frequency Chest Wall Oscillation Exercise Selection of Airway Clearance Technique Sputum Collection Induced Sputum Tracheal Aspirate Bronchoscopy Mini-bronchoalveolar Lavage Transtracheal Aspiration Lung Expansion Therapy Continuous Positive Airway Pressure Incentive Spirometry Intermittent Positive Pressure Breathing Key Points References Chapter 17

Airway Management John D. Davies Dean R. Hess Introduction Oropharyngeal Airways Types Insertion Complications Nasopharyngeal Airways Insertion Complications

Airway Management Training Anatomy of the Upper Airway and Airway Assessment Indications for Endotracheal Intubation Initial Approach to Airway Management Airway Assessment Endotracheal Tubes Preoxygenation Endotracheal Intubation: Preparation and Performance Procedure of Endotracheal Intubation Technique for Orotracheal Intubation Technique for Nasotracheal Intubation Drugs to Facilitate Intubation Complications of Endotracheal Intubation Securing the Endotracheal Tube The Difficult Airway: Assessment and Strategy Extraglottic Airways Gum Elastic Bougie Video Laryngoscopy Devices Cricothyrotomy Extubation Tracheostomy Advantages and Disadvantages of Tracheostomy Timing of Tracheostomy Open Tracheostomy Percutaneous Dilational Tracheostomy Metal Tracheostomy Tubes Current Construction of Tracheostomy Tubes Uncuffed Tracheostomy Tubes Cuffed Tracheostomy Tubes Dual-Cannula Tracheostomy Tube

Subglottic Suction Port Foam Cuff Tracheostomy Tubes Tight-to-Shaft Cuff Tracheostomy Tubes Sleep Apnea Tracheostomy Tubes Adjustable Flange Tracheostomy Tubes Fenestrated Tracheostomy Tubes Talking Tracheostomy Tubes Speaking Valves Speaking in Ventilator-Dependent Patients with a Tracheostomy Tube Eating with a Tracheostomy Trach and Stoma Buttons Securing Tracheostomy Tubes Changing the Tracheostomy Tube Decannulation Accidental Decannulation Airway Cuff Concerns Airway Clearance Open Suction Closed Suction Subglottic Suction Saline Instillation Key Points References Chapter 18

Cardiopulmonary Resuscitation Christine J. Moore Anthony L. Heard William F. Galvin Introduction Cardiopulmonary Resuscitation

Incidence and Epidemiology History, Evolution, and Milestones Current Guideline Developments Chain of Survival Risk Factors Basic Life Support The Initial Steps CABD Sequence Circulation Choking Relief for Adults and Children (1 Year and Older) Relief for a Choking Child Choking Infant Relief Difficult Bag-Mask Ventilation Cardiopulmonary Resuscitation for a Child Cardiopulmonary Resuscitation for an Infant Summary of Basic Life Support Advanced Cardiovascular Life Support Airway Management Post–Cardiac Arrest Care Stabilization of Acute Coronary Care Patients Summary of Advanced Cardiovascular Life Support Ethical Concerns Key Points References Chapter 19

Mechanical Ventilators: Classification and Principles of Operation Robert L. Chatburn Teresa A. Volsko Introduction Basic Concepts

Power Inputs Pressure, Volume, and Flow Outputs Patient Circuits Ventilator Alarm Systems Ventilator Displays Alphanumeric Values Trends Waveforms and Loops Understanding Ventilator Technology Ten Fundamental Maxims Taxonomy of Mechanical Ventilation Comparing Modes of Mechanical Ventilation Key Points References Chapter 20

Mechanical Ventilation Dean R. Hess Neil R. MacIntyre Introduction The Equation of Motion Indications for Mechanical Ventilation Complications of Mechanical Ventilation Ventilator-Induced Lung Injury Oxygen Toxicity Ventilator-Associated Pneumonia Auto-PEEP Hemodynamic Effects of Positive Pressure Ventilation Ventilator Settings Volume Control Versus Pressure Control Ventilator Modes

Breath Triggering Tidal Volume Respiratory Rate Inspiratory Time Inspiratory Flow Pattern Positive End-Expiratory Pressure Mean Airway Pressure Recruitment Maneuvers Inspired Oxygen Concentration Sigh Alarms Circuit Humidification Monitoring the Mechanically Ventilated Patient Physical Assessment Blood Gas Measurements Plateau Pressure and Auto-PEEP Hemodynamics Patient–Ventilator Interaction Sedation Choosing Ventilator Settings for Different Forms of Respiratory Failure Acute Respiratory Distress Syndrome Obstructive Lung Disease Neuromuscular Disease Intraoperative and Postoperative Mechanical Ventilation Ventilatory Support Trade-Offs Liberation from Mechanical Ventilation Respiratory Muscles Assessing Readiness for Liberation

Approaches to Liberation Recognition of a Failed Spontaneous Breathing Trial Causes of a Failed Spontaneous Breathing Trial Ventilator Discontinuation Protocols Sedation ABCDEF Bundle Key Points References Chapter 21

Noninvasive Respiratory Support Dean R. Hess Introduction High-Flow Nasal Cannula Mechanism of Action HFNC Prongs Clinical Indications Interfaces for CPAP and NIV Continuous Positive Airway Pressure Acute Care Applications CPAP for Obstructive Sleep Apnea Noninvasive Positive Pressure Ventilation Acute Care Applications Chronic Applications Ventilators for Noninvasive Positive Pressure Ventilation Clinical Application Sequential Use of NIV and HFNC Negative Pressure Ventilation, Rocking Beds, and Pneumobelts Key Points References

Chapter 22

Neonatal and Pediatric Respiratory Care Melissa K. Brown Introduction Neonatal Assessment Apgar Score Gestational Age Physical Assessment Noninvasive and Hemodynamic Monitoring Oxygen Therapy Indications Hazards Delivery Devices Mechanical Ventilation Manual Ventilation Airway Management Endotracheal Intubation Suctioning Nasal Continuous Positive Airway Pressure Noninvasive Positive Pressure Ventilation Conventional Infant and Pediatric Ventilation Indications Infant Ventilators Pressure Limit and Tidal Volume Respiratory Rate Mode Inspiratory Trigger and Expiratory Cycle Inspiratory Time Positive End-Expiratory Pressure Humidification Hazards and Complications

Liberation High-Frequency Ventilation Classification Gas Transport Theories Patient Selection High-Frequency Ventilators Management Strategies Complications Adjuncts to Neonatal and Pediatric Mechanical Ventilation Surfactant Administration Inhaled Nitric Oxide Key Points References Chapter 23

Extracorporeal Life Support for Respiratory Failure Desiree K. Bonadonna Craig R. Rackley Introduction History of ECMO Use in Respiratory Failure ECMO Basics Indications and Contraindications ECMO Management Monitoring Anticoagulation Sedation Fluid Administration Mechanical Ventilation Blood Transfusion Timing of ECMO Decannulation ECMO Outcomes

Complications Bleeding Neurologic Injury Infection Vascular Injury and Thrombosis Technological Advancements Key Points References Chapter 24

Pulmonary Rehabilitation Neil R. MacIntyre Rebecca H. Crouch Anne M. Mathews Introduction Mechanisms of Functional Deterioration in Patients with Chronic Lung Disease Program Structure Intensive Programs Maintenance Programs Perioperative Programs The Process of Pulmonary Rehabilitation Patient Selection Patient Assessment Education Exercise Other Interventions Outcomes from a Pulmonary Rehabilitation Program Reimbursement Issues Future Directions Key Points References

Chapter 25

Home Respiratory Care Angela C. King Dean R. Hess Introduction Home Care Services Goals of Home Care The Medicare Program Medicaid Coverage for Home Medical Equipment Requirements for Home Medical Equipment Companies Accreditation of Home Medical Equipment Companies Equipment Management Services Versus Clinical Respiratory Services Orders for Clinical Respiratory Services The Respiratory Therapist as Home Care Provider Requirements for the Respiratory Therapist Providing Home Respiratory Care The Initial Home Visit Bag Technique Home Environment Evaluation Environmental Issues for Patients on Home Oxygen Therapy Environmental Issues for Patients on Home Mechanical Ventilation Working with Local Emergency Medical Services and Firefighters The Physician Order Long-Term Oxygen Therapy Evidence Supporting Home Oxygen Therapy Key Issues in O2 Therapy Methods of O2 Delivery

Home O2 Delivery Devices O2-Conserving Devices Diagnostic Systems for Long-Term O2 Therapy O2 Delivery Accessory Items Patient Interface Selection of an O2 Delivery Device for the Home Newer Home Therapies Mouthpiece Ventilation Proportional Open Ventilation Home Ventilation Diagnoses and Indications for Home Mechanical Ventilation Discharge Planning for the Patient Going Home with a Mechanical Ventilator Evolution of Positive Pressure Home Mechanical Ventilators Backup Ventilator and Emergency Supplies Setting Ventilator Alarms Safety Tips Caregiver Burden Ventilator User’s Quality of Life Key Points References Chapter 26

Disaster Management Richard D. Branson Dario Rodriquez Jr. Introduction History The Threat Traumatic Injury

Chemical Weapons Epidemics and Febrile Respiratory Illness Planning for Mass-Casualty Respiratory Failure Staffing Personal Protective Equipment Oxygen Disposables Ventilators Ventilator Performance Characteristics Ventilators for Mass-Casualty Respiratory Failure Automatic Resuscitators EMS Portable Ventilators Pneumatically Powered Portable Ventilators Electrically Powered Portable Ventilators Critical Care Ventilators Noninvasive Ventilators Triage Key Points References Chapter 27

Respiratory Care of the Elderly William F. Galvin Helen M. Sorenson Introduction The Demography of Aging Terms Associated with Aging Aging Pulmonary Anatomy and Physiology Geriatric Patient Assessment Physical Assessment Comprehensive Geriatric Assessment

Atypical Disease Presentation Pneumonia Myocardial Infarction Congestive Heart Failure Tuberculosis Depression Geriatric Pharmacotherapy Medication Safety Adverse Drug Events Medication Undertreatment and Overtreatment Drug Expenditures Communicating with Older Adults Effective Communication The Angry Patient The Verbally Abusive Patient The Confused Patient Pulmonary Disease After Age 65 Years Obstructive Disease Restrictive Disease Healthy Aging Strategies Health-Damaging Behaviors Role of the Respiratory Therapist in Caring for the Elderly Key Points References Appendix 27-1 Resources for Screening Tests in the Elderly Chapter 28

Patient Safety Thomas P. Malinowski Introduction

Patient Safety High-Reliability Organizations Culture of Safety High Risk/High Reliability Safe Harbor Teamwork Commitment Robust Process Improvement Root-Cause Analysis Incident Reports Safety Initiatives and Respiratory Care Applications Rapid Response Teams Safe Medication Practices Reports and Handoffs Need for Conversation at Handoffs Clinical Alarms and Equipment Universal Protocol Discharge Education and Planning Hospital-Acquired Conditions/Infections Ventilator-Associated Events Respiratory Protocols and Patient Safety Management of Medical Information Rationale Elements of a Patient Medical Record Medical Record Documentation Standards Essentials for Respiratory Care Documentation Orders Electronic Medical or Health Records Legal Implications of the Record Patient Confidentiality Issues

Key Points References PART 3 Chapter 29

Respiratory Diseases Principles of Disease Management William F. Galvin Introduction Trends and Directions in Healthcare Delivery Terms and Concepts Associated with Disease Management Care Management Component Management Demand Management Case Management Disease Management Population Health Management Integrated Care Chronic Care Model Forces Driving Disease Management Cost and Changing Patterns of Disease Determinants of Health Social Determinants of Health The Epidemiology Triangle History and Evolution of Disease Management Pharmaceutical Industry Managed Care Organizations Population Health Alliance Core Components of Disease Management Key Components of the Chronic Care Model Goals of Disease Management Basic Principles of Disease Management

Natural Course, Causes, and Cost Drivers of Disease Diagnosis and Treatment Based on Disease Rather Than Reimbursement Patterns Patient Education and Adherence Programs for Chronic Disease Management Management of Treatment Across the Full Continuum of Care Funding for the Most Powerful Interventions Diseases Targeted by Disease Management Programs Development and Implementation of a Disease Management Program The Ellrodt and Colleagues Model FAST Approach: Lamb and Zazworsky Model Kongstvedt Model Chronic Care Model or Integrated Care Respiratory Protocols The Future of Disease Management Respiratory Therapists as Disease Managers Key Points References Chapter 30

Patient Education William F. Galvin Introduction The Rationale for Patient Education Self-Management and Self-Empowerment Forces Affecting the Patient Education Movement Role of the Respiratory Therapist Terms Associated with Patient Education Client Education, Consumer Education, and Patient Education

Illness/Wellness Continuum Clinical Practice Guidelines The Critical Role of Communication in Patient Education Multidimensional Communication Transactional Communication The Process of Communication Factors Affecting Communication Physical Appearance and Status Skills of the Sender Skills of the Receiver Questioning Techniques Teaching and Learning Aspects of Patient Education Goals in Patient Education Process of Patient Education Overview of the ASSURE Model Overview of the APIE Model Assessment Planning Implementation Evaluation Examples of Patient Education Programs Asthma Education Pulmonary Rehabilitation Tobacco Cessation Key Points References Chapter 31

Infection Control Principles Donna D. Gardner Introduction

Transmission of Infection Strategies for Infection Control Regulatory Agencies Cleaning, Disinfection, and Sterilization Cleaning Disinfection Sterilization Equipment Surveillance and Monitoring Precautions Standard Precautions Hand Hygiene Personal Protective Equipment Patient Placement Transmission-Based Precautions Healthcare-Associated Infections Related to Respiratory Care Equipment Ventilator-Related Issues Nebulizers and Aerosol Delivery Devices Spirometers and Pulmonary Function Testing Equipment Key Points References Chapter 32

Asthma Timothy R. Myers Timothy B. Op’t Holt Introduction Epidemiology Pathophysiology Airway Inflammation Airway Hyperresponsiveness Airway Obstruction

Pathogenesis Risk Factors Asthma Phenotypes Allergic Asthma Pollution and Environmental Irritant-Related Asthma Emotion-Associated Asthma Food and Drug Additive–Related Asthma Viruses Nocturnal Asthma Exercise-Induced Asthma Occupational Asthma Disease Severity Classification Intermittent Asthma Mild Persistent Asthma Moderate Persistent Asthma Severe Persistent Asthma Assessing Control of Asthma Asthma Exacerbation Status Asthmaticus Objective Measurements Spirometry Lung Volumes and Airways Resistance Peak Flow Meters Exhaled Nitric Oxide Pharmacologic Therapy Controller Medications Quick-Relief Medications Aerosol Therapy Nebulizers Continuous Aerosolized Bronchodilators

Pressurized Metered-Dose Inhalers Spacers and Valved Holding Chambers Respimat Dry Powder Inhalers Adjunctive Treatments Heliox Magnesium Sulfate Noninvasive Ventilation Invasive Ventilation Education Case Studies Case 1. Ambulatory Asthma Management Case 2. Life-Threatening Asthma Management Key Points References Chapter 33

Chronic Obstructive Pulmonary Disease Dean R. Hess Introduction Definitions Diagnosis, Symptoms, and GOLD Stages Etiology of Chronic Obstructive Pulmonary Disease Pathophysiology of Chronic Obstructive Pulmonary Disease Outpatient Care of Stable Chronic Obstructive Pulmonary Disease Smoking Cessation Drug Therapy Long-Term Oxygen Therapy Vaccinations Ventilatory Support Management of Sleep-Related Abnormalities

Pulmonary Rehabilitation Airway Clearance Therapy Surgery and Bronchoscopic Interventions Giant Bullectomy Lung Volume Reduction Surgery Lung Transplantation Bronchoscopic Interventions Managing Exacerbations Readmissions Palliative and End-of-Life Care Case Studies Case 1. Initial Presentation of Chronic Obstructive Pulmonary Disease Case 2. Exacerbation of Chronic Obstructive Pulmonary Disease Key Points References Chapter 34

Interstitial Lung Disease Stephen P. Bergin Lake D. Morrison Introduction Pathophysiology Classification Clinical Presentation and Diagnostic Evaluation Symptoms and Signs Pulmonary Function Testing Radiographic Findings Laboratory Findings Bronchoscopy Surgical Lung Biopsy

Pathology Prognosis Management Specific Interstitial Lung Diseases Idiopathic Pulmonary Fibrosis Sarcoidosis Interstitial Lung Disease with Connective Tissue Disease Eosinophilic Granuloma Respiratory Bronchiolitis Interstitial Lung Disease Pulmonary Alveolar Proteinosis Drug-Induced Interstitial Lung Disease Acute Interstitial Lung Disease Key Points References Chapter 35

Pulmonary Vascular Disease Tala Dahhan Charles William Hargett Introduction Pathophysiology Normal Pulmonary Vascular Physiology Pulmonary Vascular Pathophysiology Pathophysiology of Acute Pulmonary Embolism Epidemiology Diagnosis Acute Pulmonary Embolism Chronic Pulmonary Hypertension and Right Heart Failure Management of Selected Pulmonary Vascular Diseases Acute Pulmonary Embolism Chronic Cor Pulmonale

Pulmonary Arterial Hypertension Other Classes of Pulmonary Hypertension Case Studies Case 1. Acute Right Ventricular Failure Case 2. Idiopathic Pulmonary Arterial Hypertension Key Points References Chapter 36

Pneumonia Lingye Chen Bryan D. Kraft Introduction Definition and Classification of Pneumonia Community-Acquired Pneumonia Etiology Gram-Positive Bacteria Gram-Negative Bacteria Atypical Organisms Diagnostic Workup Risk Stratification Therapy Complications of Community-Acquired Pneumonia Prevention Aspiration and Anaerobic Pneumonia Actinomycosis Nosocomial Pneumonia Hospital-Acquired Pneumonia Ventilator-Associated Pneumonia Pathogenesis of VAP Diagnosis of VAP

Ventilator-Associated Events Microbiology Treatment Prevention of VAP Viral Pneumonia Influenza Virus Other Viral Pneumonias Mycobacterial Pneumonia Tuberculosis Nontuberculous Mycobacteria Fungal Pneumonia Aspergillosis Zygomycosis Histoplasmosis Blastomycosis Cryptococcosis Coccidioidomycosis Candidiasis Pneumonia in Immunocompromised Patients Clinical Considerations Radiologic Considerations Diagnostic Considerations Treatment Considerations Pneumonia and HIV/AIDS Bacterial Pneumonia Pneumocystis Pneumonia MTB and HIV Infection AIDS-Defining Pneumonias Case Studies Case 1. Community-Acquired Pneumonia

Case 2. Pneumonia in an Immunocompromised Host Key Points References Chapter 37

Cystic Fibrosis Teresa A. Volsko Catherine A. O’Malley Bruce K. Rubin Introduction History Pathogenesis Genetics of Cystic Fibrosis CFTR Functions and Host Defense Diagnosis Immunoreactive Trypsinogen Testing Sweat Testing CFTR Mutational Analysis Nasal Epithelial Potential Difference Extrapulmonary Manifestations Upper Respiratory Tract Exocrine and Endocrine Pancreas Gastrointestinal Tract Hepatobiliary System Reproductive Tract Sweat Glands Respiratory Manifestations Symptoms Chest Radiography Pulmonary Function Respiratory Microbiology

Infection Control Recommendations Major Respiratory Complications Hemoptysis Pneumothorax Respiratory Failure Standard Therapy of Lung Disease Maintenance Therapy Exacerbations Lung Transplantation Key Points References Chapter 38

Acute Respiratory Distress Syndrome Craig R. Rackley Christopher E. Cox Michael A. Gentile Introduction Definition Incidence Etiology Clinical Manifestations Pathobiology Management High-Flow Nasal Cannula Mechanical Ventilation Pharmacologic Agents Patient Position Fluid Management Extracorporeal Membrane Oxygenation Outcomes

Prevention Key Points References Chapter 39

Postoperative Respiratory Care Mark L. Simmons Rachel A. Newberry Introduction Preoperative Assessment and Management Age Smoking History Preexisting Lung Disease Heart Disease Obesity General Health Status Surgery Grades and ASA Status Classification Patient Education Preoperative Testing Electrocardiogram Chest Radiograph Arterial Blood Gas Measurements Pulmonary Function Tests Other Lab Tests Intraoperative Risk Factors Postoperative Respiratory Failure: Assessment and Management Hypoxemia Hypercapnia Nutrition Pain Management Patient Temperature

Muscle Strength Lung Expansion Atelectasis Etiology and Risk Factors Clinical Manifestations and Diagnostic Findings Management Pulmonary Emboli and Pulmonary Thromboembolic Disease Etiology and Risk Factors Clinical Manifestations and Diagnostic Findings Management Pneumonia Etiology and Risk Factors Clinical Manifestations and Diagnostic Findings Management Mechanical Ventilation for Respiratory Failure Key Points References Chapter 40

Heart Failure Samuel K. McElwee William S. Stigler Introduction Definition Epidemiology Etiology Cardiac Physiology Cellular Biology and Biochemistry of Cardiac Function Cardiac Pump Function Determinants of Ventricular Function Preload

Afterload Contractility Pathophysiology of Heart Failure Mechanisms Classification Adaptive Mechanisms Pathophysiology of Pulmonary Edema Heart–Lung Interactions Changes in Intrathoracic Pressure Changes in Lung Volume Changes in Pulmonary Vascular Resistance Mechanical Effects of Lung Expansion Abdominal Pressure Changes Ventricular Interdependence Clinical Aspects of Heart Failure Symptoms Functional Classification Physical Examination Radiography Measurement and Monitoring of Heart Function Electrocardiography Echocardiography Exercise Stress Test Radionucleotide Imaging Coronary Angiography Computed Tomographic Angiography Hemodynamic Monitoring Treatment for Chronic Heart Failure Nonpharmacotherapy Pharmacotherapy

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Beta Blockers Diuretics Aldosterone Antagonists Hydralazine and Nitrates Digoxin Percutaneous Coronary Intervention Surgical Treatments Treatment for Acute Heart Failure Pharmacologic Therapy Tailored Therapy Mechanical Circulatory Support Acute Myocardial Infarction Ventilatory Support of the Patient with Heart Failure Noninvasive Ventilation Invasive Mechanical Ventilation Cardiac Effects of Mechanical Ventilation Discontinuing Mechanical Ventilation Chronic Noninvasive Ventilation in Sleep-Disordered Breathing Case Studies Case 1. Ischemic Congestive Heart Failure Case 2. Acute Valve Insufficiency Case 3. Diastolic Dysfunction from Hypertension Case 4. Chronic Congestive Heart Failure from Cardiomyopathy of Coronary Artery Disease Case 5. Coronary Bypass Surgery Key Points References

Chapter 41

Trauma Bryce R. H. Robinson Richard D. Branson Introduction The Primary and Secondary Surveys Thoracic Trauma Airway and Breathing Injuries Laryngotracheal Injuries Pneumothorax Circulation Injuries Hypovolemic Shock Hemothorax Cardiac Tamponade Injuries Encountered During the Secondary Survey Pulmonary Contusion Blunt Cardiac Injury Aortic Injury Diaphragmatic Injury Esophageal Injury Chest Wall Injury Head Trauma Intracranial Physiology Types of Intracranial Lesions Subdural Hematoma Primary Survey Issues of Head Injury Hypoxia Hyperventilation Hypotension Deficits Secondary Survey Issues of Head Injury

Treatment of Head Injuries Ventilator Strategies in Trauma Patients Key Points References Chapter 42

Burn and Inhalation Injury Daniel F. Fisher Introduction Burn Injury Phases of Burn Care Burn Coverage Types of Grafts Estimating Burn Size Inhalation Injury Physiology of Inhalation Injury Diagnosis of Inhalation Injury Management of Inhalation Injury Acute Upper Airway Obstruction Bronchospasm Small Airways Obstruction Pulmonary Infection Respiratory Failure Carbon Monoxide Exposure Hydrogen Cyanide Poisoning Case Studies Case 1. Minor Burn with Smoke Inhalation Case 2. Second- and Third-Degree Burns (70% TBSA) with Severe Inhalation Injury Key Points References

Chapter 43

Sepsis Dean R. Hess Neil R. MacIntyre Introduction Pathogenesis Recognition Treatment Implications for Respiratory Care Key Points References

Chapter 44

Neuromuscular Dysfunction Francis C. Cordova John Mullarkey Gerard J. Criner Introduction Overview Pathophysiology of Neuromuscular Disease on Respiratory Function Control of Breathing Respiratory Muscle Function Lung and Chest Wall Mechanics Gas Exchange Abnormalities Sleep and Neuromuscular Disease Upper Airway Function Evaluation of Respiratory Function in Patients with Neuromuscular Disease Clinical History Physical Examination Arterial Blood Gas Measurements Pulmonary Function Tests

Radiographic Assessment Assessment of Respiratory Muscle Function Maximum Mouth Pressures Maximum Voluntary Ventilation Transdiaphragmatic Pressure Measurement Upper Motor Neuron Disorders Stroke Spinal Cord Injury Parkinson Disease Multiple Sclerosis Lower Motor Neuron Disorders Amyotrophic Lateral Sclerosis Poliomyelitis and Postpoliomyelitis Syndrome Disorders of the Peripheral Nerves Phrenic Nerve Injury Guillain-Barré Syndrome Critical Illness Polyneuropathy and Neuromyopathy Disorders of the Neuromuscular Junction Myasthenia Gravis Lambert-Eaton Syndrome Botulism Inherited Myopathies Duchenne and Becker Muscular Dystrophies Myotonic Dystrophy Acid Maltase Deficiency Facioscapulohumeral Muscular Dystrophy Limb-Girdle Muscular Dystrophy Mitochondrial Myopathy Acquired Inflammatory Myopathies Systemic Lupus Erythematosus

Steroid Myopathy Treatment of Neuromuscular Dysfunction Respiratory Muscle Training Assisted Coughing Glossopharyngeal Assistance Mechanical Ventilation Diaphragmatic Pacing Key Points References Chapter 45

Sleep-Disordered Breathing Bashir A. Chaudhary Shelley C. Mishoe Introduction Descriptions and Common Terms Types of Sleep-Disordered Breathing Prevalence Screening for Sleep-Disordered Breathing Obstructive Sleep Apnea Pathogenesis Clinical Features Complications of Obstructive Sleep Apnea Diagnosis of Obstructive Sleep Apnea Treatment of Obstructive Sleep Apnea Mortality Associated with Obstructive Sleep Apnea Central Sleep Apnea Cheyne-Stokes Breathing High-Altitude Periodic Breathing Obesity Hypoventilation Syndrome Restless Legs Syndrome

Prevalence Treatment of RLS Key Points References Chapter 46

Perioperative Management of Lung Transplant Recipients Jordan W. Whitson Introduction Lung Transplant History Disease States for Transplantation Transplant Recipient Criteria Lung Allocation Score Donor Evaluation and Selection Donor Management Surgical Procedure Postoperative Management Key Points References

Chapter 47

Lung Cancer Lutana H. Haan Joseph P. Coyle Jody L. Lester Introduction Epidemiology Demographics Etiology and Risk Factors Classification Screening Case Study: Lung Cancer Screening

Solitary Pulmonary Nodule Diagnosis and Staging Signs of Metastasis Workup Tests Used to Diagnose and Stage Lung Cancer Staging Prognosis Case Study: Early-Stage Lung Cancer Treatment Chemotherapy (Systemic Therapy) Radiation Therapy Targeted Therapies Surgery Complications Palliative and End-of-Life Care Palliative Care Symptom Control in End-of-Life Care Case Study: Metastatic Lung Cancer Key Points References Chapter 48

Neonatal and Pediatric Respiratory Disorders Sherry L. Barnhart Introduction Apnea of Prematurity Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes

Respiratory Distress Syndrome Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Bronchopulmonary Dysplasia and Chronic Lung Disease Pathophysiology and Etiology Clinical Manifestations and Diagnosis Management Complications and Outcomes Transient Tachypnea of the Newborn Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Pneumonia in the Neonate Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Meconium Aspiration Syndrome Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Persistent Pulmonary Hypertension of the Newborn

Pathophysiology Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Congenital Diaphragmatic Hernia Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Congenital Pulmonary Anomalies Pulmonary Hypoplasia Pulmonary Aplasia Pulmonary Agenesis Congenital Pulmonary Airway Malformation Bronchogenic Cyst Pulmonary Sequestration Air Leak Syndrome Pneumothorax Pulmonary Interstitial Emphysema Pneumomediastinum Pneumopericardium Retinopathy of Prematurity Pathophysiology Clinical Manifestations and Diagnosis Management Complications and Outcomes Bronchiolitis

Pathophysiology Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Laryngotracheobronchitis Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Epiglottitis Pathophysiology and Etiology Clinical Manifestations Diagnosis Management Complications and Outcomes Key Points References PART 4 Chapter 49

Applied Sciences for Respiratory Care Respiratory Anatomy William F. Galvin William Randall Solly Introduction Growth and Development of the Respiratory System Prenatal Development Postnatal Lung Development Gross Anatomy of the Respiratory System

Upper Respiratory Tract Lower Respiratory Tract Anatomy of the Thorax Bony Thorax Respiratory Muscles Lungs Pleurae Microanatomy of the Respiratory System Mucociliary Clearance Airway and Vascular Smooth Muscle Mast Cell, Macrophages, and Dendritic Cells Alveolar Cells Interstitial Space Key Points Suggested Reading Chapter 50

Ventilation and Oxygenation William C. Pruitt Introduction Ventilation Dead Space Ventilation Alveolar Ventilation Physiologic Mechanisms of Hypercapnia Carbon Dioxide Transport Carbon Dioxide Dissociation Curve The Alveolar Gas Equation Diffusion Fick’s Law Ventilation-Perfusion Mismatch

Assessment of Oxygenation Shunt Mechanisms of Hypoxemia Oxygen Transport The Oxyhemoglobin Dissociation Curve O2 Content in the Blood O2 Delivery and O2 Consumption Tissue Hypoxia Mixed Venous O2 Key Points References Chapter 51

Respiratory Mechanics Dean R. Hess Introduction Airways Resistance Compliance Pleural Pressure Gradient The Chest Wall Causes of Uneven Ventilation Respiratory Mechanics During Mechanical Ventilation Equation of Motion Alveolar Pressure Esophageal Pressure Intra-abdominal Pressure Transdiaphragmatic Pressure Stress Index Flow Stress and Strain End-Expiratory Lung Volume

Respiratory System Compliance Chest Wall Compliance Lung Compliance Airways Resistance Work of Breathing Pressure–Volume Curves Flow-Volume Loops Tension-Time Index and Pressure-Time Product Key Points References Chapter 52

Control of Breathing Shawna L. Strickland Introduction Control of Breathing Role of the Medulla Oblongata Role of the Pons Respiratory Reflexes Innervation of the Lungs Central and Peripheral Chemoreceptors Factors That Affect Control of Breathing Effects of Acid–Base Disorders Respiratory Acidosis Metabolic Acidosis Respiratory Alkalosis Compensated Metabolic Alkalosis High Altitude and Control of Breathing Acute Effects Chronic Effects Hypoxic Drive

Opioid Drugs and Respiratory Drive Abnormal Breathing Patterns Respiratory Drive and Exercise Assessing Respiratory Drive Key Points References Chapter 53

Cardiovascular, Renal, and Neural Anatomy and Physiology Georgianna G. Sergakis Crystal L. Dunlevy Sarah M. Varekojis Introduction Cardiovascular Anatomy and Physiology The Heart Intrinsic Conduction Extrinsic Conduction The Circulatory System Renal Anatomy and Physiology External Anatomy of the Kidney Internal Anatomy Nephron Blood Supply Physiology of the Kidney Glomerular Filtration Tubular Reabsorption Tubular Secretion Urine Neural Anatomy and Physiology Brain Intracranial Pressures and Cerebral Perfusion Pressure

Spinal Cord Peripheral Nervous System Key Points Suggested Reading Chapter 54

Physical Principles Dean R. Hess Introduction Basic Physics Molecules and States of Matter Units of Measurement Mass, Force, Stress, Pressure, and Work Wall Tension and Surface Tension Temperature Thermodynamics and Heat Exchange Gas Laws Gas Mixtures and Partial Pressures Humidity, Water Vapor, and Evaporation Evaporation and Condensation Gases in Solution, Diffusion, and Osmosis Conversion of Gas Volumes Conservation of Energy Fluid Flow Principle of Continuity Bernoulli and Venturi Principles Viscosity Laminar and Turbulent Flow Hagen-Poiseuille Equation Flow, Resistance, and Pressure Application of Physical Principles to Measurement

Principles of Measurement Common Methods of Measuring Flow in Respiratory Care Key Points Chapter 55

Chemistry for Respiratory Care Carl F. Haas Allan G. Andrews Andrew J. Weirauch Introduction Basic Chemistry Matter Chemical Bonding Chemical Reactions Liquid Mixtures Inorganic Molecules Water Oxygen and Carbon Dioxide Electrolytes Acids, Bases, and Buffers Salts Organic Molecules Carbohydrates Proteins Lipids Nucleic Acids Vitamins Hormones Cytokines Enzymes Fluid Balance

Metabolic Pathways Key Points Suggested Reading Chapter 56

Respiratory Microbiology Ruben D. Restrepo Diana M. Restrepo-Serrato Introduction Bacteria Bacterial Microbiology Common Bacteria Associated with Respiratory Disease Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Klebsiella pneumoniae Pseudomonas aeruginosa Acinetobacter baumannii Chlamydophila pneumoniae Mycoplasma pneumoniae Legionella pneumophila Rickettsiae Mycobacteria Viruses Fungi Pneumocystis jirovecii Parasites Common Respiratory Infections Upper Respiratory Tract Infections Lower Respiratory Tract Infections Sampling Methods

Sputum Induction Bronchoscopy Transtracheal Aspiration Endobronchial Ultrasound Bronchoscopy Nonbronchoscopic Bronchoalveolar Lavage Tracheal Aspirates Pleural Fluid Analysis Microbiology Techniques Sputum Culture Respiratory Tract Culture Virologic Studies Antimicrobial Therapy Antimicrobial Resistance Targeted Antimicrobial Therapy Key Points References Chapter 57

Respiratory Drugs Crystal L. Dunlevy Introduction Pharmacokinetics, Pharmacodynamics, and Drug Delivery Systemic Corticosteroids Inhaled Corticosteroids Beta-Adrenoceptor Agonists Short-Acting β2-Agonists Long-Acting β2-Agonists Epinephrine Anticholinergic Agents Methylxanthines Phosphodiesterase Inhibitors

Leukotriene Modifiers Mast Cell Stabilizers Anti-IgE Therapy Inhaled Antimicrobial Therapy Secretion Modifiers Acetylcysteine Dornase Alfa Hypertonic Saline Antihistamines Anticholinergic Agents Medications to Treat Interstitial Pulmonary Fibrosis Neuromuscular Blocking Agents Sedatives Etomidate Benzodiazepines Opioids Ketamine Propofol Dexmedetomidine Medications to Treat Pulmonary Arterial Hypertension Vasopressors and Inotropes Drug-Induced Methemoglobinemia Drugs That Prevent Deep Vein Thrombosis, Stress Ulcers, and Delirium Diuretics Key Points References PART 5 Chapter 58

The Respiratory Care Profession History of the Respiratory Care Profession

Jeffrey J. Ward Introduction Historical Events and Key Advances in Medical-Related Sciences Ancient Times The Middle Ages The Renaissance: The 14th to 17th Centuries The 18th Century The 19th Century Evolution of Respiratory Care in the 20th and 21st Centuries Historical Events That Signaled the Evolution of Respiratory Care Clinical Oxygen Therapy Medicated Aerosols Airway Management and Resuscitation Mechanical Ventilation Major Recent Historical Advances in Medicine and Medical Technology Milestones in the Organizations Within the Respiratory Care Profession: Beginning Years History of the Professional Association Professional Publications History of the Credentialing Organization and State Licensure History of Respiratory Care Education and Program Accreditation Respiratory Care’s Continuing Evolution: Contemporary and Future Changes Key Points References

Chapter 59

Professional Organizations Lynda T. Goodfellow Introduction American Association for Respiratory Care Specialty Sections Governance Board of Directors House of Delegates Board of Medical Advisors President’s Council Executive Office Coalition for Baccalaureate and Graduate Respiratory Therapy Education and National Association of Associate Respiratory Care AARC Horizon Goals for 2020 American Respiratory Care Foundation National Board for Respiratory Care Examinations Therapist Multiple Choice Examination Clinical Simulation Examination Pulmonary Function Technology Examination Neonatal/Pediatric Respiratory Care Specialty Examination Sleep Disorders Specialty Examination Adult Critical Care Specialty Examination Commission on Accreditation for Respiratory Care Accreditation Process National Association for Medical Direction of Respiratory Care Publications American College of Chest Physicians

Membership Educational Offerings Relationship with Respiratory Care American Thoracic Society Research and Education Patient Care Advocacy Relationship with Respiratory Care American Society of Anesthesiologists Research and Education Relationship with Respiratory Care Society of Critical Care Medicine Journals and Relationship with Respiratory Care Interprofessional Education Collaborative Relationship to Respiratory Care Association of Schools of Advancing Health Professions Publications Relationship to Respiratory Care The Joint Commission Relationship to Respiratory Care National Asthma Educator Certification Board Certified Asthma Educator AE-C Examination Association of Asthma Educators American Academy of Sleep Medicine Publications Membership Board of Registered Polysomnographic Technologists Examinations New Directions in Respiratory Care Key Points

References Chapter 60

Ethics of Healthcare Delivery Douglas E. Masini Introduction Definition of Ethics Foundations of Ethical Thinking Personal Belief System Attitudinal Orientation Personal Value System Moral Philosophy Ethical Versus Legal Behavior Ethical Orientation Legal Standards Ethical Theories Teleological Theory Deontological Theory Analysis Method Ethical Principles Beneficence Capacity Nonmaleficence Veracity Autonomy Confidentiality Justice Fidelity to Patients Role of Professional Organizations in Ethics Need for Professional Ethics AARC Code of Ethics

Ethics Committees Case Studies Case 1. Two Lives Inseparable Case 2. A Fifty for Your Trouble Case 3. A Double-Edged Sword Case 4. To Intubate or Not to Intubate Case 5. Nosy Therapists Case 6. You Can Tell Mom Case 7. Who Gets the Therapy? Case 8. A Couple of Beers Key Points References Appendix 60-1 Chapter 61

Healthcare Economics Garry W. Kauffman William F. Galvin Introduction Basic Healthcare Functions Stakeholders in the U.S. Healthcare System The Respiratory Therapist’s Role in Balancing Cost and Care Forces Influencing Healthcare Costs Increase in Cost Without Increase in Quality Technology Aging Population Fragmentation of the Industry Excess Capacity Unnecessary Care and Defensive Medicine Growth of Underinsured and Uninsured Consumerism

Summary of Forces Influencing Healthcare Costs A Brief History and Overview of Financing Healthcare Retrospective Payment Prospective Payment Capitation The Managed Care Era Health Maintenance Organizations Preferred Provider Organizations Point-of-Service Plans Exclusive Provider Organizations Reimbursement Methodologies Fee for Service Cost Plus or Charge Minus Prospective Reimbursement Diagnosis-Related Groups All-Patient Refined Diagnosis-Related Groups Resource-Based Relative Value Scale Bundled Charges Managed Care Approaches Case Mix The Future of Healthcare Funding Hospital Readmissions Value-Based Purchasing Hospital-Acquired Conditions Program Respiratory Therapists’ Documentation and Demonstration of Value Documenting Care: Charting The Three Rights Demonstrating Value Key Points

References Chapter 62

Respiratory Care Research and Evidence-Based Practice Dean R. Hess Introduction Research Design The Study Question Controls Matching Randomization Blinding or Masking Crossover Observational Versus Interventional Prospective and Retrospective Inclusion and Exclusion Criteria Institutional Review Boards and Informed Consent Clinical Trial Registration Measurements Incidence and Prevalence Missing Values and Dropouts Statistical Issues Bias Study Types Case Reports and Case Series Case Control Studies Cross-Sectional Studies Cohort Studies Animal Studies Equipment Evaluations Surveys

Randomized Controlled Trials What Is Evidence-Based Respiratory Care? Hierarchy of Evidence Evidence for a Diagnostic Test Sensitivity and Specificity Likelihood Ratio Receiver Operating Characteristic Curve Evidence for a Therapy Meta-analysis Finding the Evidence Internet Search Google Scholar PubMed Cumulative Index to Nursing and Allied Health Literature Web of Science Ovid Journal Websites Narrative Reviews and Systematic Reviews Clinical Practice Guidelines Key Points References Glossary Index

Preface © Andriy Rabchun/Shutterstock

e present here the fourth edition of Respiratory Care: Principles and Practice. Our intent is for this to be a continuation of a good thing rather than a completely new start. But it is more than a cosmetic makeover: We reviewed every word on every page, updating the content throughout to be relevant to current respiratory care practice. No chapter remained untouched; indeed, many have been substantially rewritten. This is a new edition of an already solid text—not just the previous edition repackaged with a new cover. Patient assessment is covered at the beginning of the text, followed by respiratory therapeutics, respiratory diseases, applied sciences, and, finally, the professional aspects of respiratory care. We have strived to hone this edition to address all of the topics important to contemporary respiratory care practice. Accordingly, we have added completely new chapters related to lung transplantation and sepsis. The inclusion of new contributors in this edition has infused new ideas and more contemporary coverage of many topics. Respiratory therapists of the 21st century must be technologists, physiologists, and clinicians. They are expected to be clinical leaders—a role that includes having input into the development of multidisciplinary care plans and implementation of respiratory care protocols. Moreover, contemporary practice is evidence based. Each of these important tenets of modern respiratory care practice is carefully and deliberately incorporated into this text. The primary audience for this text is respiratory therapy students. We have written this book for students while considering the examination matrix of the National Board for Respiratory Care (NBRC), to ensure that all of the topics on the board exams (and more) are included.

W

Nevertheless, this book is more than just a text designed to ensure success on the board exams. It includes many topics that go beyond the NBRC exam matrix and that are intended to help students become wellrounded members of the patient care team. Our goal was to make this text readable and to put the content within reach of students. As part of this effort, we include boxes, tables, and illustrations to assist learning. We have carefully edited the text for consistency in writing style throughout. The material may be challenging in places, but the intent was not to make it difficult. Rather, we seek to help students maximize their contributions when interacting with physicians and other members of the healthcare team. An important aspect of professional interactions is the ability to use the language that others use at the bedside—whether a respiratory therapist, physician, nurse, or other healthcare professional. Although this text is intended primarily for students, it will prove useful for other individuals as a reference text. For the respiratory therapist who graduated from school some time ago, this text will serve as a refresher and update. For readers who are not respiratory therapists, the content should provide insight into respiratory therapy practice and serve as a reference text. Innumerable persons must be thanked for their contributions to this project. First, I thank my co-editors. They embraced the vision and worked hard to make this text the best that it can be. Second, I thank all of the contributors, who dealt with my prodding to complete their chapters to my own and the publisher’s expectations. Finally, I am grateful to the team at Jones & Bartlett Learning, who poured their talents into this project and went out of their way to make this text second to none. The commitment of the Jones & Bartlett team has kept this project alive and moving forward. It is my hope that the fourth edition of Respiratory Care: Principles and Practice will assist students in mastering the art and science of respiratory care, that it contributes to improvements in the stature of the respiratory care profession, and—most importantly—that it improves the care of patients with respiratory disorders. Dean R. Hess, PhD, RRT, FAARC

What’s New The entire text has been updated. Several new contributors have been added for this edition, bringing a fresh approach to many topics. The fourth edition of Respiratory Care: Principles and Practice includes new content, some examples of which include the following new and expanded material: New Chapter 43, Sepsis New Chapter 46, Perioperative Management of Lung Transplant Recipients New and expanded sections and subsections throughout, including: A section on endobronchial valves in Chapter 9 A section on aerosol delivery by high-flow nasal cannula in Chapter 15 New aerosol delivery devices added to Chapter 15. Chapter 18 updated to reflect new CPR guidelines Chapter 21 was renamed “Noninvasive Respiratory Support” to reflect the increasing role of high flow nasal cannula. Section on high flow nasal cannula expanded. Two new sections in Chapter 23, on the history of ECMO use in respiratory failure and ECMO management Chapters 32 and 33 updated to reflect new guidelines for management of asthma and COPD. Expanded Chapter 47 (previously Chapter 45), Lung Cancer, has undergone a major overhaul, with new sections and a reorganization of material. Chapter 57, Respiratory Drugs, has been rewritten to reflect changes in pharmacology. Expanded Chapter 59, Professional Organizations, contains several new sections and subsections.

Features © Andriy Rabchun/Shutterstock

Respiratory Care: Principles and Practice, Fourth Edition incorporates a number of engaging pedagogical features to aid in the student’s understanding and retention of the material. A colorful layout enables ease of comprehension and supports the retention of important concepts. More than 580 full-color photographs and more than 300 tables and equations provide valuable insight into the fundamental aspects of respiratory care practice.

Chapter Outline and Objectives Each chapter begins with a framework for learning the most important topics by presenting an Outline indicating the material to be discussed and Objectives that list the chapter’s desired learning outcomes.

OUTLINE Creating a Therapeutic Climate Components of the Health History Vital Signs Techniques of Assessment Physical Examination of the Lungs and Thorax Assessment of Other Body Systems

OBJECTIVES 1. Discuss the factors essential in the creation of a therapeutic climate. 2. Explain three considerations of an effective health history.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Explain the relevance of cultural diversity in the history-taking process. List the major components of a health history. Identify the four major examination techniques. Define common terms used in the assessment of the respiratory system. Explain the technique for auscultation of the chest. Define terms associated with normal and abnormal breath sounds. List the signs associated with respiratory distress. Identify common pathologic processes of the respiratory system and pertinent physical findings that extend to other body systems. Identify the significance of various chest landmarks. Explain the significance of sounds heard during cardiac auscultation. Explain the significance of jugular venous distention. Explain common findings associated with an assessment of the neurologic system.

Key Terms Key Terms list the most important new terms covered in the chapter. Corresponding definitions can be found in the end-of-text glossary.

KEY TERMS auscultation barrel chest Biot respirations bradypnea bronchial breath sounds bronchophony bronchovesicular breath sounds Cheyne-Stokes breathing clubbing crackles cyanosis dyspnea egophony flail chest grunting hyperpnea hyperresonant hyperventilation inspection jaundice Kussmaul respirations kyphosis lordosis

murmur orthopnea pack years pallor palpation paradoxical respiration paroxysmal nocturnal dyspnea pectus carinatum pectus excavatum percussion platypnea plethora pleural friction rub precordium resonant rhonchus scoliosis stridor tachypnea tactile fremitus tympanic vesicular breath sounds wheezes whispered pectoriloquy

Boxed Features Respiratory Recap provides a review of key study points for core content. Respiratory Recap Variables Supporting a Therapeutic Climate ∎ Caring demeanor ∎ Competence ∎ Eye contact ∎ Judicious use of touch ∎ Professional image

Stop and Think This feature offers considerations for critical thinking and clinical decision making.

Stop and Think You are seeing a patient for the first time. You are told that the patient has chronic obstructive pulmonary disease (COPD). What information would you collect regarding the patient’s health history?

Age-Specific Angle covers unique differences that are age specific— pediatric/neonatal or geriatric focused. Age-Specific Angle Compared with adults, infants and children have higher respiratory rates, higher pulse rates, and lower blood pressures.

Tables Key information is presented in a clear format for review and reference. TABLE 1-2 Lung Sounds Assessed by Auscultation Sound

Characteristics

Vesicular

Heard over most lung fields; low pitch; soft and short expirations; accentuated in the thin person or child, and diminished in overweight or very muscular individuals

Bronchovesicular

Heard over main bronchus area and upper right posterior lung field; medium pitch; expiration equaling inspiration

Bronchial/tracheal (tubular)

Heard only over trachea; high pitch; loud and long expirations, often somewhat longer than inspiration

Equations Helpful equations provide an example to review and compute clinical calculations.

Clinical Practice Guidelines Clinical Practice Guidelines are crucial in the evaluation and management of patient care. Guideline recommendations published by the AARC and other professional organizations are included. CLINICAL PRACTICE GUIDELINE 2-1 Capnography/Capnometry During Mechanical Ventilation

▪

Continuous waveform capnography is recommended in addition to clinical assessment as the most reliable method of confirming and monitoring correct placement of an endotracheal tube.

▪

If waveform capnography is not available, a non-waveform exhaled CO2 monitor in addition to clinical assessment is suggested as the initial method for confirming correct tube placement in a patient in cardiac arrest.

▪ ▪ ▪ ▪

PETCO2 is suggested as a method to guide ventilator management. Continuous capnometry during transport of a mechanically ventilated patient is suggested.

▪

Quantitative waveform capnography is suggested in intubated patients to monitor the quality of cardiopulmonary resuscitation (CPR), optimize chest compressions, and detect return of spontaneous circulation during chest compressions or when rhythm check reveals an organized rhythm.

Capnography is suggested to identify abnormalities of exhaled air flow. Volumetric capnography is suggested to assess CO2 elimination and VD/VT to optimize mechanical ventilation.

Walsh BW, Crotwell DN, Restrepo RD. Capnography/capnometry during mechanical ventilation: 2011. Respir Care 2011;56(4):503–509. Reprinted with permission.

Key Points A list of bulleted statements appears at the end of each chapter. These Key Points recap a summary of the most important points in the chapter.

Key Points Pulse oximetry measures oxygen saturation by passing two wavelengths of light through a pulsating vascular bed. The accuracy of pulse oximetry is ±4%. A number of factors can affect the accuracy and performance of pulse oximetry. Pulse oximeters can measure SpHb, SpCO, and SpMet; the clinical utility of these measures has yet to be determined. The plethysmographic waveform from pulse oximeters can be used to assess pulsus paradoxus, fluid responsiveness, and respiratory rate. Capnometry measures the concentration of carbon dioxide exhaled from the lungs. Capnography can be useful for detecting esophageal intubation, adequacy of chest compressions, and return of spontaneous circulation during CPR. End-tidal PCO2 may not accurately reflect PaCO2. Volumetric capnography can be used to measure carbon dioxide production and cardiac output. Transcutaneous PO2 and PCO2 are measured with a heated electrode placed on the skin. The respiratory rate and pattern can be monitored through observation of chest wall motion, monitoring of nasal airflow, pulse oximetry, capnography, acoustic technology, and measurement of chest wall motion. A polarographic electrode can be used to measure PbtO2, but it is unknown whether this monitor affects outcomes in patients with traumatic brain injury. Near-infrared spectroscopy is a technique for noninvasive monitoring of peripheral tissue oxygenation in various tissues.

Instructor and Student Resources Qualified instructors will receive a full suite of instructor resources, including the following:

For the Instructor A comprehensive chapter-by-chapter PowerPoint deck. A test bank containing more than 1000 questions on a chapter-bychapter basis as well as a midterm and a final.

For the Student Case studies are available online as writable PDFs. New and updated Practice Questions. Animations, now with audio and captions. Each text comes with access to our Anatomy & Physiology Review Module, which includes the Heart & Lung Sounds Module. OER pathways link out to various sites that will reinforce key topics from the text.

About the Editors © Andriy Rabchun/Shutterstock

Dean R. Hess, PhD, RRT, FAARC After many years in the position, in 2016 Dean R. Hess retired as Assistant Director of Respiratory Care, Massachusetts General Hospital, but stayed on per diem and continues to be very active professionally. He is a lecturer in the MS in respiratory care leadership program at Northeastern University. Since he first began working as a respiratory therapist in 1972, his experience has included clinical, research, teaching, and administrative responsibilities. For 10 years he was Editorin-Chief of RESPIRATORY CARE, the official science journal of the American Association for Respiratory Care, and is currently the Managing Editor of this journal. He is on the Editorial Boards of the Journal of Aerosol Medicine and Pulmonary Drug Delivery and Simulation in Healthcare. His academic interests include aerosol delivery techniques, adult mechanical ventilation, and critical care monitoring. Dean is a Fellow of the American Association for Respiratory Care and the Society of Critical Care Medicine. He has published more than 200 papers and several books, and his books have been translated into several foreign languages. He has had a high level of professional activity, including committee appointments with the American Association for Respiratory Care, the American Thoracic Society, the Society of Critical Care Medicine, and two years as president of the National Board for Respiratory Care. He has lectured extensively throughout the United States and around the world. Dean has received numerous honors, including the Forrest M. Bird Lifetime Scientific Achievement Award; American Association for Respiratory Care Life Membership; American

College of Chest Physicians Simon Rodbard Memorial Honor Lecture; Jimmy A. Young Medal; Robert H. Miller, RRT, Award; Chadwick Medal; Shubin-Weil Master Clinician/Teaching Award; SCCM Presidential Citation; Hector Leon Garza MD Achievement Award; and AARC Legends of Respiratory Care. He has received teaching awards from the medicine residents at the Massachusetts General Hospital and the Harvard Pulmonary and Critical Care fellowship program.

Neil R. MacIntyre, MD FAARC Neil R. MacIntyre is a native of Southern California but received his medical degree and internal medicine training at Cornell University in New York City. After three years of service as a U.S. Navy flight surgeon at the Naval Aerospace Medical Research Lab in Pensacola, Florida, he returned to California for a pulmonary disease fellowship at the University of California, San Francisco. He was then recruited to the faculty at Duke University, where he has spent the remainder of his career. At the present time, he is Professor of Medicine (with tenure), Senior Clinical Advisor of the Pulmonary/Critical Care Division, and Medical Director of Respiratory Care Services. His research interests range from clinical pulmonary physiology to large-scale randomized trials in chronic obstructive pulmonary disease (COPD) and acute respiratory failure. Currently Neil is on the Steering Committee of the large National Institutes of Health (NIH) multicenter COPDgene Network. He was also on the Steering Committee of the NIH Acute Respiratory Distress Syndrome Network (ARDSnet) for its duration. To date he has published more than 200 peer-reviewed articles and reviews, is the editor/co-editor of eight books, and is on the editorial boards of five journals. He is the past president of the American Lung Association of North Carolina, and the National Association of Medical Directors of Respiratory Care, and he is the former vice-chair of the American Respiratory Care Foundation. Important honors include Alpha Omega Alpha, the Surgeon General’s Award for Aviation Medicine, the Forrest M. Bird Lifetime Scientific Achievement Award, and the Jimmy A. Young Medal from the American Association for Respiratory Care. He is listed in both “Best Doctors in America” and “Who’s Who in America.”

William F. Galvin, MSEd, RRT, CPFT, AE-C, FAARC William F. Galvin is Assistant Professor in the Frances M. Maguire School of Nursing and Health Professions, Program Director for the Respiratory Care Program, and a member of the teaching and administrative faculty for the Teacher Improvement Project System (TIPS) Program at Gwynedd Mercy University (GMU). He has been a respiratory therapist for more than 45 years and has been on faculty at GMU since December 1981; he first served as Director of Clinical Education for two years before becoming Director of the Respiratory Care Program in 1983. In addition to his teaching and administrative role at TIPS, he teaches in the bachelor of health science degree program. Bill earned his bachelor’s degree in political science from La Salle College and his master’s degree in education (with a concentration in health) from St. Joseph’s University. He is a registered and certified respiratory therapist, certified pulmonary function technologist, and certified asthma educator. He has provided numerous article reviews, abstracts, and contributing chapters for publishing companies such as Springhouse Corporation, Delmar/Cengage Learning, F. A. Davis, C. V. Mosby, Williams and Wilkins, W. B. Saunders/Elsevier, and Jones & Bartlett Learning. He has presented at the local, state, and national levels on topics such as communication skills, wellness, health promotion, disease prevention, patient education, interviewing and assessment skills, programmatic and regional accreditation, outcome assessment, recruitment and retention, test-taking strategies and techniques, and a variety of student survival topics and concepts related to the art of teaching and learning. He has served as a guest presenter for the American Association for Respiratory Care’s (AARC’s) Educator Academy, the AARC Asthma Educator Certification Course, the AARC COPD Educator Course, the Adult Critical Care Course, and the AARC Registry Prep Course. Bill has served on countless professional and college-level boards and committees and is the recipient of numerous awards and honors. In 1996, the AARC bestowed the honor of life membership on him; in 2005, he was inducted into the AARC Fellowship Program and was the recipient of the Education Section Practitioner of the Year Award. In 2008, he was awarded national honorary life membership in the Lambda Beta National Honor Society for Respiratory

Care. In 2012, he provided the H. Fred Helmholz Distinguished Education Lecture on the topic of Excellence in Respiratory Care Education: Creating an Exemplary RC Program. In 2015, he received the Jimmy Young Medal, the highest honor bestowed by the AARC, recognizing individuals who have made lasting and sustained contributions to the profession of respiratory care. In 2016, Bill received the Inaugural Pennsylvania Society for Respiratory Care Lifetime Achievement Award; in the following year, he received the A. Gerald Shapiro Award from the New Jersey Society for Respiratory Care for outstanding leadership and contributions to respiratory care. At the 2019 commencement exercises at Gwynedd Mercy University, he received the Christian R. and Mary F. Lindback Award for Distinguished Teaching. The Lindback Award is the most prestigious award given to full-time faculty members who over the years have demonstrated the highest achievements in teaching. Bill is an active member of his parish, has coached Little League baseball and high school basketball, and is an avid sports enthusiast. He professes his greatest joy and passion to be in the classroom, teaching and learning from his students, and he thoroughly enjoys spending time with his eight grandchildren, Rory, Everett, Maeve, Seamus, Clare, Keiran, Alice, and Quinn.

Shelley C. Mishoe, PhD, RRT, FAARC Shelley C. Mishoe is Professor at Old Dominion University (ODU), the recent former Dean of the College of Health Sciences, and a tenured professor in the School of Community and Environmental Health. She is also emeritus associate provost, dean, chair, and professor at Augusta University, formerly the Medical College of Georgia. She has many years of experience in respiratory care, including teaching, research, and administration. She recently completed two terms on the Board of Directors for the Association of Schools of Allied Health Professions and serves on the Board of Directors for Bon Secours Mercy Health System, and the Commission on Accreditation for Respiratory Care (CoARC). She is the founder of the ODU Center for Global Health and serves on the advisory board. For her efforts in community and global health, she received a Women of Distinction Award from the YWCA South Hampton

Roads. She has held various faculty positions and visiting professorships at Chang Gung University, Capella University, Wofford College, and the Medical College of Georgia, including roles as director of clinical education and program director in respiratory care. She is an inaugural Fellow of the American Association for Respiratory Care, a Fellow of the Association of Schools of Allied Health Professions, and a Fellow of the American Council on Education Fellowship Program. Among leadership roles, she was the President of CoARC (2009–2011) and gave the second annual Dr. H. Fred Helmholz Distinguished Education Lecture Series. She served for 15 years on the editorial board for RESPIRATORY CARE and in the AARC House of Delegates. Other distinctions include honorary Lifetime Member of the AARC, the AARC HOD Delegate of the Year Award, the AARC Education Section Practitioner of the Year Award, the CoARC Bonner Smith Award, the National Honorary Member of Lambda Beta Society, and the Forrest M. Bird Literary Award. She has given many invited presentations and received numerous awards for teaching and research, including three national Telly Awards for educational short films. Shelley has been awarded more than $7 million in external/federal grant funding and authored or edited numerous books and chapters, original research studies, peer-reviewed articles, case reports, editorials, book reviews, and abstracts, and has published papers on asthma, sleep-disordered breathing, rural health, critical thinking, decision making, problem-based learning, and interprofessional education. She earned a PhD from the University of Georgia, an MEd with a minor in health services administration from Augusta University, and bachelor of science and associate degrees in respiratory therapy from SUNY Upstate Medical University.

Contributing Authors © Andriy Rabchun/Shutterstock

Allan G. Andrews, MSc, RRT Respiratory Care (retired) University of Michigan Health System Sherry L Barnhart, RRT RRT-NPS, AE-C FAARC Respiratory Care Discharge Planning Arkansas Children’s Hospital Stephen P. Bergin, MD Pulmonary, Allergy, and Critical Care Medicine Duke University Medical Center Rajesh Bhagat, MD Pulmonary, Critical Care, and Sleep Medicine University of Mississippi Medical Center John E. Boatright, PhD, RRT Respiratory Care St. Catherine University Desiree K. Bonadonna, MPS, CCP, FPP Perfusion Services Duke University Medical Center Richard D. Branson, MSc, RRT, FAARC Surgery University of Cincinnati Melissa K. Brown, RRT, RRT-NPS Neonatal Research Institute

Sharp Mary Birch Hospital for Women and Newborns Robert L. Chatburn, MHHS, RRT-NPS, FAARC Respiratory Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Bashir A. Chaudhary, MD, FAASM, FACCP Sleep Institute of Augusta Respiratory Therapy Department Augusta University Lingye Chen, MD Pulmonary, Allergy, and Critical Care Medicine Duke University Medical Center Francis C. Cordova, MD Pulmonary and Critical Care Medicine Temple University Christopher E. Cox, MD, MHA, MPH Pulmonary, Allergy, and Critical Care Medicine Duke University Medical Center Joseph P. Coyle, MD Respiratory Care Boise State University Gerard J. Criner, MD Pulmonary and Critical Care Medicine Temple University Rebecca H. Crouch, PT, DPT, MS, CCS, FAACVPR Pulmonary Rehabilitation Duke University Medical Center Talal I. Dahhan, MD, MEd Pulmonary, Allergy, and Critical Care Medicine Duke University John D. Davies, MA, RRT, FAARC Respiratory Care

Duke University Medical Center William E. Downey III, MD, MS Interventional Cardiology Sanger Heart and Vascular Institute Crystal L. Dunlevy, EdD, RRT School of Health and Rehabilitation Sciences The Ohio State University Daniel F. Fisher, MSc, RRT Respiratory Care and Pulmonary Function Testing Boston Medical Center Donna D. Gardner, MSHP, RRT, FAARC Respiratory Care Texas State University Michael A. Gentile, MSc, RRT, FAARC Medical Affairs Vero Biotech Lynda T. Goodfellow, EdD, RRT, AE-C, FAARC Byrdine F. Lewis College of Nursing and Health Professions Georgia State University Lutana H. Haan, MHS, RRT, RPSGT College of Health Sciences Boise State University Carl F. Haas, MLS, RRT, RRT-ACCS, FAARC Respiratory Care University of Michigan Health System Charles W. Hargett III, MD Pulmonary, Allergy, and Critical Care Medicine Duke University Medical Center Jessie G. Harvey, MD Pulmonary and Critical Care

University of Mississippi Medical Center Jeffrey M. Haynes, RRT, RPFT, FAARC Pulmonary Function Laboratory St. Joseph Hospital Anthony L. Heard, MEd, RRT Respiratory Care Georgia Southern University—Armstrong Campus Molly Quinn Jensen, MBA, RRT, RRT-ACCS Respiratory Care St. Catherine University Garry W. Kauffman, MPA, RRT, FAARC, FACHE Kauffman Consulting Angela C. King, RPFT, RRT, RRT-NPS Mobile Medical Home Care Bryan D. Kraft, MD Pulmonary, Allergy, and Critical Care Duke University Medical Center Jody L. Lester, MA, RRT Respiratory Care Boise State University Anne M. Mathews, MD Pulmonary, Allergy, and Critical Care Duke University Medical Center Samuel K. McElwee, MD Cardiovascular Disease University of Alabama at Birmingham Thomas P. Malinowski, MSc, RRT, FAARC Pulmonary Diagnostics and Respiratory Therapy Services University of Virginia Douglas E. Masini, EdD, RRT, RRT-NPS, RPFT, AE-C, FAARC Diagnostic and Therapeutic Sciences

Georgia Southern University—Armstrong Campus Christine J. Moore, DHSc, RRT, RRT-NPS, CPFT Diagnostic and Therapeutic Sciences Georgia Southern University—Armstrong Campus Lake D. Morrison, MD Pulmonary, Allergy, and Critical Care Duke University Medical Center John Mullarkey, RRT, AE-C Respiratory Care Temple University Hospital Timothy R. Myers, MBA, RRT, RRT-NPS, FAARC Chief Business Officer American Association for Respiratory Care Rachel A. Newberry, MEd, RRT Principal Trainer- Clin Doc Wellspan Health Catherine A. O’Malley, RRT, RRT-NPS Respiratory Care Ann & Robert H. Lurie Children’s Hospital of Chicago Timothy B. Op’t Holt, EdD, RRT, AE-C, FAARC Cardiorespiratory Care University of South Alabama William C. Pruitt, MBA, RRT, CPFT, AE-C Cardiorespiratory Care University of South Alabama Craig R. Rackley, MD Pulmonary, Allergy, and Critical Care Medicine Duke University Medical Center Ruben D. Restrepo, MD, RRT, FAARC Respiratory Care University of Texas Health Sciences Center at San Antonio

Diana M. Restrepo-Serrato Independent Consultant - Immunotec Bryce R. H. Robinson, MD Surgery University of Washington Dario Rodriquez Jr., MSc, RRT Surgery University of Cincinnati Bruce K. Rubin, MEngr, MD, MBA, FRCPC, FAARC Pediatrics Children’s Hospital of Richmond Georgianna G. Sergakis, PhD, RRT, FAARC School of Health and Rehabilitation Sciences The Ohio State University Scott L. Shofer, MD, PhD Pulmonary, Allergy, Critical Care and Interventional Pulmonary Duke University Medical Center Mark L. Simmons, MSEd, RRT, RRT-NPS, RPFT Respiratory Care (retired) York College of Pennsylvania Priscilla R. Simmons, MSN, EdD, APRN, BC Nursing Eastern Mennonite University Jaspal Singh, MD, MHS, MHA Pulmonary Care Carolinas Medical Center, Atrium Health William Randall Solly, MSc, RRT, RPFT School of Nursing and Health Professions Gwynedd Mercy University Helen M. Sorenson, MSc, RRT, FAARC Respiratory Care

University of Texas Health Sciences Center William S. Stigler, MD Pulmonary and Critical Care University of Alabama at Birmingham Shawna L. Strickland, PhD, RRT, RRT-NPS, RRT-ACCS, AE-C, FAARC Associate Executive Director American Association for Respiratory Care Amy E. Treece, MD Pulmonary Disease, Critical Care, and Sleep Medicine Greenville Health System Sarah M. Varekojis, PhD, RRT, FAARC School of Health and Rehabilitation Sciences The Ohio State University Ellen E. Volker, MD, MSPH Division of Pulmonary, Critical Care and Sleep Medicine National Jewish Health Teresa A. Volsko, MBA, MHHS, RRT, CMTE, FAARC Respiratory Care and Transport Akron Children’s Hospital Momen M. Wahidi, MD, MBA Pulmonary, Allergy, Critical Care, and Interventional Pulmonary Duke University Medical Center Jeffrey J. Ward, MEd, RRT, FAARC Multidisciplinary Medical Simulation Center Mayo Clinic Andrew J. Weirauch, RRT Respiratory Care University of Michigan Health System Jordan W. Whitson, MD Pulmonary, Allergy, and Critical Care Medicine

Duke University Medical Center

Reviewers © Andriy Rabchun/Shutterstock

Stacia Biddle, MEd, RRT Program Director, Respiratory Therapy University of Akron Brent Blevins, BSN, RN, RRT Registered Nurse Riverpark Hospital Amy Ceconi, PhD, RRT, RPFT, RRT-NPS Program Director Bergen Community College Lea Endress, BS, RRT, RPFT Respiratory Therapy Instructor Respiratory Therapy Program San Joaquin Valley College David Fry, BS, RRT, CPFT Director of Clinical Education Department of Respiratory Care Temple College Wesley M. Granger, PhD, RRT (Retired) Former Associate Professor, Program Director Department of Clinical and Diagnostic Sciences Respiratory Therapy Program University of Alabama at Birmingham Jennifer Gresham, MA, RRT, RRT-NPS, Ed.D Assistant Professor, Program Chair

Department of Respiratory Care Midwestern State University Michael Haines, MPH, RRT-NPS, AE-C Respiratory Therapy Instructor San Joaquin Valley College Suezette Hicks, BA, RRT-CPFT Director Respiratory Care Program Black River Technical College Lisa Johnson, MS, RRT-NPS Vice Chair, Respiratory Care Program Clinical Assistant Professor Director of Clinical Education Respiratory Care Program Stony Brook University Robert L. Joyner Jr., PhD, RRT, FAARC Former Director, Respiratory Therapy Program Associate Professor and Chair Department of Health Sciences Salisbury University Traci Marin, PhD, MPH, RRT, RPSGT Clinical Instructor Victor Valley College Cynthia McKinley, RRT Assistant Professor Director of Clinical Education, Respiratory Care Program Lamar Institute of Technology Larry McMullin, MM, RRT, RPFT Clinical Coordinator, Assistant Professor Respiratory Care Program Ferris State University Monica Mike-Simko, BSRC, RRT Program Director, Respiratory Therapy

Laurel Technical Institute Kim J. Morris-Garcia, MEd, RRT, RRT-NPS Associate Master Technical Instructor Director of Clinical Education Respiratory Therapy and BAT Programs University of Texas at Brownsville and Texas Southmost College Jennifer M. Purdue, MA, RRT, RRT-NPS, AE-C, RN Associate Professor, Program Chair Department of Respiratory Care Ivy Tech Community College Christopher Rowse, MS, RRT, RPFT, RPSGT Professor Northern Essex Community College Georgianna Sergakis, PhD, RRT PhD, RRT, FAARC Assistant Professor, Clinical Program Director Respiratory Therapy Division The Ohio State University Frank Sinsheimer, RRT, EdD (Retired) Former Professor Emeritus, Respiratory Therapy Los Angeles Valley College Stephen G. Smith, MPA, RRT Chair, New York State Board for Respiratory Therapy Clinical Assistant Professor Stony Brook University Don Steinert, MA, RRT, MT, CLS Associate Professor University of the District of Columbia Chris Trotter, MH, EdS, RRT Associate Professor, Respiratory Care Coordinator Degree Advancement Program St. Mary’s/Marshall University Staff Therapist

Charleston Area Medical Center LaVerne Yousey, RRT, MSTE Professor of Respiratory Care, Emeritus University of Akron Rick Zahodnic, PhD, RRT, RRT-NPS, RPFT, AE-C Clinical Coordinator Respiratory Therapy Program Macomb Community College

Part 1 Respiratory Assessment

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https://t.me/mebooksfree CHAPTER

1 History and Physical Examination Priscilla R. Simmons

© Andriy Rabchun/Shutterstock

OUTLINE Creating a Therapeutic Climate Components of the Health History Vital Signs Techniques of Assessment Physical Examination of the Lungs and Thorax Assessment of Other Body Systems

OBJECTIVES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Discuss the factors essential in the creation of a therapeutic climate. Explain three considerations of an effective health history. Explain the relevance of cultural diversity in the history-taking process. List the major components of a health history. Identify the four major examination techniques. Define common terms used in the assessment of the respiratory system. Explain the technique for auscultation of the chest. Define terms associated with normal and abnormal breath sounds. List the signs associated with respiratory distress. Identify common pathologic processes of the respiratory system and pertinent physical findings that extend to other body systems. 11. Identify the significance of various chest landmarks.

12. Explain the significance of sounds heard during cardiac auscultation. 13. Explain the significance of jugular venous distention. 14. Explain common findings associated with an assessment of the neurologic system.

KEY TERMS auscultation barrel chest Biot respirations bradypnea bronchial breath sounds bronchophony bronchovesicular breath sounds Cheyne-Stokes breathing clubbing crackles cyanosis dyspnea egophony flail chest grunting hyperpnea hyperresonant hyperventilation inspection jaundice Kussmaul respirations kyphosis lordosis murmur orthopnea pack years pallor palpation paradoxical respiration paroxysmal nocturnal dyspnea pectus carinatum pectus excavatum percussion platypnea plethora pleural friction rub precordium resonant rhonchus scoliosis stridor tachypnea

tactile fremitus tympanic vesicular breath sounds wheezes whispered pectoriloquy

Introduction This chapter provides a guide to essential assessment techniques used in respiratory care. Although some techniques are not always used, providers caring for the patient with pulmonary disease should still be familiar with them. The emphasis of this chapter is on the pathophysiology underlying common respiratory abnormalities and the typical assessment findings associated with them.

Creating a Therapeutic Climate The patient’s perception of the respiratory therapist’s competence is of prime importance. When any healthcare provider is perceived as uncaring, the patient may remember that attitude most vividly. Even worse, that poor image may be generalized to characterize all members of the profession for the patient. To ensure a therapeutic, professional relationship, competence and caring must coexist. A clinician can communicate caring through a gentle demeanor and an unhurried, nonabrupt manner. Maintaining eye contact is essential. Also appropriate is the judicious use of touch, such as patting or squeezing a patient’s hand or shoulder. Respiratory therapists should dress appropriately, because a professional appearance communicates respect for the patient. Indeed, a patient’s judgment of a healthcare provider often is based on physical appearance. These measures help establish rapport and a climate of professional caring—a goal in every professional relationship. Respiratory Recap Variables Supporting a Therapeutic Climate ∎ Caring demeanor ∎ Competence ∎ Eye contact ∎ Judicious use of touch ∎ Professional image

Components of the Health History The health history provides a detailed, chronologic health record of the patient’s status. For the purpose of developing an individualized plan of care, the health history elicits information about variables affecting the patient’s health. The value of the history should not be underestimated: It guides the selection of appropriate physical examination techniques, helps the respiratory therapist develop an accurate index of suspicion, and ultimately leads to appropriate and effective therapeutic intervention. Because obtaining a comprehensive history is a time-consuming endeavor, many healthcare providers assess primarily the body systems of concern. Clearly, the heart and lungs are the systems of primary interest for respiratory therapists. Respiratory Recap The Health History ∎ Chief complaint ∎ History of present illness ∎ Occupational and environmental history ∎ Geographic exposure ∎ Activities of daily living ∎ Smoking history ∎ Cough and sputum production ∎ Family history ∎ Medical history ∎ Review of systems

Chief Complaint The chief complaint (CC) is the problem or concern that prompted the patient to seek healthcare. When documenting the CC in the patient record, the examiner should use the patient’s own words, placed within quotation marks.

History of Present Illness The history of present illness (HPI) is the chronologic narrative account of the patient’s health problem. It should describe in detail information relevant to the CC, including a description of the onset of the problem, the date the symptoms occurred and whether they developed gradually or suddenly, and the setting in which they developed. The HPI also includes a description of the signs and symptoms associated with the problem. The mnemonic OLD CART can help the examiner gather this information: Onset (when the problem started) Location of pain, shortness of breath, or other symptoms Duration of pain, shortness of breath, or other symptoms Character, quantity, and quality of pain, shortness of breath, or other symptoms Associated manifestations (the setting in which the pain, shortness of breath, or other symptoms developed) Relieving factors or factors that diminish or aggravate the pain, shortness of breath, or other symptoms Treatment (any medications or other remedies that relieve or exacerbate shortness of breath) Respiratory Recap History of Present Illness ∎ Onset ∎ Location ∎ Duration ∎ Character ∎ Associated manifestations ∎ Relieving factors ∎ Treatment

Occupational and Environmental History The examiner should inquire as to whether the patient is employed,

retired, or laid off. Are there any current or past hazards at work, such as exposure to asbestos, coal dust, silica, molds, dust, or animals? Is the patient under stress at work? Is the patient satisfied with his or her job?

Geographic Exposure Has the patient traveled to foreign countries? Has the patient been in military service?

Activities of Daily Living Has the patient experienced difficulty with or change in the ability to provide self-care?

Smoking History Does the patient smoke cigarettes, or has the patient done so in the past? How long has the patient smoked cigarettes? This answer is usually expressed in pack years and is calculated as follows: One pack a day for a year is known as 1 pack year; two packs a day for a year is 2 pack years; and so on. What is the patient’s willingness to quit? The examiner should also inquire as to whether the patient smokes a pipe, cigars, or illicit drugs such as marijuana (recreational use is now legal in some states) or crack cocaine.

Cough and Sputum Production The examiner should ask about the presence of cough and sputum. If the patient has a cough, the timing of the cough (e.g., in the morning, at night, or after eating) and whether sputum is produced should be noted. If sputum is produced, the examiner should determine its amount, consistency, color, and odor, as well as whether the frequency of the cough and the amount of sputum have increased recently.

Family History Any family history of genetically transmitted disease (e.g., cystic fibrosis, alpha-1 antitrypsin deficiency), cancer, heart disease, tuberculosis (TB), or human immunodeficiency virus (HIV) should be noted.

Medical History Dates of past health problems, hospitalizations, symptoms, and treatment should be noted in the history, as well as whether the problem is ongoing, resolved, or recurrent. Are immunizations current? Does the patient have any food, drug, insect, or environmental allergies? Stop and Think You are seeing a patient for the first time. You are told that the patient has chronic obstructive pulmonary disease (COPD). What information would you collect regarding the patient’s health history?

Review of Systems The review of the patient’s systems provides the opportunity for the examiner to methodically question the patient about the health of each body system. It differs from the physical examination in that the data are collected verbally. A thorough review of each system is unnecessary, but the examiner should include a detailed review of the systems affected by the present illness. If the patient answers with a negative response, the provider should note the denial of that specific complaint—for example, “Patient denies pain with deep inspiration and coughing.”

Vital Signs Pulse, respirations, and blood pressure are considered vital signs. These items are commonly measured, along with body temperature, as indicators of the patient’s health status. The pulse rate and rhythm can be measured by cardiac auscultation or palpation of any artery, with the radial artery being most commonly used for this purpose. The provider counts the pulse for a minimum of 15 seconds and then mathematically adjusts the count to obtain the rate per minute. The normal pulse rate for adults is 60 to 100 beats per minute; the rate is more rapid for infants and children. To measure respiratory rate, the examiner inspects the movement of the chest for 1 minute. The normal respiratory rate for adults is 12 to 20 breaths per minute; it is more rapid for infants and children. Blood pressure is measured either with a sphygmomanometer or an indwelling arterial catheter. Normal blood pressure for adults is 120/80 mm Hg. Measurements are lower for infants and children. Body temperature can be measured via the oral, rectal, or axillary sites using a traditional thermometer. Infrared sensors are also used for the forehead or tympanic sites. Core temperature monitoring is measured in the distal esophagus or pulmonary artery. Normal body temperature is 37° C (98.6° F). The term fever refers to a higher than normal body temperature (hyperthermia), whereas hypothermia comprises a temperature lower than normal. Age-Specific Angle Compared with adults, infants and children have higher respiratory rates, higher pulse rates, and lower blood pressures.

Respiratory Recap Respiratory Assessment Techniques ∎ Inspection ∎ Palpation ∎ Percussion

∎ Auscultation

Techniques of Assessment Inspection As an examination technique, inspection ranges from casual observation to visual scrutiny of the patient.

Palpation Palpation is the process whereby the examiner uses the hands to feel for body movement, lumps, masses, and skin characteristics. Palpation can be either light or deep.

Percussion Percussion requires the examiner to place a finger firmly against a body part and strike that finger with a fingertip from the other hand. The technique for the right-handed examiner is as follows: Hyperextend the middle finger of the nondominant hand (pleximeter finger). Press the distal interphalangeal joint firmly on the surface to be percussed. Avoid contact with any other part of the hand because vibrations may be dampened. Hold the forearm of the other arm close to the surface, with the hand turned up at the wrist, and partially flex the middle finger (plexor). Strike the pleximeter with the tip of the plexor with a quick, sharp, and relaxed wrist motion, and aim at the distal interphalangeal joint (Figure 1-1). Withdraw briskly to avoid dampening the vibrations. Use one to two blows at each location.

FIGURE 1-1 Percussion technique. © Jones & Bartlett Learning. Courtesy of MIEMSS.

The resulting sounds can suggest either normal underlying tissue or typical sounds associated with given abnormalities. Five percussion tones (Table 1-1) are commonly recognized: flat, dull, resonant, hyperresonant, and tympanic. A flat percussion note is soft, high pitched, and of short duration. It can be elicited by percussion of the thigh. A dull percussion note is of medium intensity, pitch, and duration. It is heard over the liver or a tumor. A resonant note is loud, low in pitch, and of long duration. It may be heard over normal lung tissue. A hyperresonant note is very loud, lower in pitch, longer in duration, and commonly heard over an emphysematous lung. A tympanic note is loud and drum-like, with a high pitch. It may be heard over a gastric bubble. TABLE 1-1 Characteristics of Percussion Notes

Description

Respiratory Recap Percussion Notes ∎ Flat ∎ Dull ∎ Resonant ∎ Hyperresonant ∎ Tympanic

Auscultation After inspection, auscultation is the most commonly used physical assessment technique, particularly for assessment of the respiratory system. Auscultation involves listening to body sounds with a stethoscope placed on the patient’s bare skin. The stethoscope has several important components (Figure 1-2). The diaphragm is the larger side of the stethoscope head; it is made of rigid plastic. The bell is the smaller cup on the other side of the head; it is covered with a plastic or rubber ring. Although the bell is useful for detection of certain cardiac and vascular sounds, the diaphragm is used more frequently. Note that both adult and pediatric diaphragms and bells exist, with the latter being smaller. Some stethoscopes come with interchangeable parts. The examiner should ensure that the appropriate sizes are being used.

FIGURE 1-2 Stethoscope, illustrating the diaphragm and the bell. © Martin Kubát/Shutterstock.

Quality stethoscopes have tubing specifically engineered to conduct sound very well. Some models magnify sound. Most stethoscopes, however, simply block other noise, thereby allowing the examiner to hear body sounds more clearly. An appropriate tubing length is about 12 inches.

Earpieces must fit snugly and comfortably. The earpieces must point toward the nose of the examiner to project sound toward the tympanic membrane of the examiner’s ears.

Physical Examination of the Lungs and Thorax The astute clinician is thoroughly familiar with human anatomy. An indepth knowledge of structure and function is vital to the interpretation of assessment findings in terms of underlying pathologic processes. Figure 1-3 illustrates thoracic landmarks and the surface anatomy of the chest.

FIGURE 1-3 (A) Thoracic landmarks. (B) Topographic landmarks of the chest. (C) Surface anatomy of the thorax.

Description

Inspection Observing Respirations The clinician must be familiar with common respiratory patterns (Figure 1-4). Tachypnea describes a persistent rate of respiration faster than 20 breaths per minute. It may be present in individuals who are hypoxemic and in those who have pain in the thoracic region.

FIGURE 1-4 Patterns of respiration. Reproduced from Mosby’s Guide to Physical Examination, Seidel HM, Ball JW, Dains JE, et al., Copyright Elsevier [Mosby] 1999.

Description Similarly, if liver enlargement or abdominal distention compromises diaphragmatic movement, tachypnea may result. At times, however, tachypnea merely represents the patient’s response to the realization that respirations are being observed and counted. Tachypnea also occurs in individuals with fever and in those with restrictive ventilatory defects, such as pulmonary fibrosis or pneumonectomy. Hyperpnea describes breathing that is rapid, deep, and labored. If it results in a lowered PCO2, the condition is called hyperventilation.

Kussmaul respirations occur when hyperventilation serves as a compensatory mechanism for metabolic acidosis, most commonly diabetic ketoacidosis. Conversely, bradypnea is a rate slower than 12 breaths per minute. It may suggest neurologic impairment or acid–base disturbance but may also be a normal finding in physically fit individuals. Dyspnea is a term that means difficult or labored breathing that leaves the individual feeling short of breath. Platypnea refers to an individual’s difficulty in breathing unless lying flat. Orthopnea indicates that an individual must sit or stand to breathe. Many individuals with chronic lung disease assume an upright position to breathe well. Such individuals often find it more comfortable to sleep in a chair. Paroxysmal nocturnal dyspnea is characterized by sudden shortness of breath that occurs several hours after the individual lies down. It commonly suggests cardiac dysfunction, in that the heart is unable to adequately pump a circulatory volume expanded by fluid reabsorbed from the legs, which became edematous during the day. Cheyne-Stokes breathing is characterized by episodes of slow, shallow breaths, which rapidly increase in depth and rate. This crescendo–decrescendo pattern is followed by periods of apnea. Such breathing may be a normal variant in young children and the elderly. Otherwise, it occurs in individuals with cerebral vascular disease and congestive heart failure. Biot respirations are symptomatic of elevated intracranial pressure and meningitis. This breathing pattern is characterized by a short burst of uniform, deep respirations, followed by periods of apnea lasting 10 to 30 seconds. Respiratory Recap Patterns of Respiration ∎ Tachypnea ∎ Hyperpnea ∎ Kussmaul respirations ∎ Bradypnea ∎ Dyspnea ∎ Platypnea ∎ Orthopnea ∎ Paroxysmal nocturnal dyspnea

∎ Cheyne-Stokes respirations ∎ Biot respirations

Use of Accessory Muscles Muscles of the back, neck, and abdomen are known as accessory muscles of respiration. Although they play a relatively minor role in normal respiration, their function becomes more prominent during exercise or respiratory distress. Use of accessory muscles implies an increased work of breathing or diaphragm weakness. Retractions suggest a barrier to inspiration, which may occur anywhere along the respiratory tract. To overcome this barrier, the respiratory muscles contract more vigorously, resulting in a more negative intrapleural pressure. Retractions resemble a sucking in of structures, such as the intercostal spaces, suprasternal space, and subclavian spaces. In such a situation, the examiner documents that the patient “has retractions,” “is retracting,” or “is using accessory muscles.”

Nasal Flaring and Pursed-Lip Breathing Individuals in respiratory distress commonly exhibit nasal flaring, presumably in an attempt to decrease the resistance to airflow through the nostrils. Those with emphysema commonly purse their lips during the expiratory phase to maintain airway patency and better control expiratory flow.

Flail Chest and Paradoxical Respiration Flail chest is a term describing the appearance of a thorax with multiple rib fractures, which lead to instability of the chest wall. In this situation, the chest wall moves outward on expiration and inward on inspiration. This movement, which is contrary to normal chest movement, is known as paradoxical respiration. Flail chest with paradoxical respiration indicates a serious injury and results in hypoxia if left untreated. The chest and the abdomen also should move in synchrony during the respiratory cycle. Paradoxical inward movement of the abdomen during the inspiratory phase indicates diaphragm weakness or paralysis. Paradoxical inward movement of the chest wall during inspiration

indicates paralysis of the chest wall muscles, as may occur with high thoracic spine or low cervical spine injury.

Shape of the Chest The examiner should observe the shape of the patient’s chest, as abnormalities of the thorax can be significant factors in lung disease. Typically, a patient with emphysema has a barrel chest (Figure 1-5). The lateral diameter of the chest is normally twice the anteroposterior diameter; however, with a barrel-shaped chest configuration, the anteroposterior diameter is equal to the lateral diameter. Although obstructive lung disease causes this characteristic change in chest configuration, certain other abnormalities of thoracic shape may result in restrictive lung disease. Pectus excavatum, or a funnel-shaped sternum, describes a sternum that is depressed and deviated somewhat like a funnel (Figure 1-6). Similarly, pectus carinatum, or a pigeon-breasted sternum, describes a chest that bows out at the sternum, similar to that of a pigeon. These abnormalities in thoracic configuration may result in lung disease as the patient ages. Scoliosis, for instance, causes lateral curvature of the spine, kyphosis causes forward curvature of the spine, and lordosis causes backward curvature of the spine (Figure 1-7).

FIGURE 1-5 A. Normal. B. Barrel chest.

FIGURE 1-6 Pectus excavatum.

FIGURE 1-7 (A) Scoliosis. (B) Kyphosis. (C) Lordosis.

The examiner also should note whether the trachea is midline in the neck. A tension pneumothorax causes tracheal deviation away from the

collapsed lung. Atelectasis or lung resection causes the trachea to be deviated toward the affected side.

Skin Color The examiner should note the color of the patient’s skin. Although several abnormalities in skin color exist, cyanosis is of prime significance to the respiratory therapist. When hemoglobin is poorly saturated with oxygen, the skin assumes a bluish hue, which initially becomes apparent in the nail beds. Cyanosis may be present normally in the nail beds of a person who is vasoconstricted as a result of exposure to cold temperatures. It also may be noted in the mucous membranes of the mouth; this site is of particular use in the assessment of individuals with dark skin. Finally, cyanosis can appear around the mouth (circumoral). In healthy children, circumoral cyanosis is quite common, particularly when they are cold. The significance of cyanosis must be evaluated in light of other clinical findings. Pallor describes the diminished skin color accompanying anemia. This condition also may be seen in individuals with severe peripheral vasoconstriction accompanying shock. Detecting pallor is easier in lighter-skinned individuals, but the color of darker skin also appears paler when the individual is severely anemic. Plethora indicates the fullness of blood vessels at the skin surface. Plethora may occur with vasodilation and may be present in individuals who are hypercapnic. Jaundice is the yellowish skin color arising from an elevated serum bilirubin level. Any disorder resulting in bile being retained in the liver ultimately causes jaundice. Jaundice first becomes apparent in the sclera of the eyes. Respiratory Recap Skin Color ∎ Cyanosis ∎ Pallor ∎ Plethora ∎ Jaundice

Stop and Think Before initiating a respiratory care plan, you are assessing a patient with a history of COPD. The patient is thought to have pneumonia, precipitating an exacerbation of the COPD. What are your considerations when performing a physical assessment?

Clubbing of Fingers Clubbed fingers result from enlargement of the distal phalanges and develop as a compensatory mechanism when an individual has chronic hypoxia, such as with congenital heart defects or chronic lung disease. The appearance of clubbing is as the term implies: The finger distal to the base of the nail looks like a small club (Figure 1-8). Affected fingertips appear full, fleshy, and vascular. Clubbing is associated with lung tumors, bronchiectasis, cystic fibrosis, congenital heart disease, and liver and gastrointestinal disease. In some patients, it is hereditary. However, clubbing does not occur with COPD.

FIGURE 1-8 (A) Normal Finger (B) Mild Digital Clubbing (C) Severe Digital Clubbing.

Palpation Subcutaneous Emphysema Subcutaneous emphysema is the presence of air in the subcutaneous tissues of the neck, chest, and face. The tissues may be painful and appear swollen. In addition, a crackling or popping sound may be heard when a stethoscope is placed over the tissue. An examiner also may detect subcutaneous emphysema by palpating bubbles as the finger pads roll over the affected areas.

Respiratory Expansion The assessment of respiratory expansion is used primarily to determine whether the lungs are expanding symmetrically. Asymmetry of expansion may be present with a pneumothorax, atelectasis, lung resection, or main stem intubation. To perform this examination, the examiner places the thumbs along each costal margin at the back. The examiner then slides the hands medially to raise loose skin folds between the thumbs. The patient is asked to inhale deeply, and the examiner notes the range and symmetry of respiratory expansion by observing how the skin fold spreads out.

Tactile Fremitus Tactile fremitus is defined as palpation of vibrations of the chest wall as a patient speaks. To elicit these vibrations, the examiner presses the bony part of the palm of the hand against the patient’s chest wall. For comparison between lungs, both sides are assessed concurrently. The patient is asked to repeat the words ninety-nine or one–one–one. When the lungs are healthy, vibrations are barely palpable. When the lung tissue is consolidated, however, vibrations are increased. Consolidation occurs when lung tissue that is normally aerated is made solid—that is, when it fills with fluid, mucus, pus, or cellular debris. In the patient with large amounts of secretions in the airways, the fremitus produced by this condition may be palpated as gas flows past the secretions.

Percussion Chest percussion can be used to elicit several abnormal findings. With a pneumothorax or emphysema, the affected hemithorax produces a hyperresonant or tympanic percussion note. With consolidation, pleural effusion, or atelectasis, the percussion note is dull or flat. A useful application of percussion is to determine diaphragmatic excursion. The difference in posterior, dependent resonance between maximum inhalation and maximum exhalation represents diaphragmatic excursion (Figure 1-9). Diaphragmatic excursion is affected by emphysema, pneumothorax, pleural effusion, atelectasis, consolidation, phrenic nerve injury, and diaphragmatic weakness.

FIGURE 1-9 Measuring diaphragmatic excursion.

Auscultation As the most frequently used instrument in respiratory assessment, the stethoscope yields valuable information about the status of the lungs. Because the lower lobes of the lungs are posterior in the thorax, complete auscultation of breath sounds through the anterior chest wall is impossible. Therefore, examiners should avoid the temptation to auscultate only the anterior chest wall because of its accessibility. Auscultation of the posterior chest wall often yields more useful information. Figure 1-10 shows the sequence for lung field auscultation. The examiner first assesses the apices of the lungs as they extend above the scapulae by listening on one side of the thorax and then moving to the corresponding area on the other side. Below the scapulae, the examiner continues to move back and forth, listening to corresponding areas on both sides and comparing the sounds. Sounds generated by normal lungs differ according to location in the respiratory system (Table 1-2).

FIGURE 1-10 Suggested sequence for systematic percussion and auscultation of the thorax from the posterior (A), Posterior view (B), right lateral (C), left lateral and (D) anterior view.

Description TABLE 1-2 Lung Sounds Assessed by Auscultation Sound

Characteristics

Vesicular

Heard over most lung fields; low pitch; soft and short

expirations; accentuated in the thin person or child, and diminished in overweight or very muscular individuals Bronchovesicular

Heard over main bronchus area and upper right posterior lung field; medium pitch; expiration equaling inspiration

Bronchial/tracheal (tubular)

Heard only over trachea; high pitch; loud and long expirations, often somewhat longer than inspiration

Intensity of Breath Sounds Breath sounds may be reduced in individuals with a number of conditions. They can be diffusely decreased with shallow breathing or with the hyperinflation and decreased airflow that occur with hyperinflation (e.g., emphysema or acute asthma). Localized diminished breath sounds occur with airway obstruction, atelectasis, and main stem intubation. Decreased breath sounds at the lung bases are commonly associated with postoperative atelectasis.

Characteristics of Normal Breath Sounds Bronchial breath sounds are heard over the trachea, at the manubrium anteriorly, and between the scapulae posteriorly. These breath sounds are louder and higher in pitch. Expiratory sounds are as long as or slightly longer than the inspiratory component. Bronchovesicular breath sounds are heard over the junction between the bronchi and alveoli. Anteriorly, these sounds occur in the first and second interspaces between the ribs. Inspiratory and expiratory phases are equally long. Vesicular breath sounds are heard over the lung periphery. These sounds are soft and low pitched, and inspiration lasts longer than expiration.

Characteristics of Abnormal Breath Sounds Bronchial breath sounds heard over the periphery or in the bases of the lungs suggest consolidation of lung tissue. Consolidation occurs when lung tissue that is normally aerated fills with fluid, mucus, pus, or cellular debris. Consequently, sounds generated by air movement through the

bronchi resonate more clearly to pulmonary regions where only vesicular or bronchovesicular sounds are normally heard. Other sounds typical of consolidation are the voice sounds— bronchophony, egophony, and whispered pectoriloquy. Bronchophony is elicited when the examiner auscultates over an area of suspected consolidation and asks the patient to say the words ninety-nine. Normally, this sound is muffled, but when heard over consolidated lungs, the words are clearly audible. Similarly, egophony is elicited when the patient is asked to say the letter e. Over normal lung fields, the verbalization of the letter e sounds like e. When consolidated areas of the lung are auscultated, however, the annunciation of the letter e converts to the sound made by annunciation of the letter a. This is termed the e to a phenomenon. The third voice sound, whispered pectoriloquy, can be evoked when the patient is asked to whisper the numbers 1, 2, and 3. Normally this sound is soft, but with lung consolidation, it is clearly audible. Respiratory Recap Auscultation ∎ Intensity of breath sounds ∎ Presence of bronchial breath sounds ∎ Presence of adventitious breath sounds: crackles, rhonchi, wheezes, stridor, pleural friction rubs

Crackles Crackles, or rales (pronounced rawls, although many clinicians say rails), are commonly heard adventitious, or abnormal, breath sounds (Figure 1-11). Crackles are classified as discontinuous sounds, meaning that they wax and wane during each respiratory cycle. Usually heard at the end of inspiration, they are fine in quality and high pitched. Crackles result when the terminal airways pop open late in inspiration because fluid or secretions have accumulated. Consequently, crackles are heard most often over the lung bases.

FIGURE 1-11 Breath sounds noted in ill and well patients.

Description Crackles are a common finding in individuals with congestive heart failure. In this condition, fluid accumulates first in the interstitial spaces between the capillaries and the alveoli. As the condition worsens, the fluid fills the alveoli. Initially the crackles are heard in the bases of the lungs. Crackles that ascend higher up the lung fields reflect an increasing degree of congestive heart failure. For pneumonia, crackles are heard over the involved lobe. In some normal individuals who have remained supine for long periods, crackles may be auscultated in the dependent areas of the lung.

Rhonchi The definition of a rhonchus (singular) or rhonchi (plural) has produced some debate. To a certain degree, the use of the term varies among clinical practice sites. However, the American Thoracic Society has defined rhonchi as being deeper, rumbling sounds that are more pronounced on expiration. These sounds are likely to be continuous. Generally, they are caused by air passing through an airway partially obstructed by thick secretions, spasm of the airways, or presence of a tumor. Higher-pitched or sibilant rhonchi arise in the smaller bronchi,

such as in the case of asthma. Lower-pitched, sonorous, or snoring rhonchi are more commonly heard in association with thick secretions in the larger airways. At times, the rumbling may be palpable through the chest wall. Stop and Think How might the findings during auscultation be different for a patient with COPD, a patient with congestive heart failure, and a patient with both COPD and congestive heart failure?

Wheezes Wheezes may be either high or low in pitch. High-pitched wheezes are often called sibilant wheezes. They are musical or whistling in nature, caused by air passing through narrowed airways, such as in the bronchospasm of asthma (reactive airway disease). Most often, sibilant wheezes are heard on expiration, although they may be heard throughout the respiratory cycle. Although wheezes are most often associated with asthma, they also can be present in individuals with other conditions, such as congestive heart failure and foreign body aspiration.

Stridor and Grunting Stridor is a crowing sound commonly caused by inflammation and edema of the larynx and trachea. It may be heard after extubation, when tracheal damage has occurred with resultant edema. Most commonly, however, stridor is associated with croup in children, in which case it is frequently accompanied by a barking cough. Usually, stridor is a nocturnal assessment finding, probably related to the development of edema in the upper airway when a child assumes a dependent position during sleep. Mouth breathing related to nasal congestion often causes a drying and, therefore, thickening of secretions that further compounds the stridor. The constellation of findings includes improvement of symptoms with air humidification. Taking the child outside into the cool night air may be an effective intervention. If the child does not improve, however, the stridor must be evaluated further because of the danger of airway obstruction. Grunting is a sound heard in newborns with respiratory

distress. It occurs when the glottis is closed in an attempt to maintain lung volume. Age-Specific Angle Stridor is associated with croup in children. Grunting is associated with respiratory distress in the newborn.

Pleural Friction Rubs A pleural friction rub is a continuous grating sound like that heard when two pieces of leather rub together. Another analogy is that friction rubs sound as though the palms of both hands are sliding against each other. This sound is produced when the visceral and parietal pleurae become inflamed and no longer glide silently against each other during the respiratory cycle. Consequently, the sound is localized and exists only over the area of pleural irritation. Pleural friction rubs may be intermittent. Pleural friction rubs may accompany a pleural effusion—the accumulation of fluid in the usually empty pleural cavity. Causes of pleural effusion include malignant seeding of metastatic tumors onto the pleural linings. Pleural friction rubs also may be heard in individuals with infectious processes involving the pleural cavity. After thoracic surgery, residual blood in the pleural cavity eventually becomes sludge and may irritate the pleurae, resulting in a friction rub.

Signs of Respiratory Distress Table 1-3 lists the common physical findings of respiratory diseases. TABLE 1-3 Physical Findings of Respiratory Diseases

Description

Assessment of Other Body Systems The respiratory system interfaces with all other organ systems. Consequently, evaluation of the respiratory system does not occur in an assessment vacuum. The following discussion highlights assessment techniques used to monitor the heart, blood vessels, and brain.

The Heart and Blood Vessels Location and Significance of Various Chest Landmarks The chest wall overlying the heart is known as the precordium. Each heart valve is auscultated best by placing the stethoscope in a specific location on the precordium. To do so, the examiner locates the cartilaginous structures—interspaces—lying between the ribs, first by identifying the clavicle. Note that the space immediately under the clavicle does not count as an interspace. Next, the examiner identifies the first rib: The cartilage under the first rib is the first interspace. Count the ribs by moving the fingers down from each rib to the corresponding interspace. The accuracy of the counting process may be verified in the following way. Identify the ridge of bone that is the joint between the manubrium and the sternum, known as the sternal angle or angle of Louis. The interspace to either side immediately below the sternal angle is the second interspace. On the posterior thorax, the spinous processes of the vertebrae serve as useful landmarks. The spinous process of the seventh cervical vertebra (C7) can be identified when the patient extends the head and neck forward and down. The most prominent spinous process is C7; directly below that is the first thoracic vertebra (T1). A thorough cardiac auscultation involves systematic movement of the stethoscope over the precordium. For the novice examiner, the first step is to switch the focus of attention from counting each cardiac contraction to assessing the quality of the sounds created by the valves and any variations in the sounds associated with S1 and S2. The examiner should keep the stethoscope in each location for several cardiac cycles. Bearing in mind that S1 and S2 are heard anywhere in the precordium,

the examiner begins a thorough examination by focusing on the sounds created by the semilunar valves—the aortic and pulmonic valves. These valves are located at the base of the heart, which is actually the top of the heart where the great vessels exit. Variations associated with alterations of aortic valve function are best assessed in the second interspace to the right of the sternal border, where they are heard best because the valve points in that direction (Figure 1-12). The examiner then moves the stethoscope to the second interspace at the left sternal border, the best location for assessing pulmonic valve function.

FIGURE 1-12 Areas for auscultation of the heart.

Description All other assessments occur on the left side of the sternum. Tricuspid valve variations are heard best at the fifth interspace at the left sternal border, and the mitral valve is assessed where the fifth interspace intersects the midclavicular line. The mitral valve, or apical area, is not only useful as a landmark for auscultation but also provides other useful information. This relatively small left ventricular apex comprises the area where the left ventricle protrudes from behind the right ventricle, known as the point of maximal impulse (PMI). The left ventricle taps gently against an area of the thoracic wall no more than 2 cm in diameter

(Figure 1-13). Left ventricular hypertrophy may be the cause of an enlarged PMI.

FIGURE 1-13 Palpation of the apical pulse.

Cardiac Auscultation Listening to heart sounds involves notations of rate and rhythm, extra heart sounds, and murmurs. Heart rate and rhythm should be observed first. A regular rhythm is a rate of 60 to 100 beats per minute; however, certain irregularities are harmless variants. Conversely, other irregularities may herald serious consequences. Auscultation used to determine rate and rhythm is done with the stethoscope at the apex of the heart, a procedure known as taking an apical rate.

S1 and S2 Normal heart sounds are classified as S1 and S2 (S originates simply

from the word sound). S1, the first heart sound, results from closure of the atrioventricular (mitral and tricuspid) valves. S1 is also described as sounding like lub. As the ventricles eject most of their blood, ventricular pressure drops below aortic pressure, resulting in closure of the aortic and pulmonic valves, which in turn produces S2, the second heart sound, also known as dub. A normal variant may be auscultated with the stethoscope at the second interspace along the left sternal border. In many individuals, a split S2 may be heard here during inspiration; this sound occurs when pulmonic valve closure happens a few milliseconds after aortic valve closure. Typically, this action takes place during inspiration, as increasing intrathoracic pressure causes blood to strike the pulmonic valve with greater force.

S3 and S4 S3 and S4 are extra sounds generated by certain aberrant blood flow mechanisms. These sounds are best heard at the left fifth intercostal space at the midclavicular line, also known as the mitral, or apical, area. An S4 immediately precedes the S1, and an S3 follows immediately after the S2. These rhythms are commonly called gallops because they resemble the sound of a horse galloping. To auscultate for either an S3 or an S4, press the bell of a stethoscope lightly against the patient’s skin. Pressing too firmly obliterates the sounds. Both S3 and S4 are heard best with the patient in a left side-lying position. An S3 results from rapid ventricular filling. When ventricular pump failure occurs, an increased amount of residual blood remains in the heart chambers after a contraction. Consequently, the ventricles fill faster during diastole. This pumping of blood into an already partially filled ventricle causes the vibrations heard as an S3. An S3 occurs immediately after the S2. It resembles a split S2 but differs in location and timing. A split S2 is heard in the pulmonic area and varies with respiratory cycle, whereas the S3 is heard at the apex. S4 is a sound caused most often by a stiff ventricle, such as hypertension or after a myocardial infarction. For an S4 to occur, an atrial

contraction must take place. Consequently, this heart sound is often known as an atrial gallop. An S4 cannot exist in the presence of atrial fibrillation, a condition in which the atria do not contract. The vibrations causing an S4 are thought to arise from atrial contraction occurring in the presence of a stiffened or noncompliant ventricle. The S4 precedes the S1.

Murmurs A simple description of a cardiac murmur is an extra sound heard in conjunction with S1 and S2. Several mechanisms describe the etiology of murmurs. Murmurs occur when blood regurgitates into the chamber from which it came. Sometimes valvular dysfunction develops as a sequela to rheumatic heart disease after infection with β-hemolytic streptococci. This syndrome results in calcified valves with a distorted shape. Other murmurs arise when a large volume of blood flows through a valve, such as occurs during pregnancy, anemia, or hyperthyroidism. Murmurs may also result from blood flowing through a narrowed or stenotic valve. A final category of murmurs arises from congenital defects resulting in blood flow through openings not normally present.

Classification of Murmurs Murmurs are classified as early, middle, or late systolic—that is, occurring between S1 and S2. Others are diastolic, coming between S2 and the next S1. The intensity of murmurs is graded from I to VI (using Roman numerals). A grade I murmur is very faint and may not be heard in all positions. Generally, a highly trained ear is required to detect this sound. Murmurs identified as grades II through IV increase progressively in intensity, with a grade V murmur being very loud. A grade VI murmur may be heard without the stethoscope in contact with the chest. Murmurs differ in quality and are described as blowing, rasping, harsh, coarse, grating, whistling, or musical. In addition, they are classified according to the location at which the sound is loudest. This location corresponds to the area of the precordium where the valve in question is best auscultated, such as the fifth interspace midclavicular line or mitral area.

Respiratory Recap Cardiac Auscultation ∎ Heart rate and rhythm ∎ Extra sounds ∎ Murmurs

Murmurs and Infective Endocarditis Many murmurs are classified as functional, innocent, or physiologic, meaning that they are clinically insignificant. Others are significant in that they suggest a progressive pathologic process that may eventually require surgical intervention. Some murmurs signify a defect that requires prophylaxis against infective endocarditis. Formerly known as subacute bacterial endocarditis, infective endocarditis develops when bacteria colonize the heart valves. The immune response causes growth of fibrotic tissue, which consequently results in the development of vegetation on valves. Clearly, this interferes with efficient hemodynamics, and a murmur ensues. Another danger exists if the vegetation breaks off and the resulting emboli lodge elsewhere in the body; the bacteria then reproduce in that location. Prophylaxis against infective endocarditis is the term given to antibiotic therapy administered before any invasive or surgical procedure, including dental work. Innocent or physiologic murmurs require no such prophylaxis; however, innocence can be determined only by echocardiogram. Diastolic murmurs suggest the need for prophylaxis against infective endocarditis.

Jugular Venous Distention The inspection component of a cardiac assessment primarily involves observation of the right internal jugular vein, the vessel that reflects pressure changes better than other superficial veins. Oscillations in this vein reflect changing pressures within the right atrium. Similarly, distention of this neck vein suggests a distended right ventricle, which often accompanies right ventricular failure. Distended neck veins are normal in an individual in the supine position. Furthermore, neck veins fill temporarily with any activity that raises intrathoracic pressure, such as coughing, conversing, or bearing down (the Valsalva maneuver).

To assess for pathologic processes, the examiner determines the degree of jugular venous distention. The patient is placed in a supine position, with the head of the bed at a 45-degree angle (Figure 1-14). With a centimeter ruler, the examiner measures the vertical distance between the sternal angle and the highest level of jugular vein pulsation on both sides. Neck veins that fill to a level of 2 cm or less are considered normal. Filling higher than this level suggests increased right ventricular pressure and is associated with right-sided heart failure.

FIGURE 1-14 Technique used to measure jugular venous distention.

The Neurologic System Because of the system’s complexity, an assessment of the neurologic system can be daunting. This brief summary focuses on the most common neurologic abnormalities.

Level of Consciousness When a patient experiences an alteration in the level of consciousness because of trauma or some other hypoxic or metabolic event, the examiner commonly uses the Glasgow Coma Scale (Table 1-4) to assess the patient’s neurologic status. This scale uses a numeric scoring method to document eye-opening response, verbal response, and integrated motor response. Scores range from a low of 3 points, which suggests brain death, to a maximum of 15 points, which indicates full consciousness. TABLE 1-4 Glasgow Coma Scale Observation

Score

Eye Opening Spontaneous

4

In response to voice

3

In response to pain

2

None

1

Verbal Response Oriented response

5

Confused response

4

Inappropriate words

3

Incomprehensible words

2

None

1

Motor Response Obeys commands

6

Localizes

5

Withdraws

4

Flexes (decorticate)

3

Extends (decerebrate)

2

None

1

Other indications of neurologic integrity are normality and equality of strength in all extremities. Clearly, any less-than-normal finding suggests impairment and warrants full evaluation. Pupils may be evaluated for size, equality, reaction to light, and accommodation. Normal reactivity is documented as PEARLA, or pupils equal and reacting to light and accommodation. Although pupillary assessment is commonly performed, abnormalities in size and reaction are a late finding and may indicate significant brain dysfunction. A decreasing level of consciousness is the first finding that suggests neurologic impairment. Nevertheless, because sleep is itself a decreased level of consciousness, it is important to distinguish between normal sleep and a state suggesting a serious pathologic condition—such as carbon dioxide narcosis or respiratory failure. In critically ill, mechanically ventilated patients, sedation and decreased level of consciousness are often pharmacologically induced. The level of sedation in these patients is often assessed with the Ramsay score (Table 1-5) or the Richmond Agitation Sedation Scale (RASS; Table 1-6). Delirium in the intensive care unit (ICU) is measured with the Confusion Assessment Method for Assessing Delirium in the Intensive Care Unit (CAM-ICU) (Figure 1-15).

FIGURE 1-15 Confusion Assessment Method for Assessing Delirium in the Intensive Care Unit (CAM-ICU). Reproduced from Guenther U, Popp J, Koecher L, et al. Validity and reliability of the CAM-ICU flowsheet to diagnose delirium in surgical ICU patients. J Crit Care 2010;25 (1):144–156. Copyright 2010, with permission of Elsevier.

Description TABLE 1-5 Ramsay Sedation Scale Level

Response

1

Anxious, agitated, restless

2

Cooperative, oriented, tranquil

3

Responding to commands only

4

Asleep, brisk response to stimulus

5

Asleep, sluggish response to stimulus

6

Unarousable

TABLE 1-6 Richmond Agitation Sedation Scale Score

Term

Description

+4

Combative

Overtly combative, violent, immediate danger to staff

+3

Very agitated

Pulls or removes tube(s) or catheter(s), aggressive

+2

Agitated

Frequent nonpurposeful movement, fights ventilator

+1

Restless

Anxious, but movements not aggressive or vigorous

0

Alert and calm



−1

Drowsy

Not fully alert, but has sustained awakening (eye opening/eye contact) to voice (≥10 seconds)

−2

Light sedation

Briefly awakens with eye contact to voice ( 7.45, PaCO2 < 35 mm Hg, and HCO3– is normal, the patient has a respiratory alkalosis. If both the respiratory system and the renal system are contributing to the same acid–base disorder (low or high pH), the condition is referred to as a mixed or combined disorder. For example, a respiratory and metabolic acidosis occurs when high PaCO2 and low HCO3– create a low arterial blood pH (7.45). Step 6: Is PaCO2 or HCO3– in the opposite direction or the same direction as the pH? As explained in step 5, if both the respiratory system and the renal system move in opposite directions and contribute to the production of more acid, the disturbance

comprises a mixed acidosis. If both the respiratory system and the renal system move in the opposite directions and contribute to less acid in the body, it is a mixed alkalosis. However, if the body tries to compensate for acid–base disorders by having the renal and respiratory systems move in the same direction to maintain a normal arterial blood pH, the disturbance is considered a compensated disorder. Recall from step 1 that the pH can be normal, yet the acid–base physiology may be abnormal because the body has compensated for it. Compensation can be seen when both PaCO2 and HCO3– rise or fall together to maintain a normal pH. This adjustment occurs because CO2 is a volatile acid that lowers pH, whereas HCO3– buffers acid and raises pH. Partial compensation occurs when PaCO2 and HCO3– rise or fall together, but the pH remains abnormal. In this case, a compensatory mechanism has attempted to restore a normal pH. The body will do just enough to restore blood pH to within normal limits. Understanding this key concept helps to differentiate which system is causing the acid–base disorder and which system is compensating to restore blood pH within normal limits. Table 4-10 gives a basic overview of how changes in pH, PaCO2, and HCO3– are used to correctly interpret an acid–base disorder. The table is intended as an aid to grasp the concepts through application of these steps to ABG interpretation. Also note that for the preliminary assessment, the acid–base status is determined before looking at the values for blood oxygenation. TABLE 4-10 Overview of Changes in pH, PaCO2, and HCO3– for Interpretation of Acid–Base Disorders

Description Determining whether compensation is occurring can be challenging because the compensatory response may occur in a nonlinear manner. Additionally, the time lapse between the onset of a primary acid–base disorder and the clinical evaluation may create a problem. Recall that it takes time for the body to fully compensate for a primary acid–base disorder. Lung compensation for a metabolic acid–base disorder occurs fairly quickly, sometimes within minutes. In contrast, renal compensation for a respiratory acid–base disorder can take as long as 3 to 5 days. Therefore, uncertainty about the onset of a respiratory disorder may

complicate the interpretation of renal compensation. Various equations, including those shown in Box 4-2, are used to describe the expected degree of compensation. Clinically, the equations for respiratory compensation are most accurate because the relationship is linear and the equations are less accurate for metabolic compensation. BOX 4-2 Expected Compensation for Acid–Base Disturbances* Renal Compensation for Respiratory Acidosis Predicted [ Predicted [

] = 24 + (PaCO2 – 40) × 0.1 (acute) ] = 24 + (PaCO2 – 40) × 0.35 (chronic)

Renal Compensation for Respiratory Alkalosis Predicted [ Predicted [

] = 24 – (40 – PaCO2) × 0.2 (acute) ] = 24 – (40 – PaCO2) × 0.5 (chronic)

Respiratory Compensation for Metabolic Acidosis Predicted PaCO2 = 1.5 × [

] + 8

Respiratory Compensation for Metabolic Alkalosis Predicted PaCO2 = 0.73 × [

] + 20

* If the acid–base status exceeds the expected level of compensation, a mixed acid–base disturbance is present.

The most accurate method is the confidence band technique, shown in Figure 4-14. If the expected and actual values match, there is no evidence of a mixed disorder (i.e., changes in PaCO2 or HCO3– can be fully explained by the compensatory response). Note that maximal compensation does not return the extracellular pH to normal—which is the main reason why the pH indicated the primary disorder. The compensatory response for an acid–base disorder should be interpreted in the context of the clinical evaluation of the patient’s condition. This clinical assessment should include factors of time, therapies, and the functioning of the pulmonary and renal systems. If the changes in PaCO2 or HCO3– are not adequately explained by the compensatory response, an additional step is needed to determine what kind of second or even third acid–base

disorder may be present. This process can be greatly facilitated by reviewing other clues, some of which are summarized in Table 410. Once a diagnosis of acid–base disorder is made, additional therapies or tests can be used to determine causes.

FIGURE 4-14 Davenport diagram for acid–base disorders. Republished with permission of McGraw-Hill. From Fluid & Electrolytes: Physiology & Pathophysiology. Cogan MG, editor. New York: McGraw-Hill; 1991. Permission conveyed through Copyright Clearance Center, Inc.

Description

Step 7: Are the PaO2 and SaO2 normal, low, or high? Only after correctly interpreting the acid–base status using an ABG should the oxygenation status be interpreted. Looking at the arterial oxygenation PaO2 and SaO2 provides information about the arterial oxygen supply. PaO2 is the partial pressure of oxygen dissolved in arterial blood; its normal range is 80 to 100 mm Hg. SaO2 is the hemoglobin saturation; its normal range is 95% or greater. PaO2 and SaO2 less than the normal values often call for immediate action. Keep in mind that lower oxygen levels are expected at high altitudes, in older people, and in individuals with COPD. PaO2 less than 40 mm Hg constitutes severe hypoxemia; PaO2 between 40 and 59 mm Hg is termed moderate hypoxemia; PaO2 of 60 mm Hg or greater but less than the predicted normal for age is mild hypoxemia; and PaO2 greater than normal is hyperoxemia. The PaO2 should be interpreted relative to FIO2 and, if the patient is mechanically ventilated, the level of positive end-expiratory pressure (PEEP).

Case Studies Case 1. Acute Respiratory Acidosis A 30-year-old unconscious male patient is brought into the emergency room with the following arterial blood gas values when breathing room air: pH 7.27, PaCO2 56 mm Hg, PaO2 70 mm Hg, HCO3– 26 mmol/L, [Na+] 140 mmol/L, [K+] 4 mmol/L, and [Cl–] 105 mmol/L. The following steps should be performed: Step 1: Conduct a physical assessment. The physical examination indicates that the patient is unconscious while breathing room air; he has a slow respiratory rate, bradycardia, and hypotension. Body temperature is normal, and the chest exam is unremarkable. Step 2: Examine the arterial pH. The pH is decreased, so an acidosis is present. Step 3: Assess the PaCO2. The PaCO2 is increased, indicating hypoventilation. Step 4: Assess the HCO3–. The bicarbonate is in normal range. Step 5: Compare the PaCO2 and the HCO3– with the pH to determine the acid–base disorder. Determine whether the acidosis is of respiratory or metabolic origin. Because the PaCO2 is 56 mm Hg and HCO3– is normal, this is a respiratory acidosis. Step 6: Determine whether the PaCO2 and HCO3– are moving in the same or the opposite directions. The PaCO2 is high, but the HCO3– is normal. Thus, this is an acute respiratory acidosis with no compensation or secondary acid–base disorder. Because the patient is young and unconscious, with depressed vital signs, it is reasonable to suspect that his acute respiratory acidosis is due to drug overdose with respiratory center depression. Step 7: Look at the PaO2 and SaO2 to determine the adequacy of oxygenation. The SaO2 is not reported, but we would expect PaO2 > 90 mm Hg in someone 30 years of age breathing room air. This PaO2 indicates hypoxemia. Summarize ABG Interpretation: This patient has an acute respiratory

acidosis with mild hypoxemia. It is not necessary to calculate the anion gap or SID because it is a straightforward case.

Case 2. Partially Compensated Metabolic Acidosis A 55-year-old woman with a known history of diabetes arrives in the emergency department in a coma; she has gasping, deep respirations while breathing room air. ABG analysis shows pH 7.25, PaCO2 20 mm Hg, PaO2 90 mm Hg, HCO3– 10 mmol/L, [Na+] 140 mmol/L, [K+] 4 mmol/L, and [Cl–] 105 mmol/L. Step 1: The physical examination indicates that the patient is unconscious while breathing room air; she has a rapid respiratory rate, deep breathing, tachycardia, and high blood pressure. Body temperature is normal, and the chest exam is unremarkable. Step 2: Examine the arterial pH. The pH is decreased, so an acidosis is present. Step 3: Assess the PaCO2. The PaCO2 is decreased, indicating hyperventilation. Step 4: Assess the HCO3–. The HCO3– is low. Step 5: Compare the PaCO2 and the HCO3– with the pH to determine the acid–base disorder. Determine whether the acidosis is of respiratory or metabolic origin. In this case, the PaCO2 is low and HCO3– is low, which is consistent with metabolic acidosis. Step 6: Determine whether the PaCO2 and HCO3– are moving in the same or the opposite directions. The PaCO2 is low and HCO3– is low, so this is an acute metabolic acidosis with partial compensation. Step 7: Look at the PaO2 and SaO2 to determine the adequacy of oxygenation. The SaO2 is not reported, but a PaO2 greater than 80 mm Hg is expected in someone 55 years old who is breathing room air. This ABG indicates a PaO2 of 90 mm Hg, so there is no hypoxemia. Additional Step: Because this case involves a metabolic acidosis and the electrolytes are available, it would be appropriate to calculate the anion

gap. Anion gap = [Na+] – ([Cl–] + [HCO3–]) = 140 – (105 + 10) = 25 mmol/L This is a high anion gap; the normal AG is 12 ± 4 mmol/L. The anion gap indicates that the metabolic acidosis is due to an increase in unmeasured anions. Summarize ABG Interpretation: This patient has a partially compensated metabolic acidosis without hypoxemia. The patient history, physical examination, and high anion gap indicate increased unmeasured anions, most likely due to ketoacidosis, consistent with diabetic coma.

Case 3. Partially Compensated Respiratory Acidosis A 62-year-old man with ARDS (Acute Respiratory Distress Syndrome) is mechanically ventilated. The ABG analysis shows pH 7.25, PaCO2 70 mm Hg, HCO3– 30 mmol/L, PaO2 58 mm Hg, and SaO2 88%. The FIO2 is 0.8 and the PEEP is 12 cm H2O. Step 1: The physical examination indicates a comatose patient receiving full respiratory support. Bilateral infiltrates are present on the chest x-ray. Step 2: Examine the arterial pH. The pH is decreased, so acidosis is present. Step 3: Assess the PaCO2. The PaCO2 is increased, indicating hypoventilation. Step 4: Assess the HCO3–. The HCO3– is increased. Step 5: Compare the PaCO2 and the HCO3– with the pH to determine the acid–base disorder. Because the PaCO2 and HCO3– are high, the respiratory system is contributing to the acidosis, while the HCO3– indicates less acid or more base. Given the clinical context, this patient likely has respiratory acidosis.

Step 6: Determine whether the PaCO2 and HCO3– are moving in the same or the opposite directions. Both PaCO2 and HCO3– are elevated. This case most likely involves a partially compensated respiratory acidosis. Step 7: Look at the PaO2 and SaO2 to determine the adequacy of oxygenation. Both SaO2 and PaO2 are lower than their normal ranges. The PaO2 is interpreted as moderate hypoxemia. Summarize ABG Interpretation: This patient has a partially compensated respiratory acidosis with moderate hypoxemia when breathing 80% oxygen.

Key Points Arterial blood samples are used to analyze PO2, PCO2, pH, and So2, carboxyhemoglobin, and methemoglobin. Common preanalytic errors include sample contamination with air or heparin and a prolonged time between sample procurement and analysis. Calibration, quality control, and proficiency testing are used to ensure correct blood gas analyzer function. Temperature correction of blood gases is unnecessary. The radial artery is the preferred site for arterial puncture because it is easily accessible and relatively insensitive to pain, and the hand has collateral circulation. Arterial cannulation is performed when frequent arterial blood gas measurements are required. Capillary blood gases may be used to estimate pH and PCO2 in infants or other individuals when arterial blood gas analysis is indicated. The Henderson-Hasselbalch equation suggests the equilibrium that exists between HCO3– and CO2. The modified Henderson-Hasselbalch equation is clinically useful to check for inaccuracies due to blood gas analyzer problems, transcription mistakes, or other errors. It can also help the clinician anticipate how changing one variable will affect the overall acid– base balance. The lungs regulate nonvolatile acid in the form of CO2; the kidneys regulate volatile acids, also called fixed acids, as well as the reabsorption of filtered HCO3–. The anion gap represents the concentration of the unmeasured anions and can be used to determine the general cause of an acid–base disorder. The albumin-corrected anion gap is more accurate in critically ill patients. The strong ion difference is yet another approach to determine unmeasured anions; it is considered even more refined than using the anion gap, though more difficult to calculate.

Point-of-care testing to measure lactate levels is helpful in managing metabolic acidosis. The primary acid–base disturbances are respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis. Combined acid–base disturbances occur when both the lungs and the kidneys contribute to either acidosis or alkalosis. The lungs can compensate for metabolic acid–base disturbances, whereas the kidneys can compensate for respiratory acid–base disturbances.

References 1. Chen K, Puan RB, Price KJ, Koller CA, Nates JL. The role of point-of-care testing in the early diagnosis of pseudo-hypoxemia in myeloproliferative disorders. Respir Care 2010;55(6):777– 779. 2. Jousi M, Saikko S, Nurmi J. Intraosseous blood samples for point-of-care analysis: agreement between intraosseous and arterial analyses. Scand J Trauma Resusc Emerg Med 2017;25(1):92. 3. Boyd M, Woolley T. Point of care testing. Surgery (Oxford) 2016;34(2):91–93. 4. Miles LF, Giraud K, Ferris R, Klein AA, Martinez GC, Jenkins DP, Saulankey K. Evaluation of a novel in‐line point‐of‐care blood gas analyser. Anaesthesia 2016;71(9):1044–1052. 5. Steinfelder-Visscher J, Teerenstra S, Klein Gunnewiek JMT, Weerwind PW. Evaluation of the i-STAT point-of-care analyzer in critically ill adult patients. J Extra Corpor Technol 2008;40(1):57–60. 6. Roels E, Gommeren K, Farnir F, Delvaux F, Billen F, Clercx C. Comparison of 4 point‐of‐care blood gas analyzers for arterial blood gas analysis in healthy dogs and dogs with cardiopulmonary disease. J Vet Emerg Crit Care 2016;26(3):352–359. 7. Knowles TP, Mullin RA, Hunter JA, Douce FH. Effects of syringe material, sample storage time, and temperature on blood gases and oxygen saturation in arterialized human blood samples. Respir Care 2006;51(7):732–736. 8. Charalambous M, Soteriades E, Savvas C, Christou C. TCT-289 Allen test: is it really necessary before transradial catheterization? JAAC 2013;62(Suppl B):B94. 9. Kushimoto S, Yamanouchi S, Endo T, Sato T, Nomura R, Fujita M, et al. Body temperature abnormalities in non-neurological critically ill patients: a review of the literature. J Intensive Care Med 2014;2(1):14. 10. Higgins C. Temperature correction of blood gas and pH measurement: an unresolved controversy. Acutecaretesting.org, 2016:1–7. https://acutecaretesting.org//media/acutecaretesting/files/pdf/temperature-correction-of-blood-gas-and-ph-measurement —an-unresolved-controversy.pdf. Accessed August 5, 2018. 11. Terman S, Nicholas KS, Hume B, Silbergleit R. Clinical practice variability in temperature correction of arterial blood gas measurements and outcomes in hypothermia-treated patients after cardiac arrest. Ther Hypothermia Temp Manag 2015;5(3):135–142. 12. Bacher A. Effects of body temperature on blood gases. Intensive Care Med 2005;31(1):24– 27. 13. Dorwart WV, Chalmers L. Comparison of methods for calculating serum osmolality from chemical concentrations, and the prognostic value of such calculations. Clin Chem 1975;21(2):190–194. 14. Davis JW, Dirks RC, Kaups KL, Tran P. Base deficit is superior to lactate in trauma. Am J Surg 2018;215(4):682–685. 15. Ibrahim I, Chor WP, Chue KM. Is arterial base deficit still a useful prognostic marker in trauma? A systematic review. Am J Emerg Med 2016;34(3):626–635. 16. Ingelfinger JR, Berend K. Diagnostic use of base excess in acid–base disorders. N Engl J Med 2018;378(15):1419–1428. 17. Berend K, de Vries APJ, Gans ROB. Physiological approach to assessment of acid–base disturbances. N Engl J Med 2014;371(15):1434–1445. 18. Spoelstra-de Man A, Smorenberg A, Groeneveld A, Eller K. Different effects of fluid loading with saline, gelatine, hydroxyethyl starch or albumin solutions on acid–base status in the

critically ill. PLoS One 2017;12(4):e0174507. 19. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007;2(1):162–174. 20. Boniatti MM, Cardoso PR, Castilho RK, Vieira SR. Acid–base disorders evaluation in critically ill patients: we can improve our diagnostic ability. Intensive Care Med 2009;35(8):1377–1382. 21. Columbo J. A commentary on albumin in acidosis. Int J Crit Illn Inj Sci 2017;7(1):12–13. 22. Nagaoka D, Nassar Junior AP, Maciel AT, Taniguchi LU, Noritomi DT, Azevedo L, et al. The use of sodium–chloride difference and chloride–sodium ratio as strong ion difference surrogates in the evaluation of metabolic acidosis in critically ill patients. J Crit Care 2010;25(3):525–531. 23. Mallat J, Barrailler S, Lemyze M, Pepy F, Gasan G, Trochon L, et al. Use of sodium–chloride difference and corrected anion gap as surrogates of Stewart variables in critically ill patients. PLoS One 2013;8(2):e510. 24. Glasmacher SA, Stones W. A systematic review and diagnostic test accuracy meta-analysis of the validity of anion gap as a screening tool for hyperlactatemia. BMC Res Notes 2017;10(1):556. 25. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Crit Care Med 1998;26(11):1807–1810. 26. Antonogiannaki E-M, Ioanna Mitrouska I, Vassilis Amargianitakis V, Georgopoulos D. Evaluation of acid–base status in patients admitted to ED: physicochemical vs traditional approaches. Am J Emerg Med 2015;33(3):378–382. 27. Busse L, Chawla L, Panchamia R, Choi D, Nobakht E, Brasha-Mitchell E, et al. Strong ion gap can be accurately estimated with a simple bedside equation. Crit Care 2013;17(Suppl 2):P444. 28. Kotake Y. Unmeasured anions and mortality in critically ill patients in 2016. J Intensive Care 2016;4:45. 29. Singer AJ, Taylor M, LeBlanc D, Williams J, Thode HC. ED bedside point-of-care lactate in patients with suspected sepsis is associated with reduced time to IV fluids and mortality. Am J Emerg Med 2014;32(9):1120–1124. 30. Khan M, Brown N, Mian AI. Point-of-care lactate measurement in resource-poor settings. Arch Dis Child 2016;101(4):297–298. 31. Gattinoni L, Carlesso E. Supporting hemodynamics: what should we target? What treatments should we use? Crit Care 2013;17(Suppl 1):S4.

CHAPTER

5 Blood Chemistries and Hematology Jessie G. Harvey Rajesh Bhagat Neil R. MacIntyre

© Andriy Rabchun/Shutterstock

OUTLINE Serum Electrolytes Serum Chemistries Associated with Renal Function Cardiac Enzymes and Proteins Miscellaneous Serum Chemistries Coagulation Tests Hematology Laboratory Standards and Quality Control

OBJECTIVES 1. 2. 3. 4. 5. 6.

Discuss the physiology of normal fluid and electrolyte balance. List causes of abnormal electrolyte levels. Discuss the effects of renal function on serum chemistry. Discuss the role of serum enzymes in assessing liver and cardiac function. Describe laboratory tests used to assess coagulation. Discuss abnormalities of hemoglobin, platelets, and leukocytes.

KEY TERMS activated partial thromboplastin time (aPTT) anion gap bilirubinemia blood urea nitrogen (BUN) brain natriuretic peptide (BNP) cardiac enzymes C-reactive protein (CRP) creatinine diabetic ketoacidosis extracellular fluid hematocrit hemoglobin hypercalcemia hyperchloremia hyperkalemia hypermagnesemia hypernatremia hyperosmolar hyperphosphatemia hypocalcemia hypochloremia hypokalemia hypomagnesemia hyponatremia hypophosphatemia intracellular fluid lactate leukocytes leukocytosis leukopenia oncotic pressure platelets procalcitonin proteins prothrombin time (PT) serum electrolytes troponin

Introduction Circulating blood is composed of water, proteins, electrolytes, and cells. The fluid left after removing the cells from blood is plasma. When both cells and coagulation proteins are removed from blood, the leftover fluid is serum. The water component of blood moves across both tissue barriers and cell membranes, depending on hydrostatic and oncotic pressures (osmotic pressure exerted by colloids in a solution—for example, serum proteins in intravascular blood). By comparison, protein and electrolyte movements into and from blood vessels often depend on complex tissue or cell membrane pumps. Blood cells generally remain within the blood vessels except under conditions of blood vessel injury or inflammation. Measuring the chemical and cellular properties of blood can yield considerable information about disease states. These measurements often express concentrations of a substance. Some, however, measure a functional property, such as coagulation activity or osmotic pressure. This chapter covers the common measurements performed on blood samples from patients. For each measurement, the discussion includes a review of the physiologic (and pathophysiologic) importance of the blood substance or property, followed by a brief review of commonly used measurement techniques. Diagnoses that should be considered in the event of an abnormal value also are reviewed.

Serum Electrolytes Body Water In the average person, approximately 60% of total body weight is water.1,2 Two-thirds of that water is in the intracellular compartment (i.e., within cells) and one-third is in the extracellular compartment (i.e., interstitium and blood, which make up 75% and 25%, respectively, of this compartment). The compartments are separated by cell membranes that set up active and passive forces regulating water, electrolyte, and solute movement, with resulting electrolyte concentration gradients and oncotic pressures. The most common serum electrolytes are the cations Na+, K+, Ca+2, and Mg+2 and the anions HCO3–, PO4–, and SO4–. Extracellular fluid is characterized by higher amounts of Na+, Cl–, and HCO3–, whereas intracellular fluid has higher amounts of K+, Mg+2, PO4–, and SO4–. These cations and anions are regulated in the compartments over a narrow normal range. Mechanical, inflammatory, and other pathologic processes frequently affect the integrity of these compartments, leading to consequent movement of electrolytes, proteins, and water. A change in body or compartment level of one substance often triggers a sequence of compensatory events in the body to maintain fluid homeostasis. Initial assessment of the overall water volume status is critical in any evaluation of a patient’s fluid and electrolyte status. No single test precisely quantifies total body water (TBW) easily in the clinical setting. Instead, clinicians rely on history taking and physical examination. The intent is to decide whether the patient is hypovolemic, euvolemic, or hypervolemic with respect to TBW (Box 5-1). BOX 5-1 Assessment Tools Used to Evaluate Total Body Water Decreased total body water (hypovolemia) is associated with the following: Symptoms: Thirst, decreased urine output, dizziness on standing. Signs: Thready, rapid pulse, low blood pressure, orthostatic hypotension, decreased skin turgor, sunken eyes, depressed fontanelle in infants, dry mucous membranes; also associated with muscle tremors, rigidity, seizures and rarely with hallucinations, delirium, and manic behavior.

Laboratory data: Elevated hematocrit (if hypovolemia is not due to blood loss), sodium (hypernatremia), and protein levels. Urine is concentrated, and urine potassium loss (kaliuresis) is seen, associated with decreased serum potassium levels. Increased total body water (hypervolemia) is associated with the following: Symptoms: Weight gain, loss of diurnal rhythm of diuresis, dyspnea, orthopnea. Signs: Pedal edema, elevated jugular venous pressure, wheezing, crackles, ascites. Laboratory data: Are not characteristic but may show serum hyponatremia (dilutional) and hypoproteinemia.

Respiratory Recap Body Water ∎ Approximately 60% of total body weight is water. ∎ Two-thirds of body water is in the intracellular space. ∎ One-third of body water is in the extracellular space.

Sodium The sodium cation (Na+) is the most common electrolyte in extracellular fluid, and its normal serum values range from 135 to 145 mmol/L.2–9 Na+ is important for a variety of cell membrane functions and in determinations of serum osmotic pressure. In the hypovolemic patient with normal total body Na+ content, the relationship between Na+ and TBW allows for calculation of the free water deficit, as follows:

This formula is useful in calculations of the appropriate amount of free water to be administered in patients with water-deficit states. The

relationship between Na+ and TBW also can be used to predict the change in serum Na+ after administration of various intravenous fluids, as follows:

The physiologic effects of Na+ depend on its concentration in extracellular water.8 If the serum sample contains significant amounts of substances that expand serum volume but not blood volume, the measured serum [Na+] will appear low even though the water concentration is normal (pseudohyponatremia or isotonic hyponatremia). This state reflects a reduction of the fraction of serum that is water and an artificially low serum sodium concentration. Substances that expand serum volume but not blood volume include isotonic mannitol, proteins, and lipids.4,5 Hypertonic hyponatremia results from shifts of fluid from the extracellular space to the intracellular space, with these shifts being driven by osmotically active substances, such as glucose, hypertonic mannitol, and the toxins methanol and ethylene glycol.9 To assess for this condition, osmolality can be measured directly and compared with an estimated value, as follows:

where BUN is blood urea nitrogen. If the measured osmolality is within 20 mOsm/kg of the estimated serum osmolality (i.e., there is no osmolar gap), the Na+ value reflects the true value and rules out the presence of unmeasured substances. Normal serum osmolality is 285 – 295 mOsm/kg. Decreased serum Na+ levels are associated with water moving osmotically within cells and creating a significant change in the

relationship between intracellular and extracellular fluid compartments. This shift is associated with weakness, lethargy, muscle cramps, anorexia, nausea, vomiting, headache, confusion, delirium, stupor, seizures, and coma. Because the relationship between Na+ and fluid is so intertwined, a useful practice is to divide the causes of hyponatremia into hypovolemic, euvolemic, and hypervolemic categories. This classification depends on the estimation of TBW by physical examination and the response of the kidney in moving Na+ into the urine (Box 5-2). BOX 5-2 Classification of Hyponatremia Hypovolemic Hyponatremia Total body sodium deficit higher than TBW deficit Renal loss (urine sodium > 20 mmol/L) Diuresis: osmotic or diuretic excess Mineralocorticoid deficiency Extrarenal loss (urine sodium < 10 mmol/L) Vomiting Diarrhea Fluid movement into the third space*

Euvolemic Hyponatremia Increased TBW undetectable by clinical evaluation Syndrome of inappropriate ADH secretion: malignancy (paraneoplastic syndrome), drugs, CNS lesions Hypothyroidism Immediate postoperative period (first 24 hours) Glucocorticoid deficiency Polydipsia: psychogenic, beer potomania

Hypervolemic Hyponatremia Dilutional: TBW increase greater than total body sodium Congestive heart failure Nephrotic syndrome Cirrhosis Acute and chronic renal failure * Extracellular space is sometimes grouped into three volumes: (1) plasma volume, (2) interstitial fluid volume, and (3) various actual or potential cavities such as the pleural space, peritoneal space, and gut lumen. ADH, antidiuretic hormone; CNS, central nervous system; TBW, total body water.

Both low-Na+ (hyponatremia) and high-Na+ (hypernatremia) conditions are evident in a number of disease states and demonstrate important clinical manifestations. A clinically increased serum [Na+] (hypernatremia) is of concern because it suggests dehydration. In contrast, increased total body sodium levels are seen in patients with hypervolemic hyponatremia; however, their serum sodium levels are diluted because of excess water. Hypernatremia is associated with increased serum osmolality, and its clinical features are the same as those associated with water loss. Box 5-3 lists the causes of hypernatremia. BOX 5-3 Causes of Hypernatremia Water Loss Greater Than Sodium Loss Osmotic and loop diuretics Post obstructive nephropathy Sweating Diarrhea and fistulas

Pure Water Loss Diabetes insipidus: central, peripheral, and combination Excessive sweating: exercise, fever, and hot environment

Increase in Total Body Sodium Primary hyperaldosteronism Cushing syndrome Hypertonic sodium bicarbonate administration in situations such as cardiac arrest

Laboratory techniques used to estimate sodium concentration include flame atomic emission spectroscopy, ion-selective electrode (ISE) potentiometry (direct and indirect), the chromogenic ionophore technique, and enzymatic (or enzyme activation) methods. ISE (either direct or indirect) is the most commonly used method. The direct ISE method has the advantage that hyperproteinemic and hyperlipidemic states do not affect accuracy. A potential source of error is protein buildup on membrane surfaces of the measuring electrode.

Potassium

Approximately 90% of total body potassium (K+) is found in the intracellular space.9–13 K+ homeostasis is regulated by acid–base status, insulin, catecholamines, and aldosterone. Alkalosis and elevated insulin, catecholamine, and aldosterone levels lower serum K+ through either renal excretion or intracellular potassium shifting. In contrast, acidosis and reduced insulin, catecholamine, and aldosterone levels raise serum potassium levels. K+ is essential for maintenance of the electrical membrane potential; thus, changes in serum K+ levels affect neuromuscular activity as well as cardiac electrical impulses. The normal serum range for this ion is 3.5 to 5.5 mmol/L. Serum K+ levels below normal (hypokalemia; Box 5-4) affect neuromuscular function, causing muscular weakness, malaise, fatigue, and myalgias. Severe K+ depletion has been associated with paralysis and rhabdomyolysis. Life-threatening cardiac arrhythmias with electrocardiogram (ECG) changes (U waves, QT prolongation, T wave changes) are commonly associated with severe hypokalemia. Other common manifestations include paresthesia, abdominal cramps, and ileus. Spuriously reduced potassium levels, known as pseudohypokalemia, may accompany markedly elevated white blood cell (WBC) counts, as in cases of leukemia. Prompt laboratory processing of the sample can help prevent such results. Hypokalemia may be associated with hypomagnesemia. BOX 5-4 Causes of Hypokalemia Increased loss of potassium GI losses: vomiting, especially with pyloric obstruction; villous adenoma of colon; diarrhea; non-β islet cell tumor of pancreas Renal losses: diuretics, such as thiazides and loop diuretics; renal tubular acidosis I and II; hyperaldosteronism; ureteroenterostomy Intracellular shift of potassium: insulin, testosterone, β2 agonists, respiratory and metabolic alkalosis, hypokalemic periodic paralysis Decreased intake: malnutrition, alcoholism, and anorexia nervosa Miscellaneous: magnesium depletion, Bartter syndrome, Liddle syndrome, licorice abuse

Serum K+ levels above normal (hyperkalemia; Box 5-5) produce hyporeflexia and muscle weakness. Although paralysis can arise in cases of severe hyperkalemia, death due to cardiac arrhythmias usually occurs first. On the ECG, peaked T waves, widened QRS, and eventually sine

waves develop before the appearance of actual cardiac arrest. Falsely elevated K+ levels, known as pseudohyperkalemia,13 may be seen when the blood sample is hemolyzed or the WBC or platelet count is unusually elevated. Elevated serum potassium levels are frequently encountered in patients with renal disease or failure. BOX 5-5 Causes of Hyperkalemia Increased intake or tissue release, especially in the face of compromised renal function: tumor lysis syndrome, rhabdomyolysis, hemolysis, blood transfusion Drugs: potassium-sparing diuretics, cyclosporin, trimethoprim, angiotensin-converting enzyme (ACE) inhibitors, heparin, nonsteroidal anti-inflammatory drugs (NSAIDs) Renal causes: acute and chronic renal failure, type IV renal tubular acidosis, pseudohypoaldosteronism Aldosterone deficiency: Addison disease, hereditary adrenal enzyme defects

Techniques used to estimate potassium levels include flame atomic emission spectroscopy, ISE (direct and indirect), chromogenic ionophore, and enzymatic (enzyme activation). ISE is the most frequently used technique. Stop and Think A 60-year-old male smoker has come for a scheduled outpatient bronchoscopic exam for a right upper lobe mass. His pulse is 60 beats/min, and his blood pressure is 120/80 mm Hg. The chest and cardiovascular exam are essentially normal. The patient does not have pedal edema. His [Na+] is 130 mEq/L. The remainder of the laboratory tests are normal. What is the cause of low sodium?

Chloride Chloride (Cl–) is the most common anion in the extracellular space.2–9,13 Usually, changes in serum Cl– follow changes in serum sodium levels. Exceptions are hyperchloremic (elevated serum Cl–) acidosis14 and chloride-responsive, hypochloremic (reduced serum Cl–) alkaloses. Although hypochloremia in experimental situations is associated with vasoconstriction and increased reactivity to norepinephrine (especially in cerebral vessels), clinically important isolated chloride changes are

almost never seen. Normal Cl– levels are 98 to 107 mmol/L in the serum and 110 to 250 mmol/L in the urine. The presence of other halides may affect the estimation of Cl–; in particular, erroneously high Cl– values (hyperchloremia) may be found when bromide is present in the sample. Four laboratory methods are used to estimate Cl– levels: a colorimetric method (mercuric/ferric thiocyanate), coulometric titration, ISE, and an enzymatic method. ISE methods are the most commonly used.

Total Serum Carbon Dioxide Serum contains carbon dioxide in the form of dissolved carbon dioxide (CO2), carbon dioxide loosely bound to the amine group of plasma proteins, bicarbonate anion (HCO3–), carbonate anion (CO3–2), and carbonic acid.15,16 Serum carbon dioxide acts as one of the major buffering systems to control the acid–base milieu of the body. The normal range is 22 to 32 mmol/L. The Henderson-Hasselbalch equation describes the relationship of dissolved CO2, pH, and HCO3–. Methods used to estimate total serum CO2 include gas release, pH indicator, carbon dioxide electrodes, enzymatic methods, and calculation from the acid–base estimation. The most commonly used methods include the ISE and colorimetric methods. Steps to ensure the accuracy of results include anaerobic handling of the sample. Most autoanalyzers permit immediate analysis of the sample. However, if the sample is left uncapped, the total CO2 levels can decrease by 6 mmol/L/hour.

Unmeasured Anions Anionic proteins and other substances (Box 5-6) also can exist in serum.15 Generally, these are not measured in routine serum electrolyte determinations. However, their presence can be suspected by calculation of the anion gap, as follows: BOX 5-6 Unmeasured Anions Lactate (liver disease, tissue hypoxia)

Ketones (diabetic and alcoholic ketoacidosis) Salicylates (toxic ingestion) and Uremic acidosis Glycolate and oxalate Ethylene glycol Free fatty acids Methyl malonate

Anion gap = ([Na+] + [K+]) – ([CO2] + [Cl–]) If the anion gap exceeds 12 mmol/L, excessive unmeasured anions are likely present. Because its concentration is normally low, [K+] often is omitted from this calculation. Stop and Think A 72-year-old male with history of hypertension and end-stage renal disease (treated with hemodialysis) is admitted to the hospital with pneumonia. You are about to start his nebulizer treatment with albuterol. You notice on the bedside cardiac monitor that his heart rate is 50 beats/min, the T waves look tall, and the QRS complexes are wider than what they were with the nebulizer treatment you gave 4 hours earlier. Which electrolyte abnormality do you need to think about?

Calcium Calcium (Ca+2) has multiple functions in the body.9,17,18 Besides being a major structural substance in bone, it plays an important role in maintaining cellular conduction in the neuromuscular system. Ca+2 is also an important participant or catalyst in several metabolic cascades (e.g., the coagulation pathways). This ion is mainly absorbed in the bowel and excreted in the urine. Bones serve as a major calcium reservoir. The important Ca+2 regulators are vitamin D, calcitonin, phosphate, and parathyroid hormone. In general, vitamin D and parathyroid hormone increase Ca+2 levels, whereas calcitonin and phosphate reduce them. In serum, most Ca+2 is bound to albumin. As a consequence, measured Ca+2 levels are sensitive to the factors regulating or affecting serum protein levels (especially albumin). Because unbound (i.e., ionized) calcium is the metabolically important entity, measured total

serum Ca+2 should be corrected for albumin concentration (i.e., a reduction in Ca+2 level of 0.8 mg/dL for every gram per deciliter of albumin below normal). Ionized calcium also can be measured directly. In adults, normal total serum Ca+2 levels are 8.6 to 10.0 mg/dL (2.15 to 2.50 mmol/L), whereas normal ionized Ca+2 levels are 4.6 to 5.3 mg/dL (1.16 to 1.32 mmol/L). A low ionized calcium level (hypocalcemia) is usually due to either decreased absorption or decreased mobilization of calcium from the bones. Causes may include malnutrition, parathyroid hormone activity, vitamin D abnormalities, certain drugs, and renal dysfunction (which produces hyperphosphatemia). Pancreatitis, massive blood transfusions, and tumor lysis syndrome can precipitate Ca+2, thereby reducing serum levels. Low Ca+2 levels frequently coexist with low magnesium levels, especially in malnourished individuals with alcoholism. Alkalosis can disrupt calcium ion balance and cause the symptoms of hypocalcemia. Clinical features of hypocalcemia consist of perioral numbness and tingling progressing to tetany. Physical examination evidence of proteinenergy malnutrition, previous parathyroidectomy, pancreatitis, and tumor lysis syndrome should increase the suspicion for reduced Ca+2 levels. Increases in Ca+2 levels (hypercalcemia) are caused by multiple factors (Box 5-7). The clinical features of hypercalcemia include anorexia, vomiting, polyuria, mental confusion, obtundation, and death. The ECG may show a shortened QT interval. BOX 5-7 Causes of Hypercalcemia Abnormal Protein Syndromes Multiple myeloma and paraproteinemias

Increased Parathyroid Hormone or Related Peptides Malignancy of lung or kidney (due to paraneoplastic syndrome or osteolytic bone metastases)

Increased Absorption Usually vitamin D related (milk alkali syndrome), granulomatous diseases (such as tuberculosis and sarcoidosis), lymphoma

Excessive Renal Phosphate Excretion Familial syndrome, sarcoidosis

Abnormal Bone Resorption or Formation

Prolonged bed rest, Paget disease

Laboratory tests used to measure serum Ca+2 include atomic absorption, cresolphthalein complex formation, arsenazo III dye, and ISE methods to estimate ionic calcium levels. Autoanalyzers frequently use ISE methods. Atomic absorption remains the gold standard for measuring calcium, although this test is rarely used in the clinical setting.

Magnesium Magnesium (Mg+2) is the other major cation in the serum (besides Ca+2) that helps maintain cellular membrane potentials.9,19 Mg+2 is also important in maintaining potassium homeostasis through regulation of cell membrane potassium channels. Only 1% to 2% of total body Mg+2 is present in the serum, and one-third of this amount is bound to proteins. Mg+2 is mainly absorbed in the small bowel (mostly in the initial parts) and is excreted by the kidneys. In adults, the normal serum Mg+2 range is 1.8 to 3.0 mg/mL (0.7 to 1.1 mmol/L). Box 5-8 lists causes of low Mg+2 levels (hypomagnesemia). Low levels often are associated with hypokalemia. Indeed, concurrent hypomagnesemia and hypokalemia make it difficult to correct the potassium levels until the Mg+2 levels are corrected. Hypomagnesemia is also associated with hyponatremia, hypocalcemia, and +2 hypophosphatemia. Low Mg levels result in tremulousness, hyperreflexia, ataxia, convulsions, and death in extreme cases. BOX 5-8 Causes of Hypomagnesemia Absorption Problems Malnutrition per se or due to alcoholism, diarrhea, intravenous alimentation, intestinal bypass surgery Psychological problems: bulimia, laxative abuse, or aggressive weight reduction Others: short bowel syndrome or malignancies, especially in the bowel

Excessive Loss in Urine Use and abuse of diuretics, postobstructive diuresis, acute tubular necrosis, hypercalcemia, and hereditary renal magnesium wasting

Miscellaneous

Association with hyperaldosteronism, diabetic ketoacidosis, and excessive lactation Exchange transfusions Acute intermittent porphyria

Hypomagnesemia-induced cardiac dysrhythmias originating in the atria or the ventricles can be fatal. In patients with rapid polymorphic ventricular tachycardia (torsades de pointes), intravenous magnesium infusion can be lifesaving. Hypertension in patients with hypomagnesemia can be difficult to control. Hypomagnesemic dysmotility in gastrointestinal muscles is clinically manifested as dysphagia. High Mg+2 levels (hypermagnesemia) are uncommon but can be seen in patients with renal failure, especially those undergoing inappropriate dialysis or alimentation regimens. Another cause of hypermagnesemia is abuse of magnesium-based laxatives. In addition, hypermagnesemia is sometimes induced to treat eclampsia. This condition’s clinical manifestations include hyporeflexia, muscle weakness, hypotension, bradycardia, coma, and death. Laboratory methods used to estimate serum levels of Mg+2 include colorimetric methods using calmagite, methyl thymol, or chlorophosphonazo III; ISE methods; and atomic absorption. Although atomic absorption remains the gold standard, ISE methods are increasingly being used to estimate serum Mg+2 levels.

Phosphorus More than 80% of total body phosphorus is found in the bones.9,20 The phosphate ion (PO4–) is a major intracellular anion, which participates primarily as a cofactor in intracellular metabolic processes. Extracellular phosphate salts function as buffers and play a role in calcium homeostasis. (i.e., serum PO4– and Ca+2 exist in a reciprocal, balanced relationship). PO4– is absorbed through the gastrointestinal tract (vitamin D dependent) and excreted through the kidneys (enhanced by parathyroid hormone). In adults, normal serum PO4– levels range from 2.7 to 4.5 mg/dL (0.87 to 1.45 mmol/L). Low PO4– (hypophosphatemia) levels are primarily caused by decreased absorption, intracellular shifts, or increased excretion (Box 5-

9). Severe stress causing glucagon and cortisol release may be responsible for the low serum PO4– levels seen in trauma patients. Clinical features of hypophosphatemia include decreased contractility of muscles causing cardiomyopathy, hyporeflexia, and hypoventilation. If severe, this condition can lead to rhabdomyolysis. Hypophosphatemia also can produce confusion, seizures, and coma. Chronic deficiency can cause osteomalacia. BOX 5-9 Causes of Hypophosphatemia Decreased Absorption Malnutrition, alcohol abuse, vitamin D deficiency, laxative abuse, and antacid abuse

Intracellular Shift High-energy states and parenteral nutrition with carbohydrate overload

Increased Excretion Hyperparathyroidism, diuretics, hyperglycemia, and alcohol abuse

High PO4– levels (hyperphosphatemia) are unusual but can be seen in individuals with chronic renal failure, in which the hyperphosphatemia is often overshadowed by other metabolic and electrolyte abnormalities. Other conditions producing hyperphosphatemia include hypoparathyroidism (with low calcium levels also being seen), pseudohypoparathyroidism, and Paget disease of the juvenile, which is characterized by muscle weakness and high alkaline phosphatase levels. To estimate serum PO4– levels, ammonium phosphomolybdate complex levels are read directly by an ultraviolet monitor, or the complex is reduced to molybdenum and its levels estimated.

Lactate An increase in lactate is caused by either increased production as a result of anaerobic metabolism or reduced degradation of lactate as a result of problems in the liver.21,22 Lactate most commonly forms in ischemic cells as a consequence of anaerobic glycolysis and the use of pyruvate to generate adenosine triphosphate (ATP). Thus, its

measurement is frequently used to indicate the severity of shock and provides a rough idea of tissue perfusion, oxygen delivery, and oxygen use. For individuals in shock, increased lactate is associated with increased mortality. Increased lactate is also seen in patients with bowel ischemia. An elevated serum lactate level is an important cause of anion gap metabolic acidosis. Lactate has both D and L isomers. Humans normally produce L-lactic acidosis, which most laboratories easily estimate. Theoretically, D-lactate (normally produced by ruminants and bacteria) can be elevated in certain types of individuals (e.g., those with bowel abnormalities). Currently D-lactic acidosis is a research curiosity, with rare cases involving humans. Normal lactate in adults is less than 2 mmol/L. Methods used to estimate lactate include chemical oxidation, enzyme reactions, and enzyme electrodes. Other methods involve gas chromatography and photometry. Thus, the introduction of enzyme electrodes has made estimation of serum lactate levels much simpler. Because lactate is unstable, samples should be processed immediately. Lactate increases by 0.4 mmol/L in whole blood kept at room temperature for 30 minutes (0.1 mmol/L on ice). Respiratory Recap Serum Electrolytes ∎ Sodium ∎ Potassium ∎ Chloride ∎ Total carbon dioxide ∎ Unmeasured anions ∎ Calcium ∎ Magnesium ∎ Phosphorus ∎ Lactate

Stop and Think An 85-year-old female was admitted last night with pain in the abdomen. After she complains of shortness of breath, you are called to give her a nebulizer treatment. On arrival, you see

the patient is lying still, afraid to move, and pale. She complains to you about increasing pain in her abdomen. You observe that her respiratory rate is 32 breaths/min (on admission, the respiratory rate was 20 breaths/min) and she is using accessory muscles. On auscultation, her lung sounds are normal without rhonchi or crackles. You suspect she has a metabolic acidosis. What is the most likely cause of this patient’s increased respiratory rate?

Serum Chemistries Associated with Renal Function Good urine production (quantitative as well as qualitative) is a marker of end organ perfusion as well as renal function.23 The most important tests of renal function are the quantity of urine produced and the characteristics of that urine (i.e., pH, specific gravity, microscopic analysis, and culture). However, two other measurements are frequently used to assess renal function: the serum blood urea nitrogen (BUN) and creatinine levels.

Blood Urea Nitrogen Serum blood urea nitrogen (BUN) levels indicate the body’s ability to clear nitrogenous wastes in the form of urea in the urine. Urea (along with ammonia) is a breakdown product of amino acids. Thus, it can be increased by increases in gastrointestinal protein absorption from either dietary factors or heme in the bowels (i.e., gastrointestinal bleeding). Similarly, urea levels can be decreased with decreases in protein intake or liver impairment. Urea is readily filtered in the glomeruli, but approximately half of it is reabsorbed. It is also broken down into ammonia in the bowel. Thus, levels of BUN reflect protein intake and metabolism, as well as glomerular and proximal tubule function in the kidney. In the adult, normal BUN is between 7 and 21 mg/dL. BUN is estimated from serum urea levels. Almost all the tests used— calorimetric methods, indicator dye, and ISE methods—directly or indirectly estimate the amount of ammonia present in the sample.

Creatinine Serum creatinine levels are a function of skeletal muscle breakdown. Thus, the levels are directly related to the muscle mass of a person. Most creatinine is filtered in the glomeruli, with very little reabsorption. A small amount also is secreted by the tubules into the urine. Thus, if the

individual’s muscle mass is relatively stable, serum creatinine level is a good indicator of glomerular filtration and, hence, renal function. Increased creatinine levels, however, also can occur in conjunction with increased muscle breakdown (e.g., corticosteroids, rhabdomyolysis) or decreased tubular excretion, such as that seen with use of trimethoprim. Decreased creatinine levels reflect decreased muscle mass, such as that associated with malnutrition or muscle atrophy. In the adult, normal values for creatinine are 0.7 to 1.4 mg/dL. The serum creatinine level is a relatively insensitive monitor of renal function and may not increase until more than 50% of renal function has deteriorated. With complete renal shutdown, creatinine levels rise approximately 1 mg/dL per day (anephric rise). Creatinine levels also can be used to calculate creatinine clearance (the amount of blood per minute cleared of creatinine by the kidney), a more precise measurement of renal function, as follows:

A simpler method used to estimate creatinine clearance is as follows:

Normal creatinine clearance is 97 to 137 mL/min (for men) and 88 to 128 mL/min (for women). Creatinine clearance decreases 6.5 mL/min per decade after 40 years of age. Estimation of creatinine is done by spectrophotometric analysis of the Jaffe reaction, enzymatic hydrolysis of creatinine, and cation-exchange high-performance liquid chromatography. Respiratory Recap

Laboratory Tests Associated with Renal Function ∎ Urine analysis ∎ Blood urea nitrogen ∎ Creatinine

Serum Enzyme Activity Enzymes are chemical substances that facilitate chemical reactions. Although most enzymatic reactions occur intracellularly, some enzymes appear in serum under physiologic conditions. In pathologic conditions, many enzymes appear in serum in increased concentrations because of either cell injury or metabolic abnormalities within the cell. A number of serum enzymes reflect liver function24 but also may indicate dysfunction elsewhere. Alanine aminotransferase (ALT) is present in liver cells, so an increased serum level of this enzyme indicates liver cell injury. Aspartate aminotransferase (AST) is present not only in liver cells but also in cardiac, skeletal, kidney, and brain tissue. Serum alkaline phosphatase (ALP) comes from either liver or bone. Elevation of liver ALP indicates intrahepatic or collecting system bile drainage abnormalities (cholestasis). Elevated γ-glutamyl transferase (GGT) serum levels also indicate cholestasis. Thus, an elevated GGT in conjunction with an elevated ALP suggests a liver or biliary abnormality. An AST:ALT ratio greater than 2 suggests alcoholic liver injury. Lactic dehydrogenase (LDH) enzymes are a family of enzymes in which elevations can reflect liver, bone, cardiac, red blood cell, or pancreatic abnormalities. LDH assays can be fractionated (isoenzymes) to indicate the organ involved if required. Amylase and lipase are two enzymes whose levels become elevated as a consequence of pancreatic injury.25 Both may be elevated in individuals with other gastrointestinal abnormalities as well. In addition, pancreatic disease caused by biliary tract disease usually induces liverassociated abnormalities in the serum.

Cardiac Enzymes and Proteins Cardiac Enzymes The term cardiac enzymes refers to a group of enzymes that are released from myocardial tissue and appear in the serum as a result of myocardial injury (usually ischemia).26,27 As the understanding of cardiac ischemia has changed, so has the use of various enzymes to estimate cardiac muscle damage. Nevertheless, cardiac enzyme abnormalities remain a standard criterion used to diagnose cardiac ischemia, in conjunction with history and ECG changes. The initial panel of cardiac enzymes included serum lactate dehydrogenase (LDH), serum glutamic– oxaloacetic transaminase (SGOT), and creatine kinase (CK). Although the myocardial-specific creatine kinase MB isoform (CK-MB) was originally used for diagnosing myocardial injury, more recently serum troponin levels have become the standard of care. CK-MB levels begin rising within 4 to 8 hours of myocardial injury, with peak activity occurring by 24 hours. CK-MB levels return to baseline within 2 to 3 days. Methods used to estimate CK include electrophoresis, ion-exchange chromatography, immunoinhibitors, and mass assay (specific for CKMB). Normal total serum CK is 15 to 130 U/L, and CK-MB typically accounts for less than 6% of the total CK. Potential sources of error in measurements of CK are hemolysis, exposure of sample to daylight, and the muscle mass of the patient (either too large or too small).

Troponins Serum troponins are cardiac regulatory proteins that are involved in the calcium-mediated interaction of actin and myosin in the cardiac muscle. Many centers are now measuring the cardiac troponin I or T isoform for diagnosing myocardial injury. Cardiac troponins begin to rise 2 to 3 hours following an acute myocardial injury, peak by about 14 to 20 hours, and return to baseline within 5 to 10 days. Unfortunately, nonuniformity in the measurement of troponins has made the comparison of values from various laboratories difficult. CK, CK-MB, troponin I, and troponin T are estimated by different methods. Rapid assays of these enzymes are very

helpful in the quick triaging of patients with suspected acute coronary syndrome. In patients with renal failure and rhabdomyolysis, reduced clearance from the serum or increased production, or both, make interpretation of the increased serum levels of these proteins difficult. In the future, other proteins and enzymes, such as fatty acid–binding protein (FABP) and glycogen phosphorylase isoenzyme (BB), may also prove useful for diagnosing myocardial injury. Methods for troponin estimation, enzyme-linked immunosorbent assay (ELISA), immunoenzyme techniques, and rapid immunochromatographic assays are available. Troponins are usually undetectable in healthy persons.

Brain Natriuretic Peptide Brain natriuretic peptide (BNP), also known as B-type natriuretic peptide, is a natriuretic hormone similar to atrial natriuretic peptide (ANP). BNP’s physiologic actions include increasing natriuresis (excretion of sodium through urine) and decreasing systemic vascular resistance and central venous pressure. These actions lead to decreased cardiac output and blood volume. In humans, the cardiac ventricles serve as the major source of BNP. The N-terminal part of the propeptide of BNP (NT-ProBNP) is an active metabolite of BNP. BNP has a shorter half-life than NT-ProBNP (15–20 minutes versus 90 minutes, respectively). Thus, BNP may more closely relate to rapid neurohormonal and hemodynamic changes after acute coronary syndrome. However, when elevated, NT-ProBNP has a higher circulating concentration, is more stable, and has less biological variability. Both elevated serum BNP and NT-ProBNP levels help to differentiate dyspnea due to heart failure from pulmonary disease; these peptides become elevated with both systolic and diastolic heart failure. Measurement of BNP is also useful to guide therapy for and prognostication of heart failure, acute coronary syndrome, and stable angina. BNP levels tend to be higher in people with renal failure and in older people, and lower in obese people and in women. Most dyspneic patients with heart failure have values greater than 400 pg/mL, whereas values less than 100 pg/mL have a very high negative predictive value for heart failure as a cause of dyspnea.28 Recombinant BNP (nesiritide) is

also used for the treatment of acute decompensated congestive heart failure. BNP and NT-ProBNP are measured by ELISA and chemiluminescent immunometric assay, respectively. Kits are commercially available. Respiratory Recap Cardiac Injury Markers ∎ Cardiac enzymes (CK-MB) ∎ Troponins T and I ∎ Brain natriuretic peptide

Stop and Think A 68-year-old male is admitted with shortness of breath. Auscultation reveals bilateral basilar crackles and pedal edema in both legs. Blood tests show a troponin I level of 5.3, BNP level of 780, and normal renal function. What is the most likely cause of this patient’s shortness of breath?

Miscellaneous Serum Chemistries C-Reactive Protein C-reactive protein (CRP) was first recognized by its ability to precipitate in the presence of the somatic C polysaccharide of Pneumococcus.29 CRP is a nonspecific marker of acute inflammation produced by the liver and adipocytes. CRP levels are elevated in infections and several chronic diseases, including cancer; rheumatologic diseases such as lupus, rheumatoid arthritis, and giant cell arteritis; inflammatory bowel disease; and osteomyelitis. Recent data suggest that elevation of CRP from baseline within the normal range as well as CRP levels above normal are predictive of risk for myocardial infarction, stroke, peripheral vascular disease, and sudden cardiac death. The availability of high-sensitivity CRP (hs-CRP) measurement techniques has helped to reduce variation and provide reproducible CRP measurements. CRP values for early risk stratification should be checked in conjunction with serum troponins as soon as possible after a patient presents with acute coronary syndrome to limit the influence of the extent of necrosis. For assessment of long-term risk, CRP values should be assessed at least 4 to 6 weeks after a myocardial infarction to allow for resolution of the acute phase reaction. Several different ELISA-based assays are available for measuring CRP. All have their own characteristics and reproducibility issues. Ultrasensitive microchip-based systems to measure CRP in other body fluids remain under investigation.

Bilirubin Bilirubin is a breakdown product of hemoglobin that is metabolized in the liver. The total serum bilirubin concentration is less than 1.1 mg/dL,24 approximately 80% of which is indirect or unconjugated. Elevation of indirect bilirubin levels suggests prehepatic bilirubinemia caused by increased bilirubin production (e.g., hemolysis) or decreased liver uptake, as seen in Gilbert syndrome. Parenchymal liver injury and bile collecting system abnormalities (i.e., posthepatic lesions) cause bile stasis

(cholestasis) and lead to an increase in direct, or conjugated, bilirubin levels.

Proteins Serum proteins include albumin, ferritin, globulins, and immunoglobulins.4,30,31 Serum albumin is exclusively synthesized in the liver. Its half-life is approximately 3 weeks, and it can be used as a marker of liver synthetic function. This protein also is a useful marker of nutritional status. Ferritin is an iron-binding protein that is most commonly elevated in iron overload. Other causes of elevated ferritin include infection or inflammation, as it is an acute-phase reactant; liver disease; and hemophagocytic lymphohistiocytosis (HLH). Serum globulins are mediators of the humoral immune system. Elevations of these proteins can be seen in individuals with tumors secreting these globulins (e.g., multiple myeloma) and other paraproteinemias. Low values are seen in individuals with various congenital immune deficiency states.

Glucose Glucose metabolism is heavily influenced by a number of nutritional, liver, hormonal, and pancreatic factors.32 Glucagon and adrenal steroids increase glucose concentrations by promoting liver breakdown of stored glycogen. Insulin is produced by islet cells in the pancreas and plays a critical role in the transfer of glucose into cells. Pancreatic injury or islet cell dysfunction (type 1 diabetes) impairs insulin production and results in serum hyperglycemia. If severe, this condition can produce diabetic ketoacidosis. Severe hyperglycemia also can cause a hyperosmolar state with coma. In addition, type 2 diabetes (cellular resistance to insulin) can produce hyperglycemia and deranged glucose metabolism. In contrast, insulin-secreting tumors or exogenous insulin overdoses lead to hypoglycemia. Severe liver injury also can produce hypoglycemia because of a depletion or failure to metabolize liver glycogen; if severe, this hypoglycemia can bring about coma and death.

Procalcitonin Serum procalcitonin levels might be a more useful marker for distinguishing bacterial infections from aseptic inflammation than the erythrocyte sedimentation rate (ESR) or CRP. Procalcitonin is a precursor protein of the hormone calcitonin and is produced in C cells of the thyroid gland. It is released during infections by microbial toxins or indirectly by humoral factors or the cell-mediated host response. This induction occurs to a lesser extent in viral or other inflammatory conditions. The reference value of procalcitonin is 0.15 ng/mL or less. Data suggest that serum procalcitonin levels may be used as guidance when assessing the need for as well as the duration of antibiotic therapy. This has the potential to safely reduce the number of antibiotic prescriptions and the duration of antibiotic use in patients. Various studies have reported varying sensitivity and specificity for procalcitonin in diagnosing bacteremia; for example, a meta-analysis reported a sensitivity of 76% and a specificity of 69%.33 Rapid semiquantitative strip-based and quantitative luminometric immunoassays are being developed to measure serum procalcitonin levels. Higher levels indicate the need for a higher level of care and possibly poor outcomes. Soluble triggering receptors expressed on myeloid cells–1 (sTREM-1) also are under investigation as a marker of infections.

Coagulation Tests The coagulation system (Figure 5-1) can be assessed in a number of ways.34,35 A simple and direct way to evaluate overall coagulation status is the bedside bleeding time. However, this method is time consuming and difficult to standardize. More commonly used techniques include measurements of the prothrombin time, activated partial thromboplastin time, and platelet count.

FIGURE 5-1 A simplified version of the role of various clotting factors in the coagulation cascade. Reproduced from Cecil Textbook of Medicine. 21st ed. Goldman L, Bennett JC. Copyright Elsevier (WB Saunders) 2001.

Description

Prothrombin Time

The prothrombin time (PT) is used to evaluate the extrinsic pathway, which involves tissue factor, factor VII, and coagulation factors found in the common pathway (prothrombin, V, X, and fibrinogen) (refer to Figure 5-1). It often is used to monitor adequate anticoagulation in patients on warfarin, which acts on these factors. The result is usually expressed as either a time or a ratio of the values with respect to normal pooled sera. To standardize PT monitoring for oral anticoagulation therapy, PT is expressed as an international normalized ratio (INR). The goals of warfarin therapy are to increase the INR to 2–3. However, in specific conditions, such as in patients with mechanical prosthetic heart valves, INR must be increased further. The prolonged PT in emergent situations can be reversed by fresh frozen plasma transfusion or administration of unactivated prothrombin complex concentrates. In less urgent situations, vitamin K can be used for reversal. PT can be prolonged in vitamin K deficiency; liver disease; deficiency or inhibition of factors VII, X, II, V, or fibrinogen; and in the presence of antiphospholipid antibodies and sometimes heparin treatment, especially after bolus administration of heparin. Direct oral anticoagulants such as rivaroxaban and apixaban can also prolong the PT. In the presence of severe, acute liver injury, the PT may rapidly (i.e., within 24 hours) become abnormal. Vitamin K absorption is also impaired in the presence of hepatocellular disease and cholestasis, contributing to the abnormal PT.

Activated Partial Thromboplastin Time The activated partial thromboplastin time (aPTT) is used to assess the intrinsic clotting pathway, especially the early stages involving factors XII, XI, IX, and VIII (refer to Figure 5-1). Measurement of aPTT is often used to monitor patients on heparin therapy. The goals of heparin therapy are to extend the aPTT to approximately twice the upper level of normal. In individuals not on anticoagulant therapy, abnormal PT or aPTT values indicate abnormalities in the coagulation system, possibly reflecting liver disorders, hematologic disorders, toxins or drugs, or disseminated intravascular coagulation (DIC) associated with a multiorgan failure. Further workup might include a number of specific clotting factor assays to identify the exact abnormality. Adding normal clotting factors to the test

sample can help determine whether a coagulation abnormality is due to factor deficiency (coagulation normalizing with mix) or a circulating factor inhibitor (coagulation not normalizing with mix). In the clinical setting, prolonged aPTT is frequently seen in patients on intravenous heparin or dabigatran therapy. Heparin is an indirect thrombin inhibitor that complexes with antithrombin (AT) and converts it into a rapid inactivator of thrombin, factor Xa, and to a lesser extent factors XIIa, XIa, and IXa. The goal of heparin therapy is to elevate the aPTT to 1.5 times the upper limit of normal range within 24 hours. The goal of maintenance therapy is to maintain the aPTT in the range of 1.5 to 2.5 times the patient’s baseline aPTT value. Heparin-related prolonged PTT corrects itself in about 2 hours after stopping IV heparin. Protamine may be used if emergent reversal is indicated. Activated PTT can be prolonged due to a deficiency of, or an inhibitor to, any of the clotting factors except factor VII. Certain lupus anticoagulants can cause aPTT prolongation by interfering with in vitro assembly of the prothrombinase complex. This also causes a paradoxical increased risk of venous and arterial thrombus.

Thrombin Time The thrombin time measures the final step of the clotting pathway—that is, the conversion of fibrinogen to fibrin. Thrombin time can be prolonged in the presence of heparin, a direct thrombin inhibitor such as hirudin or argatroban, fibrin degradation products, and hypofibrinogenemia. To ensure they are at therapeutic levels, the most commonly used anticoagulants—heparin, low-molecular-weight heparin (LMWH) and warfarin—can be monitored by PTT, antifactor Xa activity, and PT, respectively. The efficacy of traditional anticoagulants is well established, but they have several limitations, including a need for laboratory monitoring, a narrow therapeutic window, and a need for dose adjustment throughout the course of treatment. Recently approved direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, betrixaban, darexaban) have a minimal need for monitoring, but no specific antidote is available for their rapid reversal in case of emergencies. We also lack data on their long-term safety. Use of these agents should be avoided in pregnancy, in patients with mechanical valves, and in patients with

severe renal impairment. Respiratory Recap Coagulation Studies ∎ Prothrombin time (PT) ∎ Activated partial thromboplastin time (aPTT) ∎ Thrombin time ∎ Traditional anticoagulants and newer oral anticoagulants

Hematology The complete blood count (CBC) is the most frequently ordered diagnostic test in the hospital. The heading of CBC encompasses a long list of indices that varies among laboratories. Automated machines usually directly measure hemoglobin, WBC count, RBC count, platelet count, differential leukocyte fractions, and RBC distribution list, as well as calculate the hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and differential leukocyte count.

Hemoglobin and Hematocrit Hemoglobin is an iron-containing globular protein composed of two pairs of polypeptides.36,37 Its primary function is the transport of oxygen from the lungs to the tissues. Each 1 g of hemoglobin binds with 1.34 mL of oxygen. Normal values for hemoglobin in the adult are 13.5 to 15.5 g/dL for men and 12.5 to 14.5 g/dL for women. Hematocrit is the proportion of whole blood composed of RBCs (the hemoglobin-carrying cell). Normal hematocrit values in the adult are 42% to 52% for men and 37% to 48% for women. Box 5-10 lists causes of abnormal hemoglobin and hematocrit levels. High hemoglobin levels are associated with chronic hypoxemia and hematologic diseases, such as polycythemia vera. High hemoglobin or hematocrit values, or both, also may be seen in individuals with dehydration and hemoconcentration. BOX 5-10 Causes of Low Hemoglobin and Hematocrit Values Abnormal Hemoglobin Iron in the ferric form: methemoglobinemia Abnormalities in the polypeptide chain: hemoglobinopathies, such as thalassemia and sickle cell disease

Decreased Hemoglobin Production Bone marrow problems: aplastic anemia, myelosuppressive drugs, idiosyncratic reaction to drugs, infiltration of bone marrow by other cells

Deficiencies: iron, vitamin B12 cofactors, erythropoietin Miscellaneous: malignancy, chronic diseases, hypothyroidism, hypopituitarism

Increased Loss or Breakdown of RBCs Fault in the RBCs: membrane defects, enzymatic deficiencies, hemoglobin disorders Acquired causes of hemolysis: drugs, toxins, infections Hypersplenism Bleeding, alveolar hemorrhage RBC, red blood cell.

Estimation of hemoglobin levels and types of hemoglobin is done by electrophoresis (alkaline or acid), other tests used to estimate abnormal hemoglobin (e.g., solubility test for sickle cell disease), and autoanalyzers. Stop and Think A 25-year-old female with lupus is admitted for shortness of breath. Her chest x-ray is suggestive of bilateral pneumonia. The patient is scheduled for bronchoscopic exam. You notice her hematocrit, which is normally approximately 35, is down to 25; her procalcitonin is less than 0.05; and her PTT is prolonged at 58 seconds. The patient is not on any anticoagulation. What is the most likely diagnosis? What is the cause of her prolonged PTT? What is the reason for her drop in hematocrit?

Platelets Platelets are blood cells critical to clot formation after vascular injury.38 They are produced in the bone marrow, and their normal blood concentration ranges from 150,000 to 400,000 per milliliter of blood. Box 5-11 lists abnormalities in platelet function. BOX 5-11 Abnormalities in Platelet Function Thrombasthenia Abnormal platelet function with uremia von Willebrand disease Drugs

Thrombocytopenia (Decreased Platelet Count) Bone marrow problems: malignancies, drugs, myelodysplasias

Increased breakdown: structural platelet defects, immune problems (heparin-induced thrombocytopenia) Hypersplenism

Thrombocytosis (Increased Platelet Count) Essential or idiopathic After splenectomy Acute blood loss Pregnancy

Total and Differential Leukocyte Count The primary role of leukocytes (WBCs) is in fighting infections, and an elevated WBC count (leukocytosis) is often a sign of significant infection.39–41 Leukocytosis, however, also can be associated with elevated glucocorticoids (e.g., stress reaction, steroid administration) and with several types of hematologic malignancies (Box 5-12). A marked elevation in WBC count, like that seen in patients with leukemia, may interfere with the interpretation of arterial blood gas values. A low WBC count (leukopenia) is invariably a bad sign in any disease process, especially in infections, in which it often indicates overwhelming infection (Box 5-13). The differential percentage of various WBCs in the peripheral smear helps identify the disease process. Once the percentage of different cells is known, the absolute numbers can be calculated from the total WBC counts. Normal WBC counts in adults range from 4000 to 11,000 per milliliter of blood. BOX 5-12 Causes of Leukocytosis Physiologic Exercise Pregnancy Stress: pain, psychological, cold exposure, anesthesia, anoxia Trauma, hemorrhage Menstruation, pregnancy, and labor Seizure

Pathologic Infections: bacterial, fungal, viral, and parasitic Leukemoid reaction due to any of the previous causes Leukemias: uncontrolled malignant proliferation of any of the WBCs in the bone marrow

WBC, white blood cell.

BOX 5-13 Causes of Leukopenia Overwhelming infection, especially in the very young or very elderly Drug actions and adverse events Malignant involvement of the bone marrow Collagen vascular diseases such as lupus (infrequent cause) Idiopathic or not-well-understood disease processes, such as myelodysplastic syndromes

Leukocytes are classified into two groups: granulocytes and agranulocytes. The granulocytes (neutrophils, eosinophils, and basophils) have granules in their cell cytoplasm and a multilobed nucleus. They also are called polymorphonuclear leukocytes or polys. The agranuloctyes (lymphocytes and monocytes) do not have granules and have a nonlobular nucleus. When immature leukocytes are first released from the bone marrow into the peripheral blood, they are called bands or stabs. The normal differential for leukocyte count is: Bands or stabs: 3–5% Neutrophils: 50–70% relative value Eosinophils: 1–3% relative value Basophils: 0.4–1% relative value Lymphocytes: 25–35% relative value Monocytes: 4–6% relative value The differential always adds up to 100%. Most laboratories have automated instruments that use either resistance changes or flow characteristics to estimate the cell count and size of the cells. To enhance the accuracy of the results, RBCs are usually destroyed by chemicals in the blood sample before the WBC counts are performed. Currently, this process relies on flow-through techniques using electrical resistance (or flow) changes or cytometry alone or in combination with cytochemical techniques. The sophistication of the instrument depends on whether it provides a three-, five-, or sixpart differential. Ideally, the false-negative rate varies from 2% to 4%, with a false-positive rate of 8% to 15%. Falsely elevated WBC counts may be seen in individuals with undestroyed nucleated RBCs or large or

aggregated platelets. Falsely low numbers may be seen in individuals with leukoagglutination; abnormal cells, such as blasts; immature granulocytes; and atypical lymphocytes. Further limitations in WBC measurement include an inability to separate mature polymorphonuclear cells from band forms. In patients with marked leukocytosis, thrombocytosis, and, very rarely, reticulocytosis, bloodstream oxygen saturation of the hemoglobin as measured by a pulse oximeter (SpO2) may be substantially higher than SaO2 or PaO2 measured by arterial gas analysis—a condition known as pseudohypoxemia or factitious hypoxemia. Possible mechanisms for this phenomenon are rapid consumption of the oxygen dissolved in plasma or coating of the sensing electrode by a large number of active cells. Various methods of overcoming or minimizing this problem have been reported. Inexpensive methods include running the sample without delay (continuous arterial blood sampling), placing the sample immediately on ice, or precooling the syringes. More expensive strategies include adding potassium cyanide or sodium fluoride and using plasma instead of whole blood for arterial blood analysis. Autoanalyzers for CBC using spectrophotometric methods, electric impedance techniques, or light-scattering phenomena can provide reliable numbers for all the parameters in the majority of samples. Results may be compromised in the presence of hyperlipidemia, cryoproteinemia, agglutination of various cells (e.g., RBCs, WBCs, platelets), and abnormally shaped and sized cells (e.g., schistocytes, sickled cells). Atypical features are usually flagged by the machine and must be assessed by a visual review of the smear. Respiratory Recap Hematology ∎ Hemoglobin and hematocrit ∎ Platelets ∎ Leukocytes

Laboratory Standards and Quality Control An enormous amount of clinical information can be derived from an examination of blood chemistries and hematology.42–45 Indiscriminate or routine ordering of these tests should be discouraged, however, because such practices consume resources unnecessarily, cause potential harm from false-positive or false-negative results, and waste patient blood. Indeed, one of the most important causes of anemia in patients in the ICU is repeated blood drawing. The clinical relevance and significance of results are a composite product of not only the appropriateness of the test request but also patient sample identification, criteria for sample acceptance, and running of the tests by appropriate standardized methods followed by communication and interpretation of results. Point-of-care testing (POCT) has made that task even more difficult. All hematology and blood chemistry testing procedures must be standardized to ensure optimal accuracy and precision. To this end, in 1988 the U.S. federal government established published standards under the Clinical Laboratory Improvement Amendment (CLIA). Other organizations, such as the College of American Pathologists (CAP) and The Joint Commission (TJC), also have published certification standards for laboratories. All laboratories must adhere to these standards, not only to ensure quality care but also to ensure appropriate reimbursement. POCT has become increasingly popular over the past few decades as a way for clinical staff (non-laboratorians) to perform a diagnostic test at the point of patient contact (i.e., at the bedside), as opposed to samples being analyzed in a central or core clinical laboratory staffed by certified (in some states registered) laboratory technicians. In addition to more rapid turnaround times, POCT devices offer the ability to use smaller samples of blood or even to return the blood to the patient after testing. This results in improved patient and provider satisfaction. Another benefit is cost savings as a result of faster diagnoses and a reduction in costly patient complications. POCT has expanded to include technological advances in healthcare including smartphone applications. Despite the benefits of POCT, limitations on its use exist. The same quality standards mandated for central laboratories are sometimes not

applied to these devices. In addition, results, particularly values at the extreme ends of the range, may not be consistent with those obtained in the central laboratory. This can lead to confusion and may negatively impact patients. For example, the i-STAT troponin POCT device has the potential to diagnose acute coronary syndrome (ACS) more quickly than traditional methods. However, it remains a subject of debate, as studies have shown that the POCT results are often lower than the central laboratory results for troponin I. More studies are needed to determine whether cutoffs for the i-STAT troponin can be lowered to achieve a similar diagnostic accuracy. Regardless of the device used, the limitations of various methods must be kept in mind. Interpretation of values requires knowledge of other medical conditions that may affect the numbers. Indeed, an appropriate first step in the assessment of an unexpected abnormality might be to simply repeat the test. Laboratory tests can provide significant information that drives clinical decision making. The clinician assessing the results should fully appreciate both the significance of the results and the potential errors that might exist.

Key Points Two-thirds of body water is intracellular. Sodium is the most common electrolyte in extracellular fluid. Hyponatremia and hypernatremia are associated with a number of disease states. Potassium is found primarily in the intracellular space. Changes in serum potassium concentrations affect neuromuscular activity and cardiac electrical impulses. Changes in serum chloride concentrations usually follow changes in serum sodium concentrations. Unmeasured anions are estimated through calculation of the anion gap. Most calcium is bound to albumin, but only ionized calcium is metabolically important. Magnesium plays an important role in maintaining the membrane potential. Phosphorus is a major intracellular anion that participates in many metabolic processes. Increased lactate concentrations are usually due to anaerobic metabolism. Blood urea nitrogen and serum creatinine levels are used to assess renal function. Serum enzyme levels are used to assess liver and cardiac function. Bilirubin is a breakdown product of hemoglobin that is metabolized in the liver. A low serum albumin level is a marker of impaired synthesis or losses of albumin. Hyperglycemia and hypoglycemia result from derangements in glucose metabolism. Brain natriuretic peptide levels are elevated in patients with congestive heart failure. Elevated serum C-reactive protein levels are a marker for nonspecific inflammation. High-sensitivity CRP is used to monitor patients with coronary artery disease.

Serum procalcitonin levels are currently used to distinguish inflammation caused by septic bacterial and fungal sources from viral infections and noninfectious conditions. Prolonged prothrombin time and activated partial thromboplastin time are indicative of problems in blood coagulation. Reduced hemoglobin and hematocrit values are seen in anemia. Reduced platelet counts indicate problems in clot formation, which can be a problem in patients undergoing bronchoscopic biopsy or arterial blood gas testing. Reduced leukocytes suggest an immunocompromised state. A moderate elevation of the leukocyte count is seen in infections or steroid treatment and a marked elevation in leukemia and leukemoid reactions.

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25. Matull WR, Pereira SP, O’Donohue JW. Biochemical markers of acute pancreatitis. J Clin Pathol 2006;59(4):340–344. 26. Braunwald E, Morrow DA. Unstable angina: is it time for a requiem? Circulation 2013;127(24):2452–2457. 27. Apple FS, Wu AHB, Mair J, Ravkilde J, Panteghini M, Tate J, et al. Future biomarkers for detection of ischemia and risk stratification of acute coronary syndrome. Clin Chem 2005;51(5):810–824. 28. Clerico A, Fontana M, Zyw L, Passino C, Emdin M. Comparison of the diagnostic accuracy of brain natriuretic peptide (BNP) and the N-terminal part of the propeptide of BNP in chronic and acute heart failure: a systematic review. Clin Chem 2007;53(5):813–822. 29. Kao PC, Sheish S-C, Wu T-J. Serum C-reactive protein as a marker for wellness assessment. Ann Clin Lab Sci 2006;36(2):163–169. 30. Anderson LN, Anderson NG. The human plasma proteome: character and diagnostic prospects. Mol Cell Proteomics 2002;1(11):845–867. 31. Anderson LN. The clinical plasma proteome: a survey of clinical assays for proteins in plasma and serum. Clin Chem 2010;56(2):177–185. 32. Fayfman M, Pasquel FJ, Umpierrez PJ. Management of hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Med Clin North Am 2017;101(3):587– 606. 33. Hoeboer SH, van der Geest PJ, Nieboer D, Groeneveld AB. The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis. Clin Microbiol Infect 2015;21(5):474–481. 34. Tachil J. Relevance of clotting tests in liver disease. Postgrad Med J 2008;84(990):177–181. 35. Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health-Syst Pharm 2012;69(17):1473– 1484. 36. Sihler KC, Napolitano NM. Anemia of inflammation in critically ill patients. J Intensive Care Med 2008;23(5):295–302. 37. Green R, Wachsmann-Hogui S. Development, history and future of automated cell counters. Clin Lab Med 2015;35:11–24. 38. Riedl J, Ay C, Pabinger I. Platelets and hemophilia: a review of literature. Thromb Res 2017;155(1):131–139. 39. Dalal BI, Brigden ML. Factitious biochemical measurements resulting from hematologic conditions. Am J Clin Path 2009;131(2):195–204. 40. George TI. Malignant or benign leukocytosis. Hematology Am Soc Hematol Educ Program 2012;2012:475–484. 41. Cerny J, Rosemarin AJ. Why does my patient have leukocytosis? Haematol Oncol Clin North Am 2012;26(2):303–319. 42. Shahangian S, Snyder SR. Laboratory medicine quality indicators. Am J Clin Path 2009;131(3):418–431. 43. Sumita NM, Ferreira CS, Martino MD, Ponsonby AL, Allen KJ, Vuillermin PJ, et al. Clinical applications of point-of-care testing in different conditions. Clin Lab 2018;64(16–17):1105– 1112. 44. Wiencek J, Nichols J. Issues in the practical implementation of POCT: overcoming challenges. Expert Rev Mol Diagn 2016;16(4):415–422. 45. Sardi AR, Lamoureux JA, Cohn TM, Phillip-Samuel SG. Point-of-care testing of troponin levels compared with automated laboratory evaluation: a reliability study. Crit Care Nurs Q 2016;39(4):345–351.

CHAPTER

6 Cardiac Assessment Jaspal Singh William E. Downey

© Andriy Rabchun/Shutterstock

OUTLINE Evaluation of Ventricular Function Valvular Function Coronary Artery Disease Arrhythmias Refractory Hypoxemia

OBJECTIVES 1. Compare the similarity of symptoms and the interaction between the respiratory and cardiovascular systems. 2. Compare systolic and diastolic dysfunction. 3. Describe tests of cardiac function, their use in clinical practice, and their advantages and disadvantages. 4. Describe tests used to assess left ventricular function and right ventricular function. 5. Describe tests used to evaluate valvular function. 6. Discuss tests to evaluate coronary circulation. 7. Interpret common arrhythmias. 8. Describe intracardiac shunts. 9. Integrate cardiac evaluation into the assessment of the patient with cardiopulmonary

disease.

KEY TERMS afterload angina bubble echocardiogram cardiac catheterization cardiac output cor pulmonale diastolic dysfunction echocardiography ejection fraction (EF) electrocardiogram (ECG) ischemia myocardial perfusion imaging pulmonary hypertension radionuclide angiocardiography stress test stroke volume systolic dysfunction transesophageal echocardiography (TEE) valvular heart disease valvular regurgitation valvular stenosis ventriculography

Introduction Diseases of the respiratory and cardiovascular systems interact in terms of their pathophysiology, symptoms, treatment, and prognosis. Although primary diseases of either organ system may not involve the other, a significant interaction is more common. This interaction between the respiratory and cardiovascular systems often confounds the diagnosis of the primary problem and complicates its management. Understanding the basics of cardiac function, pathology, and evaluation is important for the respiratory therapist in numerous respects, some of which are described in this chapter.

Evaluation of Ventricular Function Case 1. Congestive Heart Failure A 50-year-old man comes to the emergency department with several days of worsening shortness of breath. He has a history of hypertension, diabetes, and high cholesterol. Vital signs show hypertension, hypoxia, and respiratory distress but no fever. On examination, the patient is obese and has an elevated jugular venous pressure (JVP), S3 gallop, crackles in his lung bases, and prominent bilateral leg swelling. His chest x-ray shows pulmonary edema, and his electrocardiogram (ECG) shows no signs of acute myocardial infarction (MI), although signs of chronic ischemic heart disease are evident. His brain natriuretic peptide (BNP) level is abnormally high. This patient may have dyspnea for several reasons, but the clinical clues in this case are derived from the history and physical examination, with supportive information from the chest x-ray and ECG. All these clues suggest that the patient has acute congestive heart failure (CHF). He has risk factors for heart disease (obesity, diabetes, hypertension, high cholesterol), and the examination demonstrates physical findings of leftsided heart failure (S3 gallop, crackles in the lung bases) as well as right heart failure (leg edema). The absence of fever helps to exclude an active infectious process such as pneumonia, and additional supportive information can be gleaned from the chest x-ray, ECG, and perhaps other laboratory tests. Elevated BNP, or B-type natriuretic peptide, levels can be used as a diagnostic tool to evaluate for cardiac dysfunction as a cause of dyspnea and correlate with the presence and severity of cardiac diseases such as CHF.1 Although an elevated BNP does not give insight into the cause of the dysfunction and its interpretation can be confounded for a number of reasons, it might suggest that the patient’s symptoms stem from cardiac disease. The ECG also points away from an active MI or other diagnosis complicating this picture. At this point, it would be very helpful to understand the patient’s cardiac physiology (especially left ventricular function). A transthoracic echocardiogram can be used to evaluate this

quickly and noninvasively and would provide the greatest amount of functional and prognostic information.

Left Ventricular Dysfunction The primary symptom of patients with left ventricular dysfunction is dyspnea, but additional symptoms of CHF, such as orthopnea or paroxysmal nocturnal dyspnea, may suggest that the primary cause of dyspnea is ventricular dysfunction rather than a pulmonary disorder. The initial diagnostic step used to evaluate patients with symptoms of ventricular dysfunction is to determine whether systolic dysfunction (impaired contractility) or diastolic dysfunction (impaired filling) is the major pathophysiologic mechanism. Symptoms of CHF—for example, dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea—can occur with both systolic and diastolic dysfunction as well as with valvular heart disease without any myocardial dysfunction. Although the history and physical examination can assist the clinician in differentiating cardiac causes from respiratory causes of dyspnea, it may be more difficult to determine whether CHF is due to systolic or diastolic dysfunction or valvular disease without an imaging study of left ventricular function. Moreover, many patients have simultaneous systolic and diastolic heart failure with or without valvular heart disease. Echocardiography uses ultrasonography to examine the heart structures and function. Because of its portability and noninvasiveness (safety), it is often the primary test used in the assessment of cardiac structure and function. Echocardiography provides information on the ejection fraction (EF), which is the fraction of blood pumped from the ventricle during a single cardiac contraction. The normal left ventricular ejection fraction is more than 0.50 (50%). The ejection fraction is easily obtained and reproducible, and it serves as an important prognostic factor in critical illness (Figure 6-1).

FIGURE 6-1 Echocardiogram demonstrating (A) end-diastole and (B) end-systole, with normal contractility of all regions of the myocardium.

In addition to assessing overall function, echocardiography allows for more detailed assessment of cardiac structure and function. A regional wall motion abnormality suggests ischemia as the cause of left ventricular systolic dysfunction. In contrast, nonischemic cardiomyopathies usually affect all segments of the myocardium equally (a global process). Moreover, different features of echocardiography (e.g., M-mode, Doppler modes) support more sophisticated assessment of cardiac structure and function. Cardiac catheterization techniques include other methods used to evaluate ventricular function. Cardiac output (often expressed in liters per minute) reflects forward blood flow from the heart into the systemic vasculature and provides an overall assessment of cardiovascular function. It is often calculated utilizing either the Fick method or thermodilution after placing a catheter into the pulmonary artery; recently, less invasive technologies to calculate cardiac output have become more popular though their utility remains unclear. Because numerous assumptions are involved in validating the calculation of cardiac output with these methods, measurements must be interpreted in light of other clinical data. Other tests evaluating left ventricular function include radionuclide angiocardiography, cardiac magnetic resonance imaging (cardiac MRI),

and catheter ventriculography. Radionuclide tests involve intravenous injection of a radioisotope (most commonly technetium) and the use of a camera to detect the isotope’s signal in the left ventricle; this approach measures the ejection fraction. Cardiac MRI provides detailed anatomic and functional information; it is now the accepted standard for assessment of ventricular function. Nevertheless, its use in critical illness remains limited by the patient monitoring available during the study and need for breath holding to obtain optimal images. Catheter ventriculography involves injection of radiographic contrast into a cardiac chamber and consequent assessment of that chamber’s size and motion. This technology is rarely used as the sole means to assess cardiac function as the same information can be obtained noninvasively. However, when the patient is undergoing cardiac catheterization for other reasons, it can be a useful adjunctive assessment. Respiratory Recap Tests to Assess Cardiac Function ∎ Echocardiography ∎ Electrocardiography ∎ Brain natriuretic peptide elevation ∎ Radionuclide angiocardiography ∎ Cardiac output monitoring devices ∎ Left ventriculography by cardiac catheterization ∎ Cardiac magnetic resonance imaging

Case 2. Right Ventricular Failure A 53-year-old woman presents with worsening shortness of breath and leg swelling after a long plane ride. She has a history of chronic obstructive pulmonary disease (COPD) that was previously well controlled. Vital signs show moderate hypoxemia, tachycardia, and tachypnea. On examination, the patient is obese and has a prominent right ventricular heave, diminished lung sounds throughout, and prominent bilateral leg swelling. Her chest x-ray is clear, and a subsequent ECG stress test is unremarkable but was stopped short due

to her dyspnea. A computed tomography (CT) scan of the chest with intravenous contrast shows bilateral pulmonary emboli (Figure 6-2).

FIGURE 6-2 Bilateral pulmonary emboli.

The clinicians are trying to decide whether to administer thrombolytic therapy, which is more likely to rapidly dissolve the clot than systemic heparin anticoagulation. Because thrombolytic therapy is associated with a higher risk of bleeding complications, it often is reserved for patients with cardiac dysfunction due to the embolism—generally those patients with right ventricular compromise or shock.2 Echocardiography can be used to evaluate the right ventricle as well as left ventricular size and function. If a pulmonary embolus is large, it may cause strain on the right heart, manifested as dilation or hypokinesis of the right ventricle. In this

patient, the echocardiogram demonstrated elevated right ventricular systolic pressures and evidence of strain. Based on this information, the patient received thrombolytic therapy, which resolved the clot quickly without further complications. Stop and Think You are providing respiratory care for a patient with COPD and known cardiac disease. What tests might be used to sort out the relative contributions of right-sided and left-sided heart failure?

Right Ventricular Function Evaluation of pulmonary artery pressures and right ventricular function is important to determine the severity of impact on the heart of pulmonary disease. For example, patients with severe COPD or severe obstructive sleep apnea may demonstrate elevated pulmonary artery pressure, resulting in hypertrophy and dilation of the right ventricle, a condition known as cor pulmonale. A finding of pulmonary hypertension with chronic respiratory disease (such as COPD) suggests a poor prognosis.3 Findings of peripheral edema, elevated JVP, hepatomegaly, and ascites in patients with lung disease suggest right ventricular dysfunction, or right-sided heart failure. The right ventricle is a thin-walled structure that normally ejects blood into the low resistance of the pulmonary vasculature. Because of its lower muscle mass, it is very sensitive to an acute increase in afterload (pulmonary artery pressure). When subject to an abrupt increase in afterload, right ventricular systolic dysfunction may develop. If pulmonary hypertension develops more slowly, the right ventricle may adapt by the process of hypertrophy so that the right ventricular ejection fraction remains normal at rest but may decrease during exercise because of an increase in pulmonary artery pressure. If cardiac output does not increase during exercise, the patient may develop dyspnea. If the pulmonary artery pressure increases over time, further elevation of the right ventricular systolic pressure, and subsequently diastolic pressure, occurs. The elevation in right ventricular diastolic filling pressure results in the signs of right-sided CHF, such as

jugular venous distention, lower-extremity edema, hepatomegaly, and ascites. Echocardiography provides valuable information about global right ventricular function. In addition to quantitative assessment of right ventricular function and qualitative assessment of right ventricular size and wall thickness, Doppler echocardiography can be used to estimate the pulmonary artery systolic pressure and suggest whether right ventricular dysfunction is caused by pressure overload or volume overload. Right heart catheterization with a pulmonary artery catheter is used to assess right heart dysfunction and measure cardiac output. Although right heart catheterization is a much more accurate means of measuring right ventricular and pulmonary artery pressures compared to echocardiography,3 it is invasive. As such, this procedure not only exposes the patient to greater risk but also may be difficult to perform in a patient who has acute issues. Evidence suggests that right heart catheterization is associated with poorer clinical outcomes in critically ill patients, and its use has fallen out of favor when less invasive methods are available.4 Respiratory Recap Tests to Evaluate Right Ventricular Function ∎ Echocardiography ∎ Electrocardiogram ∎ Right heart catheterization (i.e., pulmonary artery catheterization)

Valvular Function Case 3. Valvular Disease A 26-year-old man comes to the emergency department with 1 day of severe shortness of breath and high fever. He is in respiratory distress, hypoxemic, and unable to provide a history. On examination, he is thin, is hypotensive, and has a loud, harsh systolic murmur best heard underneath his left nipple. In addition, bilateral crackles are heard on pulmonary examination. Further inspection shows needle track marks indicating intravenous drug use. The chest x-ray shows pulmonary edema but no discrete infiltrate suggestive of pneumonia. ECG is normal except for sinus tachycardia. The patient is intubated and placed on mechanical ventilation. Lab results show a markedly elevated white blood cell (WBC) count. Blood cultures are drawn, and the patient is started on intravenous antibiotics. Mitral valve endocarditis (a life-threatening infection of the mitral valve) is suspected. Several factors may explain this patient’s dyspnea, but the clinical clues in this case are derived from the history and physical examination, with supportive information from the chest x-ray. These assessments lead the clinician to suspect the patient has endocarditis. The high fever and elevated WBC count indicate the presence of an acute infectious process. The ensuing hypotension, loud apical murmur, and pulmonary edema represent the most salient clues to the diagnosis of endocarditis. The chest x-ray and the murmur point away from community-acquired pneumonia as the etiology, whereas the ECG also points away from an active MI and excludes an arrhythmia. In this case, the patient’s mitral valve has become infected and thereby damaged, causing leakage of the valve during each systolic contraction. This leak results in elevated left atrial pressure and subsequently elevated pulmonary venous pressure, causing pulmonary edema and dyspnea. Because a significant proportion of the left ventricular output is then directed backward into the left atrium, hypotension may result from decreased cardiac output. The optimal confirmatory test in this case is an echocardiogram, which may be performed via a transthoracic approach (simpler, noninvasive, but lower

resolution of the valve) or a transesophageal approach (more invasive but much more sensitive to valvular pathology).

Evaluation of Valvular Function Both acquired and congenital heart disease may affect valvular function. Figure 6-3 shows the normal valvular anatomy. Hemodynamically, valvular heart disease can be differentiated into two types: stenotic lesions resulting in impaired valve opening and regurgitant lesions caused by impaired valve closure. Both may be present concurrently.

FIGURE 6-3 Normal cardiac valve anatomy.

Description Normally, the valve opens when the pressure in the proximal chamber of the heart exceeds the pressure in the distal chamber. Although the pressure difference (gradient) is responsible for opening the valve and blood flow across the valve, the normal valve gradient remains minimal as blood flows between chambers of the heart. When disease causes narrowing of the valve orifice, a greater pressure difference between the

chambers of the heart that are separated by the stenotic valve is required to sustain flow. Stenotic valvular lesions therefore result in pressure overload of the proximal or upstream heart chamber, eventually resulting in the symptoms and signs of heart failure. The severity of valvular stenosis is determined by measuring the pressure gradient across the valve. The pressure gradient reflects not only the severity of the stenosis but also the rate of blood flow across the valve. This gradient is then combined mathematically with the measured flow across the valve to calculate the valve area. Valve area measurements have been correlated with severity of disease for leftsided valvular lesions (mitral and aortic stenosis), but the clinical application of valve areas is less clear for the right-sided heart valves; therefore, pressure gradients alone are used to express the severity of stenosis on the right side. Because different chambers have different normal pressures, significant gradients differ from valve to valve. Severe aortic valve stenosis is defined as a mean gradient >40 mm Hg. Severe mitral stenosis is defined as a mean gradient >10 mm Hg. Severe pulmonic stenosis is defined as a peak gradient >64 mm Hg and tricuspid stenosis as a peak gradient >5 mm Hg. Valvular regurgitation is caused by abnormal or impaired valve closure. Normally, when pressure in the downstream chamber exceeds pressure in the upstream chamber, the leaflets of the interceding valve close and coapt to prevent regurgitation of blood flow into the proximal chamber. Acquired or congenital valvular disease may result in abnormal valve closure. In such cases, a proportion of the ventricular stroke volume flows backward, rather than contributing to forward blood flow. With mitral regurgitation, a portion of the blood pumped by the left ventricle flows not forward into the aorta, but rather backward into the left atrium. The amount of backflow depends on the degree of valvular pathology and relative pressures. In this scenario, the left ventricle needs to increase its workload both to meet the forward demands of blood flow and to account for the additional regurgitant volume moving into the left atrium. The extra work due to chronic regurgitation may eventually result in volume overload and dilation of the ventricle. Clinically, patients may develop symptoms of congestive heart failure from the increased pulmonary venous pressure due to the leak itself as well as that due to the resulting systolic dysfunction.

Respiratory Recap Types of Valvular Heart Diseases ∎ Stenotic lesions ∎ Regurgitant lesions

Echocardiography Echocardiography is the most useful initial test to evaluate valvular function. Two-dimensional echocardiography allows visualization of valve leaflet anatomy and mobility. The appearance of thickened, calcified leaflets with poor mobility suggests valvular stenosis (Figure 6-4). In addition, with different angles of ultrasound transmission, the orifice of the valve can be visualized and measured. Echocardiography is also useful in evaluating the sequelae of valvular stenosis, such as left ventricular hypertrophy (LVH) secondary to aortic stenosis or left atrial enlargement secondary to mitral stenosis.

FIGURE 6-4 Two-dimensional echocardiography (short-axis view). (A) Normal aortic valve (AV) orifice. (B) Calcified, stenotic aortic valve. The continuous wave Doppler analysis across the aortic

valve demonstrates a high-velocity jet (>4 meters per second), consistent with severe aortic stenosis. Courtesy of Geoffrey A. Rose, MD, FACC, FASE.

Although echocardiography does not measure pressure gradients directly, Doppler echocardiography allows calculation of the pressure difference across a stenotic valve. Specifically, the modified Bernoulli equation relates flow velocity to pressure gradient (ΔP = 4 × v2, where P is measured in mm Hg and v in m/s). Two-dimensional echocardiography is also useful in the assessment of secondary changes of valvular regurgitation, such as increased ventricular size and impaired systolic function—factors that influence the decision about when to intervene. Particularly relevant to the respiratory care provider is the ability of echocardiography to estimate right ventricular systolic pressure, which may reflect the presence of pulmonary hypertension as well as signs of right heart failure. Transesophageal echocardiography (TEE) is a procedure in which a smaller ultrasound transducer is passed via the esophagus posterior to the heart. This allows closer investigation of valvular heart disease because of the proximity of the transesophageal probe to the heart and the absence of intervening anatomic barriers such as the lungs and ribs.5 TEE includes all aspects of transthoracic imaging, including twodimensional, Doppler, and color Doppler techniques, and is useful in assessments of valve morphology and function. It has particular advantages in evaluations of both the mitral valve, because of this valve’s posterior position (Figure 6-5), and the prosthetic valves, which may be difficult to visualize by transthoracic echocardiography because of shadowing of the ultrasound beam.

FIGURE 6-5 Transesophageal echocardiography demonstrating significant mitral stenosis. The left atrium (LA) and left ventricle (LV) are depicted, along with the stenotic mitral valve opening (arrow). Courtesy of Geoffrey A. Rose, MD, FACC, FASE.

Cardiac Catheterization Cardiac catheterization is an invasive, accurate means to quantify valvular stenosis and regurgitation. The pressure gradient can be directly assessed with the use of fluid-filled catheters to measure the pressure in the distal and proximal heart chambers across the stenotic valve. The pressure gradient across a stenotic valve is inversely related to the valve area (i.e., the smaller the valve area, the larger the pressure gradient). Respiratory Recap Tests to Assess Valvular Function ∎ Electrocardiography ∎ Radionuclide angiography ∎ Echocardiography

∎ Cardiac catheterization

Coronary Artery Disease Case 4. Coronary Artery Disease A 60-year-old woman comes to the emergency department with several hours of crushing substernal chest pain. In the past, she experienced this symptom while she was exerting, but the condition abated with rest. This time, however, it developed while she was standing at work. The pain is severe and radiates down her left arm and up to the left side of her face. The patient also feels sweaty, nauseated, and lightheaded. Her medical history is notable for hypertension, high cholesterol, and a family history of heart disease. Her coworker calls for emergency help, and she is given sublingual nitroglycerin and oxygen, which have no impact on her pain. An ECG shows ST-segment elevation in the anterior precordial leads (Figure 6-6). The patient is given aspirin therapy and transported to the local emergency department. On examination, she is diaphoretic, tachycardic, in mild respiratory distress, and obviously in pain. A chest xray is clear. Cardiac troponin is normal.

FIGURE 6-6 ECG with ST-segment elevation characteristic of acute anterior myocardial infarction.

This patient has classic symptoms of angina, which is chest pain due

to coronary ischemia (lack of oxygen to the heart muscle tissues that depend on the blood flow from the blocked vessel). Not all patients have such classic symptoms. Myocardial ischemia can also present as jaw or arm pain without chest pain and abrupt-onset dyspnea. Before the onset of the acute symptoms that brought her to the emergency department, the patient’s symptoms would have been classified as stable angina (occurring with exertion and abating easily with rest), but now her symptoms would be deemed unstable. She likely has an occluded coronary artery that, if it persists, will result in more extensive cardiac damage. The normal cardiac troponin does not exclude an acute coronary syndrome, as it does not become elevated until approximately 4 hours after the onset of myocardial ischemia. The patient undergoes emergent coronary angiography to both definitively assess the coronary arteries and set the stage for emergent coronary revascularization. The latter involves angioplasty to open the blocked coronary artery and likely placement of a stent to maintain the patency of the artery.

Evaluation of the Coronary Circulation The most common cause of abnormal coronary perfusion is coronary artery disease (CAD) caused by atherosclerosis. Significant CAD primarily affects the left ventricle because of the high metabolic requirements of this chamber. Therefore, left ventricular diastolic dysfunction, systolic dysfunction, and mitral valve dysfunction may occur as a result of limited blood supply to the coronary circulation (i.e., myocardial infarction and/or coronary ischemia). Chest pain and dyspnea are the most common symptoms of CAD. CAD can present as stable angina, in which symptoms occur with increased myocardial metabolic demand, such as during exercise. It can also present as an acute coronary syndrome, typically caused by an acute worsening of coronary artery narrowing due to rupture of a cholesterol plaque with superimposed thrombosis. Depending on the degree of obstruction, the amount of myocardial tissue supplied by the diseased artery, and the extent of collateral supply, acute coronary syndrome may manifest as ST elevation myocardial infarction (STEMI), myocardial infarction without ST elevations (non-STEMI), or unstable

angina. These conditions are differentiated by the presenting ECG (ST elevations or not) and the presence or absence of myocardial necrosis (typically measured via troponin). Major determinants of myocardial oxygen demand include myocardial wall tension, contractility, and the heart rate. Furthermore, the heart’s response to ischemia follows a progressive pattern (the ischemic cascade). As ischemia persists, additional abnormalities of cardiac function develop. Figure 6-7 summarizes the ischemic response. When blood flow via a coronary artery decreases significantly, diastolic dysfunction of the left ventricle is the first demonstrable abnormality of cardiac function. Continued ischemia leads to systolic dysfunction, electrocardiographic changes, and finally the symptoms of angina. Prolonged lack of blood flow results in myocardial infarction.

FIGURE 6-7 The ischemic cascade of cardiac dysfunction during coronary artery occlusion. Adapted from Nesto RW, Kowalchuck GJ. The ischemic cascade: temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia. Am J Cardiol 1987;57:23C–27C.

Clinical tests used to evaluate the coronary circulation include the ECG, anatomic assessments, and functional tests. All provide diagnostic and prognostic information, and the rationale for the choice of one test over another is based on the clinical scenario and the information sought.

Specific Tests to Assess Coronary Circulation Electrocardiogram The ECG is a simple, readily available technique that should be the first test performed in the diagnosis of coronary artery disease.6 Manifestations of acute ischemia or ongoing infarction on the ECG include T wave inversion, depression of ST segments, and elevation of ST segments. Completed infarction may manifest on the ECG as loss of R waves or development of Q waves. Typically, ischemia appears as T wave inversion and/or ST depression. ST elevation in the setting of an acute coronary syndrome suggests ongoing infarction of a sizable portion of the myocardium. Nevertheless, myocardial ischemia may sometimes occur with minimal or no abnormalities on the ECG. Furthermore, ECG changes can occur in conditions other than CAD, such as metabolic abnormalities, LVH, and COPD. For these reasons, ECG abnormalities must be interpreted in the context of the patient’s symptoms, history, and physical examination results.

Anatomic Tests Anatomic tests provide information on the presence, distribution, and severity of CAD. In some cases, the anatomy of CAD provides important prognostic information. For instance, significant stenosis of the left main coronary artery and stenosis involving the proximal segments of all three coronary arteries are associated with decreased long-term survival with medical therapy alone, indicating the need to consider revascularization

by either percutaneous or surgical means.7 Most commonly, cardiac catheterization is performed to assess the pertinent anatomy, though cardiac CT angiography is an increasingly viable alternative technique.8 In general, stenosis of 70% or greater is considered significant (Figure 68).

FIGURE 6-8 Right coronary angiogram of a patient with angina and an abnormal exercise treadmill test result. The purple arrowhead demonstrates the catheter in the ostium of the right coronary artery. The yellow arrowhead demonstrates a 95% mid–right coronary artery stenosis.

Functional Tests Functional tests assess for impaired blood flow with resultant ischemia or impaired cardiac function. With impaired coronary circulation, the blood supply to the myocardial tissue may be adequate at rest, yet insufficient to meet the increased demands of exercise or acute illness. Functional tests assess not the degree of coronary narrowing, but rather the resultant ischemia. Increased myocardial oxygen demand can be induced by exercise or pharmacologically (e.g., with dobutamine). Under these conditions, ECG, perfusion imaging with nuclear agents or MRI, or assessment of resultant dysfunction by echocardiogram can assess ischemia. Myocardial perfusion imaging involves intravenous injection of a radionuclide agent (such as thallium-201 or technetium-99m), which accumulates in the myocardium in proportion to regional myocardial perfusion. The comparison of perfusion images obtained at rest and with exercise allows determination of whether perfusion is normal both at rest and with exercise, normal at rest but failing to increase with exercise (ischemia), or decreased both at rest and with exercise due to a prior myocardial infarction (Figure 6-9). A region of myocardium that is normal at rest but hypoperfused during exercise is called a reversible perfusion defect. This abnormality suggests the presence of a significant lesion in the coronary artery that limits the increase in myocardial blood flow to that region normally seen during exercise. A region of myocardium that is hypoperfused both at rest and during exercise is called a fixed perfusion defect; it is consistent with a prior infarction (i.e., the cardiac tissue of the affected area has essentially been replaced by scar tissue, which requires less blood flow than cardiac muscle).

FIGURE 6-9 Nuclear cardiology perfusion imaging of the left ventricular myocardium during exercise and rest. The left ventricle is depicted in three different views during exercise and rest. The perfusion images demonstrate hypoperfusion (decreased blood flow) to the inferior wall during exercise (yellow arrows). After the patient rests, the blood flow returns, consistent with myocardial ischemia in that region.

In addition, an individual coronary lesion’s physiologic impact can be assessed during cardiac catheterization. In this procedure, the clinician advances a pressure transducer on a 0.014-inch-diameter coronary guide-wire distal to the lesion. This technique allows for assessment of the decrement in perfusion pressure caused by the lesion. It has the advantage of allowing definitive assessment of the physiologic impact of a given lesion at the time of cardiac catheterization. In addition, long-term outcomes are strongly predicted by treatment guided by these findings. In Case 4, a functional test might have been helpful in the preceding weeks to diagnose and treat the patient for stable angina. Now, however, the patient is having an acute coronary event, and revascularization of

the culprit lesion will improve her outcome. Therefore, proceeding directly to an anatomic test to assess and guide revascularization is appropriate, as both diagnosis and treatment may potentially be provided in a single procedure. Respiratory Recap Tests to Assess Coronary Circulation ∎ Electrocardiogram: ST-segment changes ∎ Exercise stress testing ∎ Radionuclide myocardial perfusion imaging ∎ Stress echocardiography ∎ Coronary arteriography ∎ Coronary CT angiography

Arrhythmias Case 5. Cardiac Arrhythmia A 75-year-old woman with a history of CAD develops severe lightheadedness and diaphoresis. On examination, her pulse is 25 beats per minute and blood pressure is 80/45 mm Hg. She is taken to the emergency department, where an electrocardiogram (Figure 6-10) reveals third-degree block. She is taken immediately for a pacemaker insertion and has a full recovery.

FIGURE 6-10 Complete heart block (third degree).

Respiratory therapists commonly encounter cardiac arrhythmias in their patients. Arrhythmias can develop from many medical conditions, both cardiac and noncardiac, as well as from medications or other interventions. In normal function (Figure 6-11), the cardiac impulse begins with firing of the sinoatrial (SA) node high in the right atrium, with

subsequent propagation of the electrical signal throughout the atria. The ventricles are electrically isolated from the atria, with the exception at the atrioventricular (AV) node. The electrical impulse, after beginning in the atria, then traverses the AV node to reach the ventricular conduction system. This ventricular conduction system consists of the right and left bundle branches. Having reached them, the electrical impulse then propagates through the right and left bundle branches to reach the ventricular myocardial tissue and hence trigger contraction.

FIGURE 6-11 Electrical activity in the heart. The electrical signal normally starts at the sinus node, which causes the right and left atria to contract. The atrioventricular (AV) node is triggered next. The AV node sends a signal through the His/Purkinje system via the conduction pathways. The conduction pathways then signal the right and left ventricles to contract.

Dysfunction of the conduction system manifests as arrhythmias. Bradyarrhythmias (slow heart rhythms) may result from slowed or failed firing of the SA node or impaired propagation of the electrical signal at

any level. Impaired propagation at the level of the AV node and below is relatively common. AV node dysfunction frequently results from use of medications such as beta blockers or calcium channel blockers; it may also be a transient manifestation of increased vagal tone. Impaired propagation in the ventricular conduction system is less likely to be a response to medications or vagal tone. Whereas symptomatic bradycardia is common and usually managed conservatively, symptomatic bradycardia arrhythmias may need to be treated with implantation of a pacemaker. Tachyarrhythmias (fast heart rhythms) occur commonly in critically ill patients. The most common tachyarrhythmia is sinus tachycardia, a rapid heart rate induced by increased metabolic stress such as that occurring during exercise or illness. This condition is not pathologic but rather an appropriate and necessary physiologic response to stress. Pathologic tachyarrhythmias can be divided into those affecting primarily the atria (supraventricular arrhythmias) versus those affecting the ventricles (ventricular arrhythmias). In general, these conditions manifest on the ECG as narrow complex and wide complex tachycardia arrhythmias, respectively. Common supraventricular tachyarrhythmias include atrial flutter, atrial fibrillation, and reentrant supraventricular tachycardia. Atrial flutter most commonly results from a short circuit (reentry) around the tricuspid valve, resulting in repeated rapid regular atrial electrical activation (typically 300 beats per minute) independent of the activity of the SA node. This rapid activity bombards the AV node with electrical signals. Usually, the AV node does not transmit all of these signals to the ventricular conduction system, but instead allows only every second or third beat to be conducted—hence, atrial flutter with 2:1 or 3:1 block. The resultant ventricular rate is typically 150 or 100 beats per minute. The ECG manifests multiple P waves at a rate of 300 beats per minute with regular narrow QRS complexes resulting from every second or third of these P waves. The degree of AV block can be increased by medications that slow conduction through the AV node, such as beta blockers and calcium channel blockers. Atrial fibrillation is a result of disorganized electrical activity within the atria. This disorganized atrial electrical activity results in rapid irregular activation of the AV node, which cannot conduct all of these impulses.

The typical ECG manifestation is an absence of P waves and irregular narrow QRS complexes. As in atrial flutter, the ventricular rate can be controlled with medications that slow conduction through the atrioventricular node. Atrial fibrillation, in particular, is commonly paroxysmal and precipitated in times of acute noncardiac illness. Neither atrial flutter nor atrial fibrillation is usually life threatening when it is the sole problem, but the inappropriate tachycardia can be deleterious to myocardial metabolic demand and cardiac output, thereby potentially leading to patient compromise. Ventricular tachyarrhythmias are often immediately life threatening. They include ventricular fibrillation and ventricular tachycardia. Ventricular fibrillation is always immediately life threatening and is treated with emergent electrical defibrillation. Ventricular tachycardia is usually brief and self-limited, but sustained ventricular tachycardia is immediately life threatening and treated with emergent electrical cardioversion. Appendix 6-1 and Table 6-1 provide a more complete presentation of the different types of cardiac arrhythmias. TABLE 6-1 Summary of Cardiac Rhythms

Description *If the rate is less than 60 beats/min, it would be called sinus bradycardia. If rate is greater than 100 beats/min, it would be sinus tachycardia. †Narrow is defined as less than or equal to 0.12 second and wide as greater than 0.12 second. ‡This clinical severity is used as a general guide for clinicians in training, but the actual severity

considers numerous factors of a patient’s illness and the clinical context and, therefore, should be interpreted accordingly.

ECG in Pulmonary Disease Characteristic ECG changes may occur with other pulmonary conditions, such as acute pulmonary embolism or obstructive lung disease. If an acute pulmonary embolus results in a significant increase in pulmonary arterial pressure, a number of electrocardiographic features suggestive of acute right ventricular strain may be present: (1) S1Q3T3 (development of an S wave in lead I and Q wave and T wave inversion in lead III); (2) rightward QRS axis shift; (3) transient right bundle branch block; and (4) T wave inversion in the right precordial leads (V1–2). However, these changes are relatively insensitive and transient (as resolution or thrombolysis of the pulmonary embolus occurs). COPD also may cause characteristic electrocardiographic changes, perhaps due to hyperinflation of the lungs and a low position of the diaphragm. As a result, the heart becomes more vertical in the chest and rotates clockwise along its longitudinal axis. Other electrocardiographic abnormalities include right atrial abnormality, right axis deviation, low QRS voltage, T wave abnormalities in the right precordial leads (V1–2), and leftward shift of the transitional zone.

Refractory Hypoxemia Case 6. Intracardiac Shunt A 30-year-old woman developed severe streptococcal pneumonia and septic shock, for which she was placed on mechanical ventilation while being treated with antibiotics and supportive care. She initially required vasopressors to maintain her blood pressure. Despite what seemed to be clinical and radiographic stabilization in her condition off vasopressors, oxygenation remained a challenge. On PEEP of 10 cm H2O and FIO2 of 0.6, her PaO2 is 50 mm Hg. She had no prior history of cardiac disease and a normal cardiovascular physical examination. Initial echocardiogram did not disclose any cardiac defects, and normal right-sided pulmonary pressures were noted. The clinician ordered an echocardiogram with saline bubbles for echo contrast, which demonstrated abnormal flow of bubbles from the right atrium to the left atrium, suggesting an intracardiac shunt. Once the shunt was corrected with the use of a device to close the patent foramen ovale, the patient’s hypoxemia immediately resolved, and she was extubated without event.

Bubble Echocardiogram When evaluating patients for persistent hypoxemia, agitated saline may be used as a contrast agent (i.e., echo with bubble study). The underlying principle is as follows: If there is a shunt connecting the right and left heart chambers directly, then microbubbles from the venous side of the circulation should travel quickly from the right side of the heart to the left side. Normally, in the absence of any shunt, the pulmonary capillaries filter the bubbles, so no bubbles appear in the left heart. When agitated saline is inserted directly into the venous circulation, it can be seen by echocardiogram in the right atrium and right ventricle as a snowstorm appearance (Figure 6-12). The air bubbles cause this appearance, as air reflects ultrasound waves differently than does blood. Normally, the pulmonary capillaries and circulation then filter the air. If a cardiac or pulmonary shunt is allowing blood to bypass the pulmonary circulation,

however, the agitated saline will not only initially appear in the right atrium but quickly pass to the left atrium (Figure 6-13). In pulmonary shunts, such as in arteriovenous malformations in the lungs, the blood never passes through pulmonary capillaries; therefore, agitated saline may still appear in the left atrium, but it may take several cardiac cycles to do so. Bubble echocardiogram may therefore be used as a noninvasive test to detect shunt physiology.

FIGURE 6-12 Normal bubble echocardiogram (no shunt).

FIGURE 6-13 Bubble echocardiogram with right-to-left shunt.

Stop and Think In a mechanically ventilated patient, the SpO2 decreases from 94% to 86% when the level of positive end-expiratory pressure (PEEP) is increased from 8 cm H2O to 12 cm H2O (FIO2 = 0.8). How would you explain this response, and which cardiac assessment might be helpful?

Key Points Proper cardiac assessment is an important element in the care of patients with symptoms of pulmonary disease or documented pulmonary conditions because of the overlap in symptoms of cardiac and pulmonary disease. Clinical assessment involves integrating the history, physical examination, and laboratory studies with other diagnostic studies. Clinical tests such as blood tests, electrocardiography, nuclear cardiology, echocardiography, MRI, CT, and cardiac catheterization all have important roles in the diagnosis and prognosis of cardiac conditions, and each test may be used to assess various elements of cardiac function. Sometimes a single test can provide information about several elements of cardiac function, and the advantages and disadvantages of the specific test should be considered in the clinical context of the individual patient. Tests of cardiac function may be used not only to help diagnose cardiac disease but also to evaluate the prognosis of patients with these conditions and to guide therapeutic interventions. A bubble echocardiogram can be used to assess intracardiac or intrapulmonary shunt.

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Appendix 6-1

CG Monitoring and Dysrhythmia Recognition

Locations for Chest Electrodes Lead I Positive electrode placed just below the left clavicle Negative electrode placed just below the right clavicle Provides information about the left lateral wall of the heart

FIGURE 6A-1 Location for chest electrodes: lead I. G, ground.

Adapted from Aehlert B. ACLS Quick Review Study Guide. Mosby; 1994.

Lead II Positive electrode just below the left pectoral muscle Negative electrode just below the right clavicle Provides information about the inferior wall of the heart

FIGURE 6A-2 Location for chest electrodes: lead II. Adapted from Aehlert B. ACLS Quick Review Study Guide. Mosby; 1994.

Lead III Positive electrode placed just below the left pectoral muscle Negative electrode placed just below the left clavicle Provides information about the inferior wall of the heart P waves seen in this lead usually are of lower amplitude than in leads I and II and are more likely to be biphasic (partly positive and partly negative)

FIGURE 6A-3 Location for chest electrodes: lead III.

Adapted from Aehlert B. ACLS Quick Review Study Guide. Mosby; 1994.

Lead MCL1 (Modified Chest Lead) Negative electrode placed just below the left clavicle Positive electrode placed to the right of the sternum at the fourth intercostal space Provides information about the anterior wall of the heart May prove useful in assessment of the width of the QRS complex to differentiate supraventricular tachycardia (SVT) from ventricular tachycardia (VT)

FIGURE 6A-4 Location for chest electrodes: lead MCL1. Adapted from Aehlert B. ACLS Quick Review Study Guide. Mosby; 1994.

Because the speed of ECG paper is 25 mm/s, the distance between two vertical lines is 1 mm and represents 0.04 second. Thus, the time between two bold vertical lines (five small lines, or 5 mm) represents 0.2 second. The distance between two horizontal lines is also 1 mm. An upward deflection of 10 small lines (or two bold lines) represents 1 mV.

Dysrhythmia Recognition Normal Sinus Rhythm (NSR) Rate Rhythm P waves PR interval QRS

60 to 100 beats/min Regular Uniform and upright in appearance One preceding each QRS complex 120–200 ms 80% predicted, O2 pulse < 80% predicted suggests cardiac disease or deconditioning HRmax < 80% predicted suggests cardiac limitations not present, HR response limited (drugs, pacer), or poor effort Dysrhythmias, systolic BP decrease or increase above 190 mm Hg (women) or 210 mm Hg (men), diastolic BP increase more than 10–15 mm Hg, ischemic ECG tracings suggest cardiac disease

Step 3: Ventilatory limitations

E/MVV > 80% or PaCO2 rising indicates ventilatory limits present MVV reduced during exercise from exercise bronchospasm (>15–20% fall in FEV1) or air trapping (reduced inspiratory capacity)

Step 4: Gas exchange limitations

PaO2 (or SpO2) falling to 55–79 mm Hg (88–89%) is abnormal but not exercise limiting PaO2 (or SpO2) falling to 120 mm Hg Fall in systolic blood pressure >20 mm Hg Chronotropic insufficiency in the absence of β-blockers SpO2 < 80% Inability to sustain cadence on bicycle above 40 rpm Subject’s request to stop despite encouragement because of symptoms of dyspnea, leg or global fatigue, or otherwise

Key Points The normal physiologic response to exercise includes increases in cardiac output and ventilation, along with alterations in peripheral circulation, hemoglobin oxygen affinity, and cellular metabolism. CPET stresses the cardiopulmonary system and allows for better assessment of the limits of this system. Important indications for exercise testing include diagnosis of unexplained dyspnea, determination of prognosis and risk, and evaluation of responses that follow interventions such as pulmonary rehabilitation. A global interpretive strategy involves definition of the physiologic systems responsible for exercise limitation and subsequent determination of the abnormal responses within these systems. Timed walk tests focus primarily on functional performance.

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39. Giovacchini CX, Mathews AM, Lawlor BR, MacIntyre NR. Titrating oxygen requirements during exercise: evaluation of a standardized single walk test protocol. Chest 2018;153(4):922–928. 40. Nixon P, Orenstein D, Kelsey S, Doershuk CF. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med 1992;327(25):1785–1788. 41. Hiraga T, Maekuar R, Okuda Y, Okamoto T, Hirotani A, Kitada S, et al. Prognostic predictors for survival in patients with COPD using cardiopulmonary exercise testing. Clin Physiol Funct Imaging 2003;23(6):324–331. 42. Mancini D, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83(3):778–786. 43. Lorio A, Magrì D, Paolillo S, Salvioni E, Di Lenarda A, Sinagra G, et al. Rationale for cardiopulmonary exercise test in the assessment of surgical risk. J Cardiovasc Med 2013;14(4):254–261. 44. Benzo R, Kelley GA, Recchi L. Complications of lung resection and exercise capacity: a meta analysis. Respir Med 2007;101(8):1790–1797. 45. Morice RC, Peters EJ, Ryan MB, Putnam JB, Ali MK, Roth JA. Exercise testing in the evaluation of patients at high risk for complications from lung resection. Chest 1992;101(2):356–361. 46. Bolliger CT, Jordan P, Solèr M, Stulz P, Grädel E, Skarvan K, et al. Exercise capacity as a predictor of postoperative complication in lung resection candidates. Am J Respir Crit Care Med 1995;151(5):1472–1480. 47. Older P, Smith R, Courtney P, Hone R. Preoperative evaluation of cardiac failure and ischemia in elderly patients by cardiopulmonary exercise testing. Chest 1993;104(3):663– 664. 48. Cotes J, Zejda J, King B. Lung function impairment as a guide to exercise limitation in workrelated lung disorders. Am Rev Respir Dis 1988;137(5):1089–1093. 49. Ries AL, Bauldoff GS, Carlin BW, Casaburi R, Emery CF, Mahler DA, et al. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based clinical practice guidelines. Chest 2007;131(Suppl 5):4S–42S. 50. Punzal PA, Ries AL, Kaplan RM, Prewitt LM. Maximum intensity exercise training in patients with chronic obstructive pulmonary disease. Chest 1991;100(3):618–623. 51. Zanaboni S, Donner CF, Wasserman K. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Respir Dis 1991;143(1):9–18. 52. Cypcar D, Lemanske RF. Asthma and exercise. Clin Chest Med 1994;15(20:351–368. 53. Skalski J, Allison T, Miller T. The safety of cardiopulmonary exercise testing in a population with high-risk cardiovascular diseases. Circulation 2012;126(21):2465–2472.

Part 2 Respiratory Therapeutics

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CHAPTER

13 Therapeutic Gases: Manufacture, Storage, and Delivery John E. Boatright Molly Quinn Jensen

© Andriy Rabchun/Shutterstock

OUTLINE Chemical and Physical Properties of Therapeutic Gases Air Oxygen Manufacture and Distribution of Oxygen Carbon Dioxide Helium Nitric Oxide Nitrogen Storage and Distribution of Medical Gases Medical Gas Cylinders Regulators Safety-Indexed Connection Systems Calculating Duration of Flow from a Gas Cylinder Central Medical Gas Distribution Central Compressed Medical Air Distribution

OBJECTIVES 1. Describe the manufacture, storage, distribution, and regulation (to working outlet pressure/flows) of medical therapeutic gases. 2. Describe the physical properties, chemical symbols, and uses of air, oxygen, carbon dioxide, helium, nitric oxide, and nitrogen. 3. Describe the production processes for various medical gases. 4. Compare and contrast gaseous and liquid storage methods. 5. Describe the production, safety features, types, and uses of medical gas cylinders. 6. Discuss the established safety systems for the various equipment connections to ensure delivery of a specific gas, such as oxygen. 7. Calculate the duration of flow from a gas cylinder. 8. Describe the design, use, and troubleshooting of various bulk gas supply systems.

KEY TERMS American Standard Safety System (ASSS) carbogen carbon dioxide Compressed Gas Association (CGA) Department of Transportation (DOT) Diameter Index Safety System (DISS) Food and Drug Administration (FDA) fractional distillation of liquefied air heliox helium hydrostatic testing medical gas cylinders nitric oxide nitrogen Pin Index Safety System (PISS)

Introduction Many therapeutic and diagnostic procedures used in respiratory care involve one or more medical gases.1 Consequently, the respiratory therapist frequently serves as the expert in gas properties, handling, and equipment use. This role also includes troubleshooting equipment malfunction to ensure the safe delivery of medical gases. This chapter describes the physical and chemical characteristics of commonly used therapeutic gases; provides information about their manufacture, storage, and distribution; and discusses the regulation of gases used in acute care hospitals.

Chemical and Physical Properties of Therapeutic Gases Table 13-1 summarizes the physical properties of the therapeutic gases and nitrogen. The following sections describe these various properties in more detail. TABLE 13-1 Physical Properties of Commonly Used Therapeutic Gases

Description All values are at ATPD (ambient temperature and pressure, dry: 21.1° C, 760 mm Hg, and dry) unless otherwise noted. Adapted from Langenderfer R, Branson R. Compressed gases: manufacture, storage, and piping systems. In: Branson R, Hess D, Chatburn R. Respiratory Care Equipment. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.

Flammability Medical gases are classified as nonflammable or as flammable or

inflammable (terms used interchangeably). Nonflammable gases do not burn; examples include nitrogen, oxygen (O2), helium, air, and carbon dioxide (CO2). Some nonflammable gases (such as nitrogen and CO2) are used to extinguish fire because they displace the O2 that is necessary for combustion to occur. In contrast, a flammable or inflammable gas can ignite, burn, and potentially explode. Cyclopropane and natural gas, not currently used for medical purposes, are examples of flammable gases. O2, although not explosive or combustible, must be present for combustion to occur. Thus, O2 and air support combustion, meaning that their presence accelerates combustion. Respiratory Recap Gas Flammability ∎ Nonflammable gases do not burn, but some support combustion. ∎ The terms flammable and inflammable are used interchangeably. ∎ Inflammable gases burn and are rarely used for medical purposes. ∎ O2 is a nonflammable gas; it does not burn and will not explode. ∎ O2 supports combustion, making burning brighter, hotter, and faster.

Life Support O2 and air support life; that is, the presence of appropriate quantities of these gases supports the metabolic production of energy in the carbonbased organisms found on Earth. Gases that do not support life are also included in this chapter because they have physiologic effects and therapeutic potential for humans.

Atmospheric Concentration (by Volume) Atmospheric concentrations are given in percentage values (%), which represent the relative quantities of gas, as they are present in Earth’s atmosphere. Most clinical discussions of gas quantities use this unit of measure.

Atmospheric Pressure Atmospheric pressure, or barometric pressure (Pb), is a convenient expression of gas quantity—that is, how many molecules of gas are present in the atmosphere. Standard temperature and pressure of dry gas (STPD) is a designation for a specific set of physical conditions for a gas: temperature of 0° C, at a pressure of 760 mm Hg, without any humidity (dry gas). The term dry describes a condition that would rarely be experienced on Earth—that is, an atmospheric condition without any humidity—because even the most dry, cold Earth environments have some water molecules in the ambient gas atmosphere. Water vapor exerts pressure (PH2O) as part of the total barometric pressure. Ambient temperature and pressure dry (ATPD) states that the physical conditions for a gas are at ambient temperature and pressure, without any humidity (dry gas). Ambient refers to the atmospheric temperature and pressure conditions around an observer. In situations where no specific ATPD is specified, the default total is assumed to be the ambient pressure at sea level (760 mm Hg). The atmospheric partial pressure column in Table 13-1 represents the partial pressure of each gas in mm Hg under ATPS (ambient temperature and pressure saturated) conditions with the atmospheric pressure of 760 mm Hg. Instead of gas concentrations, respiratory therapists use the partial pressure of gases because it is a more precise expression of the absolute amount of a constituent gas present in an environment (e.g., PIO2).

Viscosity Viscosity is a measure of a fluid’s resistance to flow. The viscosity of water is low, whereas the viscosity of oil or honey is high. The SI unit used for viscosity in Table 13-1 is pascal-second (Pa-s).

Density Density is mass per unit of volume (m/V). With regard to gases, mass is the molecular weight (grams), and the standard molar volume at STPD is

22.4 L. The unit of measure for density in Table 13-1 is kilograms per cubic meter (kg/m3). Stop and Think A patient is receiving O2 via a nasal cannula. Can you explain why the 100% O2 delivered by the nasal cannula tends to cling to the patient’s face, torso, and clothing?

Relative Density The relative density (specific gravity) of a liquid compares the density of a fluid with the density of water (at 4° C, 760 mm Hg). To ascertain the relative density of a gas, the density of the gas at 4° C and 760 mm Hg is compared with the density of air. A relative density of 1 indicates that the density of the gas is identical to the density of air (for a gas).

Boiling Point The boiling point of a substance is the temperature at which it changes from a liquid to a gas (at 760 mm Hg). The change in state that occurs when a liquid becomes a gas is termed evaporation or vaporization. The freezing point is the temperature where a substance changes state from a liquid to a solid, and the process in which a solid changes state directly to become a gas is termed sublimation. Dry ice, the solid form of CO2, sublimates directly from a solid to a gas.

Critical Temperature Critical temperature (TC) is the temperature at which a substance no longer exists as either liquid or gas, nor can it be forced into a liquid state by applying pressure, although with enough pressure it can be changed into a solid. Gases can be more easily converted to liquids at certain temperatures, because as a gas’s temperature increases, it becomes more difficult to change it from a gas to a liquid. The TC of O2 is –118.6° C. Above this temperature, O2 cannot exist as a liquid no matter how

much pressure is applied.

Critical Pressure The critical pressure (PC) is the pressure required at a critical temperature to change a gas to a liquid. O2 will become a liquid if 49.7 atm (atmospheres of pressure) is applied to –118.6° C gas. Water is considered an anomalous substance because water’s critical temperature and pressure do not correspond to the typical change of state model. In a solid state, water assumes a crystalline form (ice), which is less dense than the liquid form of water (which is why ice floats in a glass of water).

Triple Point The triple point of a substance is the pressure and temperature at which it can exist in the three phases of matter in equilibrium. That is, the substance can exist in a liquid, gas, or solid, especially with a small shift in pressure or temperature in any direction. When the temperature is – 219° C and the pressure is 0.22 psia (pounds per square inch absolute), O2 can exist as either a liquid, a gas, or a solid. Note that at this very cold temperature, the pressure is nearly a total vacuum (0 psia).

Solubility in Water Solubility is a physical property of a substance, indicating its ability to dissolve in a solvent—in this case, water. Water solubility is relevant to the respiratory therapist in understanding gas transport physiology. The solubility of O2 is much less than the solubility of CO2, which affects differences in the rate of solution and dissolution in plasma, and the migration of the two gases through the alveolocapillary membrane and the cell wall.

Physical State in Cylinder

The physical state of some gases, as contained in a cylinder, may be either liquid (e.g., CO2) or gas (e.g., O2). This duality occurs because some gases assume a liquid state at the pressures required to store them in a cylinder. The degree of compression required to store CO2 in a cylinder causes it to change state from gas to liquid. When the cylinder valve is opened and the pressure in the cylinder drops below the critical pressure, the liquid at the surface evaporates and returns to a gaseous state. When the liquid in the cylinder has completely evaporated, the cylinder pressure will drop, eventually reaching zero when the cylinder is empty. Because the pressure drop in a CO2 cylinder begins very near the point at which the cylinder is empty, cylinder weight is monitored to determine the remaining amount of liquid CO2.

Air At normal atmospheric conditions, air is an odorless, colorless, transparent, tasteless mixture of gases and water vapor that is nonflammable and supports combustion. Air consists of approximately 78% nitrogen and 21% oxygen by volume. The remaining 1% consists of extremely small amounts of chemically inert trace and rare gases, such as argon, neon, helium, krypton, and xenon (Figure 13-1). The largest component of air is nitrogen, which is not directly involved in metabolic reactions and is considered inert. Nonetheless, nitrogen gas is important in maintaining the inflation of gas-filled body cavities such as the alveoli, sinus cavities, and middle ear.

FIGURE 13-1 Constituents of the atmosphere. Values represent percent concentration in Earth’s

atmosphere. Information from the Encyclopedia of Earth. Atmospheric composition. Available at: http://www.eoearth.org/article/atmospheric_composition.

Description In medical settings, compressed air is referred to as room air or ambient air. Table 13-2 shows the relative quantities of the various gases that compose Earth’s atmosphere (in both volume percent and fraction).2 The composition of the major components in dry air is relatively constant. For clinical purposes, gas quantities are commonly referred to as percentage (concentration by volume) or fraction. TABLE 13-2 Composition of Room Air Gas

Concentration by Volume (%)

Fraction

Nitrogen

78.083

0.78083

Oxygen

20.946

0.20946

Argon

0.934

0.00934

Carbon dioxide

0.033

0.00033

Neon

0.001818

—

Helium

0.000524

—

Methane

0.00016

—

Krypton

0.000114

—

Hydrogen

0.00005

—

Nitrous oxide

0.00003

—

Therapeutic Uses

Compressed air has two primary uses in respiratory therapy: (1) to dilute 100% O2 to provide 22% to 99% mixtures and (2) as a driving gas for breathing devices when used for patients who do not require O2 supplementation.

Manufacture Compressed air can be manufactured by mixing nitrogen and O2 in precise quantities. More commonly, however, atmospheric air is filtered, compressed, and stored in cylinders or directly delivered through a central piping system. The Compressed Gas Association (CGA) specifies grades of gaseous air. Medical-grade compressed air (CGA grade J) contains 19.5% to 23.5% O2, no water vapor, and minimal amounts of hydrocarbons and other impurities. Aside from its medical applications, compressed air is the breathing gas supplied in many self-contained breathing devices used in industry, scuba diving, aerospace technology, and firefighting.

Cylinders Compressed air is supplied in cylinders that are color-coded yellow. Compressed air cylinders are similar in appearance and size to O2 cylinders. Regulators (for both compressed air and O2 cylinders) reduce the high cylinder pressure (greater than 200 lb/in2 gauge [psig]) to a working pressure (50 psig), the pressure needed to adequately operate clinical equipment such as flow meters and other respiratory therapy equipment. The size and shape of the regulator cylinder connections are specifically designed to prevent the inadvertent application of an O2 regulator. The design for these connections is designated the American Standard Safety System (ASSS). Further reductions of working pressure for more refined control of flow or pressure are standardized specifically for compressed air via the Diameter Index Safety System (DISS) of connections or brand-specific quick-connects.

Piped Air Systems Piped compressed air is commonly provided in hospital medical gas systems for use in areas such as the operating room and intensive care unit (ICU). Many mechanical ventilators and O2–air blenders require sources of both medical air and O2. Large compressors provide the supply of compressed air for these piped distribution systems. Although various designs of these large compressors are available, the piston type is most commonly used. A pressure-sensitive switch senses changes in the line pressure and turns the compressor on and off to maintain line pressures of 50 psig. Typically, the system includes a holding reservoir to provide a ready supply and prevent the compressor from running all the time. Large institutions may have two compressors that alternate operation, thereby prolonging compressor life.

Portable Compressors Smaller, portable air compressors are available for hospital or home use. Because the air source of these systems is ambient air, high humidity and dust may foul the mechanism of these compressors and contaminate the delivered air. Consequently, portable compressed air systems incorporate condensers and filters to remove water and dust. Water trap drains must be maintained to prevent wet air from fouling flow meters and ventilators. Inline desiccant dryers or filters may also be needed, especially during periods of high humidity.

Oxygen Physical Characteristics The English theologian-scientist and politician Joseph Priestley is credited with first publishing findings on dephlogisticated air in 1774. The Swedish apothecary Carl Scheele, who co-published Priestley’s findings, appears to have been the first to have chemically generated what he termed fire air. Neither scientist, however, developed a clear, complete comprehension of O2; that distinction belongs to France’s Antoine Lavoisier, who named the gas oxygen, meaning acid generator. The atomic weight of oxygen (O) is 16 g/mol, and its gram molecular weight (O2) is 32 g/mol. Some differences occur in the proportions of atomic and molecular O2 present with changes in altitude. At approximately 20 km of altitude, photo-dissociation produces atomic oxygen, which is accompanied by an increase in ozone (O3); these reach their maximum concentrations at 30 km (0.003%) and 90 km (7%), respectively. Radiation strips an electron from atomic oxygen, producing the ionized species O+ and O++. These ionic forms are quite reactive and occur only at high altitudes; thus, oxygen most commonly exists in molecular form. In addition to existing in molecular form in the atmosphere, the element oxygen, in combination with other elements, can be found in a large number of compounds. Molecular O2 forms when two oxygen atoms combine by sharing two electrons in their outer orbital shells. This unique molecular bonding characteristic gives O2 a paramagnetic property—it is attracted to a magnet—that can be used to determine O2 concentration in a gas mixture. At standard temperature and pressure (STP), O2 is a colorless, transparent, odorless, tasteless gas, slightly heavier than air, with a density of 1.326 kg/m3 and a specific gravity of 1.105 at STPD. O2 is not very soluble in water. At STP, 10.2 mL of O2 dissolves in 1 L of fresh water (7.8 mL in 1 L of seawater), which is enough to sustain all aquatic life. Approximately half of Earth’s crust by weight is oxygen, and gaseous

O2 makes up 20.95% (0.2095) of the atmosphere by volume. Although the FO2 does not change, the partial pressure of O2 (PO2) varies considerably. The fraction of O2 in air remains constant at 0.2095 to an altitude of 60 miles (96.5 km) above sea level. The PO2, however, varies with changes in barometric pressure (Pb), which decreases at higher or lower altitudes compared with sea level. At 1 atmosphere (Pb = 760 mm Hg), PO2 is 159 mm Hg. The PO2 for any Pb can be calculated with the following formula: PO2 = Pb × FO2 where PO2 is the partial pressure of O2, Pb is the barometric pressure, and FO2 is the fraction of O2 in the gas. Dalton’s law quantifies the O2 portion of the atmospheric gas pressure —that is, its partial pressure (PO2). For example, on Mount Everest, the Pb is approximately 220 mm Hg, and the PO2 is only 47 mm Hg, which is the sea level equivalent of 6% O2. These changes in PO2 require mountain climbers to use supplemental O2 and airlines to pressurize aircraft during high-altitude flights. Table 13-3 illustrates several examples of the effect of altitude on PO2. Below sea level, 1 atm (760 mm Hg) is added for each 33 ft (10 m) of seawater. Freshwater has a slightly lower density than saltwater, and therefore, the pressure increases 1 atm in each 34 ft of depth. For example, for a diver 66 ft below sea level (or for a patient in a hyperbaric chamber at 3 atm), the total gas pressure is 2280 mm Hg, the PO2 is 478 mm Hg, and the equivalent sea level FO2 is 0.63 (Table 13-4). TABLE 13-3 Effects of Altitude on Barometric Pressure and Partial Pressure of Inspired Oxygen

Description TABLE 13-4 Effects of Depth on Barometric Pressure and Partial Pressure of Inspiratory Oxygen

Description Pb, barometric pressure; PO2, partial pressure of inspired oxygen.

Stop and Think A patient in a hyperbaric chamber is exposed to 3 atm and provided 100% O2 by tight-fitting mask. What is the Po2 in the patient’s trachea?

Support of Combustion O2 is a nonflammable gas, meaning it is not capable of being ignited. Nevertheless, O2 vigorously accelerates and supports combustion. The higher the PO2, the hotter, faster, and brighter is the burning. Burning (combustion) commonly occurs in air. A burning match exposed to a 42% O2 atmosphere (twice the quantity of O2 as room air) will burn twice as hot, bright, and fast as one exposed to 21% O2. In concentrations greater than 21%, therefore, O2 not only supports combustion but also accelerates the burning process. In the presence of high concentrations of O2, certain combustible items, especially petroleum-based products (e.g., oil, grease, petroleum jelly, clothing), can easily and violently ignite with great force from a trigger such as a spark, friction, pressure, or impact. Respiratory Recap Properties of Oxygen ∎ O2 is a colorless, transparent, odorless, tasteless, nonflammable gas, only slightly heavier than air at STP. ∎ Only 10.2 mL of O2 dissolves in 1 L of water at STP. ∎ Gaseous O2 can be liquefied when its temperature is lowered to –297.3° F (–182.9° C). ∎ Liquid O2 has a pale-blue color and is 1.1 times heavier than water. ∎ O2 stays in the liquid state as long as its temperature remains below the boiling point. ∎ O2 forms when two oxygen atoms combine by sharing two electrons in their outer orbital shell. ∎ FO2 in air is 0.2095 and remains constant with changes in altitude up to 60 miles (96.5 km) above sea level. ∎ Po2 varies depending on the Pb.

Manufacture and Distribution of Oxygen Photosynthesis All green land and aquatic plants produce O2 through photosynthesis—a process in which chlorophyll-containing plant cells in the presence of sunlight convert CO2 and water into glucose and release O2 as a byproduct into the atmosphere. This process of biological photosynthesis is the main source and regulator of O2 levels in the atmosphere, and chlorophyll is the chemical agent necessary for this transformation. A normal human must consume 2 to 5 lb of O2 per day (4.5 to 11.2 kg) to convert carbohydrates, fats, and proteins into heat, energy, and CO2. As a result of photosynthesis by green land and aquatic plants, the CO2 produced by animals and the burning of fossil fuels is converted to O2. The formula for photosynthesis follows: 6 CO2 + 6 H2O + Sunlight + Chlorophyll → C6H12O6 + 6 O2

Isolating Metallic Oxides Scheele and Priestley, who first described O2, generated O2 by heating metallic oxides of mercury, silver, or barium. This method is not used to mass manufacture O2.

Electrolysis of Water In electrolysis of water, an electric current passed through water causes the water to separate into its component parts—hydrogen and O2. Hydrogen bubbles off at the cathode in a 2:1 ratio to the O2 at the anode. This process is impractical for the commercial production of O2.

Fractional Distillation of Liquefied Air

The two major components of air—O2 and nitrogen—can be produced in bulk, commercial quantities by a process first described in 1907 by Karl von Linde. This process, known as the fractional distillation of liquefied air, relies on the Joule-Kelvin principle: When gases under pressure are released into a vacuum, the gas molecules lose their kinetic energy. In a vacuum, the reduction in kinetic energy causes a decrease in temperature and a reduction in the cohesive forces between the molecules, leading to liquefaction. Air liquefaction plants are large, complex industrial sites. The fractional distillation process consists of multiple stages and steps (Figure 13-2). The process begins with atmospheric air being drawn through filters and scrubbers to remove airborne contaminants. Next, it is compressed and cooled in several stages to 2000 psig and –50° F. Along the way, water vapor in the air freezes and is removed. The air is cooled further to –265° F at a pressure of 200 psig, then allowed to expand to 90 psig in a separator, where partial liquefaction takes place. The liquefied air from the separator is pumped to the top of the fractional distillation column. As it flows down the column, the nitrogen boils off and can be captured and stored in a gaseous or liquid state. O2 collects at the bottom of the column in liquid form. This liquid O2 contains a number of trace gas contaminants, primarily argon and krypton, and is further distilled to recover the argon. Distillation continues with careful control of temperature and pressure until the composition of the remaining liquid exceeds 99.0% O2, the standard of purity required by the U.S. Pharmacopoeia/National Formulary (USP/NF) for medical-grade O2.

FIGURE 13-2 The process of fractional distillation. Because N2 and O2 have different boiling points, the two gases can be separated on the basis of the temperature of the distillation chamber.

Description

Molecular Filtration Another method used to produce O2 is molecular filtration.3 This process is used widely in respiratory home care in the form of O2 concentrator devices. Molecular filtration is a generic term that refers to the filtering of gas molecules other than O2 through various methods. O2 production by molecular filtration uses the molecular sieve or pressure swing absorbent method (Figure 13-3). In this method, a vacuum draws room air into cylinders packed with crystallized zeolite, a silicate with ion exchange properties. The air is compressed (to 100 to 300 psig), and environmental nitrogen is filtered out—that is, temporarily absorbed by the zeolite. Switching to a depressurization phase, which causes the crystals to release the nitrogen as gas, reverses the process.

FIGURE 13-3 Molecular sieve. Oxygen concentrators concentrate oxygen from ambient air by filtering out nitrogen.

The final concentration of O2, as well as the flow setting for O2 exiting the sieve, varies among specific devices. Most concentrators deliver O2 in the 1 to 5 L/min range at a concentration between 0.95% and 0.98%, but that falls to 0.92% to 0.95% with higher flows. All O2 concentrators require routine mechanical maintenance and should be periodically checked (with an O2 analyzer and calibrated flow-measuring device) to

verify proper flow setting and O2 concentration. Respiratory Recap Ways to Produce Oxygen ∎ Photosynthesis ∎ Electrolysis of water ∎ Fractional distillation of air ∎ Molecular filtration

Distribution The normal physical state of O2 is a gas. When in gaseous form, O2 can be stored in cylinders and easily distributed by flexible and rigid piping systems. Because liquid O2 can be stored in much larger volumes more efficiently, hospitals use storage systems designed to contain O2 in the liquid state. These systems maintain the storage tanks at the pressure and temperature required to keep O2 in the liquid state: 716 psig and – 118° C. The process of returning the liquid O2 to gaseous O2 (which is more easily distributed and therapeutically usable) involves heating the liquid O2 and subsequent evaporation. To accomplish this heat gain, large liquid O2 storage and distribution systems use evaporator coils in which absorption of external ambient heat raises the temperature of the liquid O2 above its boiling point (which is still very cold). The heat absorption from the atmosphere needed to accomplish the evaporation of liquid O2 and its conversion to a gas results in ice formation on the evaporative coils of the storage system.

Carbon Dioxide Physical Characteristics Carbon dioxide (CO2) is a colorless, transparent, odorless to pungent, and tasteless or slightly acid-tasting gas with a specific gravity of 1.522, making it heavier than air. This gas is nonflammable and does not support combustion or animal life. Carbonic acid (H2CO3), which forms when CO2 dissolves in water, is corrosive to metals. Under normal atmospheric conditions, the atmospheric concentration of CO2 gas is very low, approximately 0.03% (FCO2 of 0.0003). CO2 in an unrefined form is released by the combustion of wood, coal, coke, natural gas, or oil and by lime kilns, the fermentation process, volcanoes, and natural springs. Animals exhale CO2 as a by-product of metabolism: O2 + Glucose → ATP + H2O + CO2 Humans exhale 5% CO2 (FECO2 = 0.05), which, along with exhaled H2O, constitutes the majority of the hydrocarbon by-products resulting from energy production by the mitochondria. In this process, the mitochondria produce adenosine triphosphate (ATP) as the energy molecule. Because CO2 is a by-product of both animal metabolism and the burning of carbonaceous fuels, the atmospheric concentration of CO2 is increasing. This increase in atmospheric CO2 (along with increases in methane gas concentrations) has resulted in an abnormal retention of planetary heat (the greenhouse effect) and is implicated in global warming. The current Occupational Safety and Health Act (OSHA) standard for the maximal allowable concentration of CO2 is 0.5% for 8 hours of continuous exposure, or 3% CO2 over a 10-minute period.

Therapeutic Uses Pure, or 100%, CO2 is not used therapeutically. In the past, small amounts of CO2 gas were sometimes added to breathing gas for control-

ventilated patients to increase PaCO2 and correct respiratory alkalosis. This application represented an alternative to the addition of mechanical dead space to ventilator breathing circuits. However, this practice has been largely abandoned. Because CO2 does not support life, it must be mixed with O2 to create carbogen if it is to be administered via inhalation. When carbogen is used therapeutically, it is for short treatment intervals of about 10 minutes, during which the patient must be monitored. The usual available mixtures are 90% O2 to 10% CO2 or 95% O2 to 5% CO2. The density, specific gravity, and viscosity of CO2 differ from those properties of O2 and air (refer to Table 13-2), and carbogen metering must take these differences into account. Carbogen has historically been used to treat hiccups (singultus), atelectasis, retinal revascularization after reattachment, anxiety-related hyperventilation, and cerebrovascular conditions. Breathing CO2 by inspiring and expiring into a paper bag remains a popular treatment for anxiety-related hyperventilation. The theorized mechanism for this treatment is that increasing the CO2 concentration of inspiratory gas through rebreathing the patient’s own exhaled CO2 will correct the hypocarbia (low PaCO2) that accompanies hyperventilation. Although this technique can be an effective distraction from the events that induced the anxiety-related hyperventilation, whether the suggested mechanism involves an increase in the CO2 concentration in breathing gas—that is, whether this technique increases the inspiratory CO2 level—requires further study. CO2 mixtures are used primarily in medicine for the calibration of capnographs, blood gas analyzers, and other laboratory and diagnostic equipment. CO2 is also used to insufflate the abdomen during laparoscopic surgery because it is absorbed and removed by the respiratory system. The nonflammable nature of this gas is important because laparoscopic procedures frequently use electrosurgical devices. Nonmedical uses of CO2 include carbonated beverage bottling, food preservation, refrigeration, and fire extinguishing. Solid CO2 (dry ice) exists at temperatures below its triple point of 69° F (21° C) and at a pressure above 60 psig. At temperatures below its triple point, dry ice will

sublimate into a gas without passing through a liquid phase. CO2 also has a low thermal conductivity, which allows dry ice to remain relatively stable. Stop and Think A fire occurs in a small kitchen where a patient’s family was using a hot plate to warm food. A CO2 fire extinguisher was available. What characteristics of that gas promote its use for this application?

Manufacture and Distribution The manufacture of CO2 for medical purposes involves refining atmospheric CO2. This process removes carbon monoxide, hydrogen sulfide, nitric acid, water, and other pollutants and impurities. The purity of CO2 gas must be at least 99.5%. Three forms of CO2 are available: cylinders at ambient temperatures, liquid at subambient temperatures, and solid CO2 (dry ice). Cylinders of CO2 commonly contain both liquid and gas if the temperature is below 31° C with pressures above 60 psig. This requires that cylinders be weighed to determine the quantity of liquid CO2 in the cylinder. This does not occur with medical mixtures of 95% to 5% and 90% to 10% O2–CO2. Figure 13-4 illustrates a cylinder containing both liquid and gas CO2.

FIGURE 13-4 A cylinder containing liquid and gas carbon dioxide (top) compared to a cylinder containing oxygen (bottom). In gases that assume the liquid state under typical cylinder pressure conditions, gas quantity and flow duration evaluation will require accounting for the amount of liquefied gas that remains in the cylinder. Modified from Dorsch JA, Dorsch SE. Understanding Anesthesia Equipment. 3rd ed. Baltimore: Lippincott Williams & Wilkins; 1994.

Helium Physical Characteristics Helium (He) is a rare gas naturally occurring in the atmosphere in extremely small amounts (0.000524% by volume). It is colorless, transparent, odorless, tasteless, and nonflammable; it does not support combustion or life. Helium is the second-lightest element (hydrogen is lighter), with an extremely low density (0.165 kg/m3) and specific gravity (0.138), slightly more than one-eighth that of air. It is not generally present in the atmosphere (less than 5 parts per million [ppm]) and is chemically and physiologically nonreactive (inert).

Therapeutic Uses Because helium is not life supporting, it must be mixed with at least 20% O2. Helium and O2 mixtures are called heliox. In higher concentrations (>50%) in these mixtures, helium is used for its low density and ability to reduce turbulence within natural or artificial airways for palliative treatment of large airway obstruction. Heliox is also used in place of compressed nitrogen and O2 mixtures for extreme hyperbaric conditions, such as in commercial and scientific deep-water operations. The use of heliox decreases the risk of nitrogen narcosis, and the low density of heliox lowers the work of breathing. Low concentrations (100 mm Hg with the application of supplemental O2. Current evidence suggests that hyperoxemia adversely impacts mortality: The greater the degree of hyperoxemia, the greater the deleterious effects. In critically ill patients and those with chronic hypercapnia, a target SpO2 of 88% to 95% is acceptable. Respiratory therapists should be vigilant in titrating O2 to achieve these target SpO2 goals.9,19

Nitrogen Washout Atelectasis Absorption atelectasis can occur with high-concentration O2 breathing, secondary to washout of nitrogen from the lungs (nitrogen washout atelectasis). During room-air breathing, the partial pressure of nitrogen in the lungs is approximately 570 mm Hg. When FIO2 increases, O2 molecules displace nitrogen molecules in the alveoli. In case of airway obstruction or reduction in ventilation, hemoglobin in the pulmonary circulation extracts O2 from the alveolus. Alveolar collapse occurs when a critically low volume is reached, and hypoxemia results from increased physiologic shunting.

Oxygen-Induced Hypoventilation To understand oxygen-induced hypoventilation, it is necessary to review both neurologic control of breathing and pulmonary vascular changes related to O2. Under normoxic conditions, the control of ventilation is managed by the CO2 drive (carbic ventilatory drive). Chemoreceptors in the central nervous system respond to the hydrogen ion concentration ([H+]) of the cerebral spinal fluid (CSF). The [H+] in the CSF is determined primarily by the PaCO2. That is, when the PaCO2 increases, so does the [H+] of the CSF. Receptors in the brain stem

sense changes in [H+] of the CSF and respond by changing the level of ventilation to maintain a normal PaCO2. These central chemoreceptors are very sensitive to small changes in H+ and maintain the PaCO2 within very narrow limits. The hypoxemic drive (also called hypoxic drive) represents a second chemoventilation mechanism. The peripheral chemoreceptors, which are located in the aortic arch and the carotid bodies, increase ventilation when the PaO2 falls to less than approximately 60 mm Hg, the hypoxemic threshold. For example, when a person climbing a mountain reaches an altitude where PIO2 causes a PaO2 of less than 60 mm Hg (12,000 to 15,000 ft), the climber experiences an increased ventilatory rate and tidal volume. The hypoxemic drive and the carbic drive act independently of each other, but the hypoxemic drive can override the carbic drive. O2-induced hypoventilation may occur in some patients who have adapted to long-term hypercarbia (elevated baseline PaCO2). Examples of diagnoses associated with chronic hypercarbia include end-stage COPD and cystic fibrosis, severe neuromuscular failure, and obesity hypoventilation syndrome. In these patients, the carbic drive no longer responds appropriately to PaCO2 levels, such that the hypoxemic drive becomes the primary ventilatory drive. These patients require hypoxemia to stimulate their ventilation (PaO2 ≈ 60–65 mm Hg and SpO2 ≈ 92%). Administration of supplemental O2 to return the PaO2 to normal or greater levels may suppress the hypoxemic ventilatory drive, leading to diminished ventilation. As a result of this O2-induced hypoventilation, the PaCO2 increases and the patient becomes more hypoxemic. Some have challenged the posited role of hypoxemic drive suppression as a complete explanation for O2-induced hypoventilation.20–24 Studies have shown that the hypoxemic drive is only marginally affected by O2 therapy. It has been suggested that (1) worsening mismatching results in increased dead space, (2) abolition of the normal hypoxic vasoconstriction allows blood to flow to poorly ventilated lung zones, and (3) O2 influences the ability of hemoglobin to bind CO2 (the Haldane effect). Regardless of the mechanism, clinicians must stay alert to the possibility of increased PaCO2 when administering supplemental O2 to patients with chronic hypercapnia. They should titrate

O2 to produce a PaO2 of 50 to 60 mm Hg with an SpO2 target range of 88% to 92%. Application of supplemental O2 that produces SpO2 in excess of 92% may increase PaCO2, resulting in respiratory acidosis. Liberal administration of O2 increases mortality without improving other patient-important outcomes.25 Never withhold or withdraw O2 in the face of high or rising PaCO2, and it is critical to titrate supplemental O2 to maintain SpO2 within the target range. If O2-induced hypercapnia results in a severely elevated PaCO2, noninvasive or invasive mechanical ventilation is indicated. Stop and Think A patient with severe COPD has a PaCO2 of 90 mm Hg and a pH of 7.35. He is using O2 at 2 L/min by cannula and has an SpO2 of 91%. Why is it important that you tell the patient to never increase the O2 flow?

Retinopathy of Prematurity Retinopathy of prematurity (ROP) is an insult to the developing retinal vasculature from an elevated PaO2. First described in 1942, this condition was originally termed retrolental fibroplasia (RLF). In ROP, O2 radicals attack the incompletely developed retinal tissue, resulting in vasoconstriction, which can progress to complete obliteration and retinal detachment. Elevated PaO2 in retinal vessel walls is one of several predisposing factors that can result in visual defects; such defects can ultimately progress to total blindness. Low birth weight, sepsis, gestational age, apnea, acidemia/hypercarbia, O2 levels, and length of exposure all interact as multiple causes. ROP is also seen in low-birthweight babies who did not receive supplemental O2. The incidence of blindness varies from 1% to 3% in all live births and from 40% to 70% in infants weighing less than 1 kg. The risk of blindness, which is inversely proportional to birth weight, is highest in neonates weighing less than 1 kg. In the 1940s and 1950s, the incidence of ROP reached epidemic proportions because O2 was used without monitoring. The development

of arterial blood gas measurements and pulse oximetry monitoring subsequently reduced the incidence of perinatal O2-related complications. The FIO2 of critically ill infants should be monitored and PaO2 and SpO2 assessed by periodic blood gases and continuous pulse oximetry. It appears that the extent of prematurity, the duration of O2 use, and the PaO2 are all factors in developing ROP.26

Closure of the Ductus Arteriosus Prior to the birth transition (in utero), the placenta provides O2 to the fetus while the fetal lungs are developing. During this time, it is important that the quantity of blood flow into the pulmonary capillary bed be limited. To achieve this effect, fetal circulation has a blood flow bypass (shunt) that redirects blood directly from the right heart into the left heart and aorta. This right-to-left shunting is accomplished via blood flow through the foramen ovale (between the two fetal atria) and the ductus arteriosus (between the pulmonary artery and the aorta). At the time of birth, both the foramen ovale and ductus effectively close. The foramen ovale flow ceases because the pressures in the atria equalize; the ductus arteriosus must be actively closed by smooth muscle contraction. The biochemical signal that initiates and stimulates ductus closure during the birth event is the dramatic, sudden increase in PaO2 that the infant experiences after beginning breathing. Neonates who experience postpartum hypoxemia are known to open the ductus (patent ductus arteriosus), which exacerbates hypoxemia due to the return to the previously necessary fetal shunt. Moreover, neonates with congenital heart defects (CHDs) often depend on patency of the ductus arteriosus for either pulmonary or systemic blood flow. Those with pulmonary atresia account for the majority of cases, but neonates with coarctation of the aorta, tricuspid atresia, and aortic arch interruption may also experience patent ductus arteriosus. Newborns with these CHDs experience profound hypoxia or circulatory collapse if the ductus closes. Increasing PO2 is the chief trigger of ductal smooth muscle contraction, so a modest PaO2 is also indicated as a palliative measure or until corrective surgery is performed. Administration of prostaglandin E1 can

prevent closure of the ductus for these newborns.27

Support of Combustion Fire hazard is a concern when dealing with normobaric O2 as well as a major hazard in hyperbaric applications. While O2 is not combustible, flammable, or inflammable, it does support more intense combustion of fuels in proportion to its concentration. Ignition can result in a flash flame via fine surface fibers of fabric or body hair. Combustible materials (e.g., cigarettes), sparking friction toys, and electric razors should be avoided in enclosures or close to open sources of O2. O2 administration is also a fire risk during laser bronchoscopy. Respiratory Recap Complications of Oxygen Therapy ∎ O2 toxicity is damage to lung tissue caused by breathing high concentrations of O2. ∎ A patient’s need for O2 must override concerns about O2 toxicity. ∎ Hyperoxemia can result in deleterious effects and increased mortality. ∎ Nitrogen washout atelectasis can occur with high concentrations of O2. ∎ O2-induced hypoventilation may occur in patients who rely on their hypoxemic drive. ∎ ROP occurs only in infants. ∎ Some infants with congenital heart defects need a low PaO2 to maintain an open ductus. ∎ O2 is not explosive, but it does increase the combustibility of other flammable materials.

Dosage Regulation and Administration Devices Once the gas pressure has been reduced to the safe working pressure of 50 psig (by a cylinder/pressure regulator system or as supplied by a bedside gas distribution station connector), a device to provide control of flow is needed. For example, when O2 or gas mixtures are administered directly to the patient via mask, aerosol, or nasal cannula, a method for metering the flow is necessary. Conversely, some equipment (such as blenders and ventilators) meter the flow internally and do not need an external flow meter device. Flow control devices can be categorized as follows: Flow restrictor: A preset, fixed flow controller. Bourdon gauge flow meter: An adjustable flow controller, with adjustable inlet pressure from a fixed outlet orifice. Thorpe tube flow meter: An adjustable flow controller, with preset inlet pressure from an adjustable outlet orifice.

Flow Restrictor The most basic flow meter is a flow restrictor (Figure 14-2). This carefully machined orifice is attached to a 50-psig gas source. It does not allow for adjustments; that is, it has a specific-size orifice that allows a specific flow of gas to pass, provided the inlet pressure is a constant 50 psig. Flow restrictors are uncomplicated, require no maintenance (because they have no moving parts or gauges), can be used in any position, and do not allow accidental changes in flow. To change the flow, the respiratory therapist must remove the single-flow flow restrictor and replace it with another orifice delivering the appropriate flow.

FIGURE 14-2 Fixed orifice flow restrictor. Reproduced from Egan’s Fundamentals of Respiratory Care, Seventh Edition. Scanlan CL, Wilkins RL, Stoller JK. Copyright Elsevier (Mosby) 1999.

Description By contrast, an adjustable flow restrictor allows the respiratory therapist to select one of a number of orifices, depending on the flow required. Adjustable multiple-orifice flow meters in combination with an indirect single-stage, preset regulator are commonly used on small cylinders in home care or patient transport because of their compact and lightweight configuration. Other applications include emergency resuscitation packs, in which compact, lightweight devices require relatively high flows to a bag-valve-mask device. Because they lack gauges that indicate the actual flow, flow restrictors should be periodically checked with a calibration flow meter. The outlet flow on a flow restrictor can be calculated using the following equation:

where is flow (L/min), P1 is the inlet pressure (50 psig), P2 is the outlet pressure (atmospheric), and R is the resistance to gas flow through the orifice. Any change to the P1 – P2 relationship alters the accuracy of the output flow—for example, if the inlet pressure varies from 50 psig or if increased resistance downstream from the orifice outlet creates backpressure.

Bourdon Gauge Flow Meters Like the flow restrictor, the Bourdon gauge flow meter has a fixed outlet orifice, but the pressure regulator is adjustable, which enables adjustment of the flow output by varying the pressure supply. The change in pressure is displayed on the face of the Bourdon gauge, which has been calibrated (labeled) in L/min, corresponding to the predictable flows at the variable inlet pressures. The Bourdon gauge is positioned between the pressure source and the fixed orifice. The gas pressure is transmitted to the gauge through a hollow tube. As the pressure increases, the closed distal end of the curved hollow tube assumes a straighter position (Figure 14-3). It is linked to a gear system and an indicator needle pointing to the calculated output flow for that pressure. Clinical devices frequently have two gauges: one that indicates cylinder pressure, and one that indicates the flow output (Figure 14-4). The gauge closest to the cylinder indicates the pressure contents of the cylinder.

FIGURE 14-3 Bourdon flow gauge, showing the hollow pressure tube and gearing mechanism in an unpressurized state (A) and a pressurized state (B). An increase in pressure causes straightening of the tube and movement of the indicator needle. Modified from Ward JJ. Equipment for mixed gas and oxygen therapy. In: Barnes TA, ed. Core Textbook of Respiratory Care Practice. 2nd ed. Mosby; St. Louis, 1994.

FIGURE 14-4 (A) An adjustable, direct-acting, single-stage, high-pressure-reducing regulator. (B) A single-stage, adjustable American Standard Safety System (ASSS) regulator with two Bourdon gauges. The gauge to the right, closest to the connection to the gas source, is calibrated in pounds per square inch (psi), indicating the contents of the cylinder. The Bourdon gauge closest to the outlet is calibrated in liters per minute (L/min). To set the flow, the operator turns the knob, increasing or decreasing the regulator pressure and, in turn, the outlet flow through the fixed orifice. (C) Pin-indexed (PISS) Bourdon gauge flow meter on an O2 cylinder. (A) Reproduced from Scanlan CL, Wilkins RL, Stoller JK. Egan’s Fundamentals of Respiratory Care. 7th ed. St. Louis: Mosby; 1999; (B) Courtesy of Western Enterprises, a Scott Fetzer Company.

Description With Bourdon gauge flow meters, the flow meter is accurate if the outlet flow is unrestricted. However, when resistance is added downstream of the fixed outlet orifice, such as with the addition of a long length of tubing and respiratory equipment, the outlet pressure (P2) rises and the actual outlet flow decreases (Figure 14-5). In fact, if the Bourdon gauge outlet became completely obstructed, the gauge continues to show flow even though none is present. Because pneumatic nebulizers

present a large downstream resistance to the flow meter, they should not be used with a Bourdon gauge if it is necessary to have an accurate measurement of the flow.

FIGURE 14-5 Bourdon gauge illustrating (A) that with a constant inlet pressure and a known fixed outlet orifice size, a predictable outlet flow is achieved and is indicated on the gauge face. Adding resistance downstream of the fixed outlet orifice (B) diminishes flow, yet the gauge reading remains unchanged because it measures the pressure prior to the resistance. If the outlet orifice becomes completely obstructed (C), allowing no flow, the gauge continues to indicate a flow is occurring, even though there is none, because it continues to read the pre-obstruction pressure.

Bourdon gauges are commonly used on medical gas cylinders for transport when a mask or nasal cannula is used. These compact flow meters are handy because they allow flow to be changed (in contrast to flow restrictors), and they can be read correctly without being held in a vertical (gravity-dependent) position.

Thorpe Tube Flow Meters The most commonly used type of medical gas flow meters—called pressure-compensated Thorpe tube flow meters, rotameters, or simply

flow meters—have a needle valve to adjust the flow and a hollow tube with an indicator float device. The name rotameter implies use of a rotating bobbin or float instead of a spherical-type indicator. Rotameters are often used to administer anesthetic gases, which require greater accuracy in flow indication. Unlike flow resistors and Bourdon gauges, a pressure-compensated Thorpe tube flow meter displays the actual outlet flow regardless of downstream resistance. As long as the inlet pressure remains constant, this device provides correct readings of outlet flow. For this reason, these flow control and flow measurement devices are the most prevalent type of dosage regulation device in hospitals for direct, quick-connect application to piped outlet stations. A Thorpe tube flow meter consists of a clear, tapered glass tube with a diameter that is larger at the top than at the bottom. The tube has graduated markings calibrated to indicate flow (usually in liters or milliliters per minute). A float in the glass tube indicates the gas flow, and a needle valve controls the flow. Opening the needle valve causes gas to flow from the pressure source. Gas entering the bottom of the Thorpe tube creates a pressure differential to lift the float. As the float rises in the tapered tube, the diameter of the tube increases (equivalent to an increase in the outlet orifice size), enabling more gas to flow around the float. The float stabilizes when the upward force of the pressure differential across the float equals the downward force of gravity. The location of the needle valve in the Thorpe tube flow meter is important for its ability to provide accurate readings. It can be located distal (downstream) or proximal (upstream) to the Thorpe tube (Figure 14-6). Placing the needle valve distal to the Thorpe tube creates a pressure-compensated flow meter. When increasing backpressure is applied to the outlet of the flow meter, the float drops, reflecting the decrease in outlet flow but without disturbing the pressure relationship above and below the indicator. The pressure-compensated Thorpe tube flow meter is preferred for clinical applications because it provides an accurate display of flow in the face of downstream resistance, provided it is in a vertical position and the inlet pressure remains constant. Figure 14-7 shows the effects of backpressure on pressure-compensated Thorpe tube flow meters, non-pressure-compensated flow meters, and Bourdon gauge flow meters.

FIGURE 14-6 (A) Non-pressure-compensated Thorpe tube flow meter (left) in which the needle valve is placed before the Thorpe tube, along with a diagram of a flow meter (right) with the needle valve placement after the Thorpe tube (backpressure compensated). (B) Commercially available Thorpe tube flow meter. (A) Modified from Cairo JM, Pilbeam SP. Mosby’s Respiratory Care Equipment. 6th ed. Mosby; St. Louis, 1999; (B) © Jones & Bartlett Learning. Courtesy of MIEMSS.

Description

FIGURE 14-7 Comparison of the accuracy of pressure-compensated and noncompensated Thorpe tube flow meters and a Bourdon gauge when faced with increasing levels of downstream backpressure. The pressure-compensated Thorpe tube’s indicated flow is the actual flow regardless of backpressure. With a noncompensated Thorpe tube, actual flow is higher than the indicated flow at increasing downstream pressure. With the Bourdon gauge, indicated flow is progressively higher than actual flow as backpressure increases. Modified from McPherson SP, Spearman CB. Respiratory Therapy Equipment. 5th ed. Mosby; St. Louis, 1995.

Description

Non-pressure-compensated flow meters continue to be used for laboratory or industrial applications. The non-pressure-compensated version of the Thorpe tube flow meter has the needle valve located proximal to the Thorpe tube. When a flow-restricting device is attached to a non-pressure-compensated Thorpe tube flow meter, thereby increasing the downstream resistance, the pressure relationship above and below the ball becomes distorted within the Thorpe tube. This forces the float downward and provides a reading lower than the actual flow. To determine whether a Thorpe tube flow meter is a pressurecompensated model, the needle valve is closed and the flow meter subsequently pressurized as the cylinder valve is opened or is connected to a station outlet. If the Thorpe tube flow meter is pressure compensated, the float will rise to the top of the tube and then fall back as gas rushes in and fills the tube to the needle valve. Most Thorpe tube flow meters commonly used in respiratory therapy use a ball as the float, although the float may assume various shapes and configurations. Sighting the float at eye level is important to avoid inaccuracy due to parallax. A ball float is read through the center of the ball, whereas rotameter floats are read at the top surface. Although most clinical flow meters are scaled from 0 to 16 L/min, the need for more accurate reading of low flows for infants and O2-sensitive adult patients has fostered development of 0- to 1-L/min or 0- to 5-L/min versions. Most Thorpe-type flow meters also have a flush setting beyond the calibrated range. Although no industry standard exists, most flow meters provide greater than 60 L/min on the flush setting. High-flow O2 delivery systems (requiring calibrated flow measurements) have prompted manufacturers to develop 0- to 75-L/min Thorpe tubes. Respiratory Recap Flow Meters ∎ Flow restrictors are preset, fixed flow meters. ∎ Pressure-compensated Thorpe flow meters indicate actual flow unless the source gas pressure varies from 50 psig or the float tube is not set in the vertical position. ∎ Bourdon gauges, although less accurate, are used whenever a patient application requires that the regulator not be in a vertical position.

Stop and Think A patient is receiving O2 by nasal cannula at 4 L/min. She needs to be transported to the magnetic resonance imaging (MRI) unit. The E cylinder must be attached horizontal to the hospital bed. What would be your considerations when selecting a cylinder and flow meter?

Oxygen Administration Devices O2 therapy systems are categorized as either low-flow/variableperformance devices or high-flow/fixed-performance devices. Variable-performance devices (referred to as low-flow devices) provide variable and approximate FIO2, whereas fixed-performance devices (referred to as high-flow devices) are designed to provide a fixed and known FIO2. The descriptive names most commonly employed in the clinical setting—that is, low flow and high flow—can be confusing. The distinguishing characteristic of the two types of devices is whether it provides a premixed, precise, and known FIO2 (fixed performance) or whether the FIO2 received by the patient depends on the patient’s breathing pattern and volume in combination with supplemental 1.0 FIO2 gas administered by the device (variable performance). Suppose a patient using a nasal cannula (a low-flow device) receives a flow of 100% O2 at 6 L/min. The flow of gas coming from the nasal cannula is continuous across both inspiration and expiration, but during inspiration the patient will inhale an inspiratory volume composed of some of the 100% O2 and some air present in the room (21% O2). In consequence, the FIO2 that enters the trachea and is delivered to the alveoli varies from patient to patient, and from breath to breath, depending on the tidal volume and respiratory rate and pattern. Thus, low-flow devices provide variable performance because the delivered FIO2 cannot be accurately known. In contrast, high-flow devices produce flow outputs that meet or exceed the patient’s full inspiratory flow demand and are more likely to maintain a fixed FIO2. Like low-flow devices, high-flow devices provide gas continuously (throughout inspiration and expiration) but at the desired O2 concentration (FIO2). The major difference between high-flow and low-flow devices is that the high-flow device provides such a high flow of premixed gas that the patient is not likely to inhale any room air. Examples of high-flow devices include air-entrainment devices such as masks and large-volume nebulizers.

Low-Flow (Variable-Performance) Devices The primary distinguishing feature of low-flow O2 administration devices is that the patient experiences a variable FIO2 through variations in minute ventilation (especially changes in tidal volume, inspiratory flow, and respiratory rate). Such a device delivers 100% O2 to the patient’s upper airway, which is mixed during inspiration with variable amounts of inhaled room air to produce the final delivered FIO2. Examples of low-flow O2 administration devices are the nasal cannula, simple mask, partial rebreathing mask, nonrebreathing mask, open O2 mask, and transtracheal O2 catheter.

Low-Flow Nasal Cannula The nasal oxygen cannula (Figure 14-8) is the most widely used device for administering low-flow O2 to infants, children, and adults in the hospital and the home. The low-flow nasal cannula is easily applied and well tolerated by most patients when used with flows up to 6 L/min. This device consists of a delivery tube that ends in two short prongs, each about 0.5 inch long and made of soft, pliable plastic. Cannula prongs are available in a variety of styles, in sizes for adults and infants, as curved or straight, and as tapered or nontapered. The nasal prongs are held in place either with an elastic band around the patient’s head or by loops of the delivery tubing over the patient’s ears, which are then held in place with an adjustable slide placed under the chin.

FIGURE 14-8 (A) Nasal cannula with elastic strap. (B) Over-the-ear–style nasal cannula. (C) Various styles of nasal prongs.

(A) and (B) Adapted from Scanlan CL, et al. Egan’s Fundamentals of Respiratory Care. 7th ed. Mosby; 1999; (C) Courtesy of Teleflex Incorporated. Unauthorized use prohibited.

When O2 is delivered by low-flow nasal cannula to adults, the expected delivery may be an FIO2 of 0.22 to 0.24 at 1 L/min and approximately 0.40 at 5 to 6 L/min. Actual FIO2 levels achieved with a nasal cannula at specific O2 flows have been debated for many years. A wide range of FIO2 levels are delivered to the trachea because of the variability of this device.28–36 Although the standard cannula is typically set at flows of 1 to 6 L/min, flow can be increased to 10 to 15 L/min, which can achieve tracheal concentrations of 0.4 to 0.5. That level of flow is uncomfortable for patients, however, and should be considered only for short-term use. Figure 14-9 show a graphic representation of the factors that affect FIO2 when O2 is delivered by nasal cannula. One area of confusion relates to the effect of mouth breathing with nasal cannula. Although mouth breathing might lower the FIO2, the nasal cannula is an effective O2 delivery device even when the patient inspires through the mouth because O2 still flows through the nose into the pharynx.

FIGURE 14-9 Factors that affect the volume of oxygen inspired by nasal cannula. Reproduced from Shigeoka JW, Bonekat HW. The current status of oxygen-conserving devices (editorial). Respir Care 1985;30(10):833–836.

Description

Physical examination findings and SpO2 measurements are the most important clinical assessments with the low-flow nasal cannula. A bedside estimate may be useful when initiating therapy for patients with normal breathing conditions and flows up to 5 L/min, however. Generally, the delivered FIO2 increases approximately 0.025 (2.5%) per each 1 L/min above the ambient O2 level (Equation 14-1). EQUATION 14-1 Estimation of FIO2 with Adult Low-Flow Nasal Cannula Shapiro Formula FIO2 = 0.20 + (0.04 × L/min O2) For 2 L/min, estimated FIO2 = 0.20 + (0.04 × 2 L/min) = 0.20 + 0.08 = 0.28 or 28%

Vincent Formula FIO2 = 0.21 + (0.03 × L/min O2) Example: If cannula provides 2 L/min, estimated FIO2 = 0.21 + (0.03 × 2 L/min) = 0.21 + 0.06 = 0.27 or 27%

Duprez Formula

Example: For E = 10 L/min, Ti/Ttot = 0.33, and flow of 2 L/min, FIO2 = 0.21 + 1/(4 × 10) × 2 = 0.26. Adapted from Duprez F, Mashayekhi S, Cuvelier G, Legrand A, Reychler G. A new formula for predicting the fraction of delivered oxygen during low-flow oxygen therapy. Respir Care 2018;63(12):1528–1534.

When the low-flow nasal cannula is applied to the patient, the clinician should confirm flow from the distal prongs by feeling for gas flow. Absent or inappropriately low flow should prompt the respiratory therapist to troubleshoot the gas source, the flow meter, or whether the cannula or connecting tubing may be kinked. A leak at the humidifier bottle seal (if used) is also possible. O2 flow to a low-flow nasal cannula should initially be titrated to each

patient using vital signs and pulse oximetry. At a minimum, the respiratory therapist should record set O2 flow, respiratory rate, and SpO2 in the patient’s record. When adult patients’ respiratory rates exceed 20 breaths/min, FIO2 will likely be below calculated bedside estimates. The FIO2 may vary greatly depending on the patient’s inspiratory flow demand and physical size. The more closely the patient’s inspiratory flow matches the delivered O2 flow, the higher and more consistent the FIO2 will be. Special attention should be paid to smaller patients, taller patients, and those with variable inspiratory demands to ensure the target SpO2 values are maintained properly to avoid hypoxemia and hyperoxemia. Further titration of flow to the low-flow nasal cannula is ultimately guided by a combination of patient exam findings and the SpO2 or arterial blood gas values. The most practical application of an estimated FIO2 is to determine the approximate FIO2 for patients whose pulmonary conditions have worsened, so as to establish an FIO2 starting point to selecting higher FIO2 and/or high-flow O2 therapy systems. As a comfort compromise, some clinicians combine a low-flow nasal cannula with additional flow from an O2 mask to provide a higher FIO2. A frequent patient complaint while using a low-flow nasal cannula is drying of the nasal mucosa. Use of bubble humidifiers may address this problem to some extent. These unheated devices are inefficient,37,38 however, and many hospitals do not routinely use them. Patients may also experience discomfort due to the pressure of the tubing or elastic band when they are in long-term contact with the face or ears. Gauze padding can be added to protect pressure points on the ears and/or cheekbones. Commercially available foam ear protectors are also available for this purpose (Figure 14-10).

FIGURE 14-10 Ear pads to decrease pressure sores with use of nasal cannula. Courtesy of Westmed, Inc.

Low-flow nasal cannulas are available in sizes appropriate for infants, toddlers, and children. Because of these patients’ small tidal volumes and rapid respiratory frequencies, the O2 flow to infants and children should be precisely controlled by use of flow meters with an appropriate scale (0 to 1 or 2 L/min in increments of 0.25 or 0.0625 L/min). A flow of 0.25 L/min by nasal cannula to an infant can achieve an FIO2 of 0.35, and an FIO2 of more than 0.60 at 1 L/min is possible. Because even minor alterations in flow can result in drastic FIO2 changes, oxygen–air blenders have been used to independently set both flow and FIO2 to the cannula to allow greater control.

Respiratory Recap Low-Flow Nasal Cannula ∎ Factors affecting the inhaled volume of O2: flow, concentration of O2 from flow meter, volume inspired, respiratory rate, total respiratory time or cycle time, inspiratory time, inspiratory flow, inspiratory flow pattern ∎ Factors that might cause air dilution of inspired O2: open-mouth or closed-mouth breathing, diameter of cannula compared to lumen of nares, volume of anatomic airways acting as a reservoir and dead space

Simple Mask The simple oxygen mask (also called a nonreservoir oxygen mask) is used when a higher FIO2 is needed than can be attained with a nasal cannula or when a cannula is not appropriate because of nasal obstruction, such as in emergency situations and during and after minor surgical procedures. The simple oronasal mask is a disposable plastic product available in infant, child, and adult sizes, with a length of smalldiameter O2 supply tubing connected to the base of the mask. The mask fits over the bridge of the nose and often is held in place with a malleable aluminum strip, which helps minimize leakage toward the eyes. It covers the nose and mouth down to below the lower lip or to under the chin and is held in place by an elastic band around the head. There is no sealing device (similar to resuscitation masks), and exhaled air leaves via side holes and between the mask and face; inboard inhalation of room air also can occur (Figure 14-11).

FIGURE 14-11 Simple O2 mask. Image Courtesy of Teleflex Incorporated. © Teleflex Incorporated. All rights reserved.

The simple O2 mask increases the inspired O2 concentration by acting as an O2 reservoir that adds a volume in an adult mask of 100 to 200 mL, which is inhaled at the beginning of inspiration. The patient also inhales room air through a series of small holes in the mask. The amount of O2 enrichment of the inspired air depends on the mask volume, the pattern of ventilation, and the O2 flow to the mask. It is difficult to predict the delivered FIO2 at specific flows. During normal breathing, the FIO2 may range from 0.3 to 0.6 with flows of 5 to 10 L/min, respectively. O2

levels can be higher with small tidal volumes or slow breathing rates. With higher flows and normal breathing patterns, FIO2 may approach 0.4 to 0.8. Because the mask accumulates CO2 during exhalation, the O2 flow must be sufficient to wash out the mask and prevent rebreathing.39 A general recommendation is that a minimum flow of 5 L/min should be used to avoid accumulation of exhaled CO2. Stop and Think You are asked to assess a patient with COPD. When you arrive at the bedside, you note that he is receiving O2 at 2 L/min by simple mask. His SpO2 is 90%. What would be your response?

All oronasal masks present the same problems, which include claustrophobic feelings for some patients, speech muffling, and difficulty with eating and drinking. Additionally, any mask administration device increases the possibility of aspirating regurgitated stomach contents.

Partial Rebreathing Mask The partial rebreathing mask combines the simple mask with an attached nonvalved 300- to 600-mL reservoir bag. This device’s name is actually somewhat inaccurate: Although some insignificant rebreathing of exhaled gas occurs, the mask’s actual indication is primarily for administering relatively high O2 concentrations to severely hypoxemic patients. The O2 supply tube is positioned between the mask and the reservoir bag. The O2 flow is set at a rate sufficient to keep the bag at least partially inflated throughout inspiration. This flow varies depending on the patient’s respiratory pattern but is usually between 8 and 15 L/min, which produces an FIO2 in the range of 0.4 to 0.7, depending on the patient’s respiratory pattern. Exhaled gas exits the mask through the vents on the sides, because fresh 100% O2 from the supply tubing continues to inflate the reservoir. When the patient takes the next breath, the inspiratory gas consists of a mixture of 100% O2 from the O2 source, the 100% O2 that filled the

reservoir during exhalation, and some room air inhaled through the mask ports. Partial rebreathing masks are not commonly used in present-day practice.

Nonrebreathing Mask The nonrebreathing mask (NRB) (Figure 14-12) uses the same basic system as the partial rebreathing mask but incorporates valves both between the bag and the mask and on at least one of the exhalation side ports. Removing the valves converts the nonrebreathing mask to a partial rebreathing mask. Small-bore tubing directs O2 into the mask and into the reservoir bag. A one-way valve prevents exhaled gas from entering the reservoir; instead, the entire exhaled volume exits the mask through the mask ports and between face and mask. During exhalation, the reservoir bag can refill with O2. At the beginning of inspiration, the mask exhalation port valves close, minimizing room air from being drawn in, and the reservoir valve opens, allowing the patient to inhale 300 to 500 mL of O2 from the reservoir in addition to the O2 flow. If the system were perfect, delivery of 100% O2 would be possible. These inexpensive disposable masks cannot provide an airtight fit on the face, however, and their valves are simple rubber or vinyl disks that do not provide a perfect seal. Nevertheless, at flows of 10 to 15 L/min, an FIO2 of 0.6 to 0.8 is achievable during normal breathing conditions. As with the partial rebreathing mask, the O2 flow must be set at a rate high enough to prevent the bag from emptying by more than half. The NRB is indicated for patients who require a high FIO2 but tend to have a relatively normal respiratory pattern. Such patients include those with trauma, MI, or carbon monoxide exposure.

FIGURE 14-12 (A) (A) Nonrebreathing mask. Removal of the valves converts to a partial repreathing mask. (B) Commercially available nonrebreathing mask. (A) Image Courtesy of Teleflex Incorporated. © Teleflex Incorporated. All rights reserved; (B) © Andrew Gentry/Shutterstock, Inc.

A risk of suffocation arises with the NRB if the mask valves stick or the O2 supply fails. Thus, some safety system must be provided to allow room air to enter and prevent suffocation. Some manufacturers provide spring-loaded antisuffocation valves at the neck of the reservoir bag for this purpose. The spring-loaded antisuffocation valve opens if the pressure in the mask becomes subatmospheric, as happens when the O2 supply fails. Other manufacturers provide the NRB with a valve on only one side of the mask.

Open Oxygen Mask The open O2 mask (OxyMask by SouthMedic) is a low-flow O2 mask that employs a unique design: It combines the simple O2 mask with large openings that allow both room-air entrainment and clearing of exhaled carbon dioxide with low flows (Figure 14-13). The open O2 mask can be used with flows as low as 1 L/min and up to 15 L/min or flush, to achieve FIO2 ranging from 0.24 to 0.90.

FIGURE 14-13 The open oxygen mask. OxyMask, http://thebetteroxygenmask.com/oxymask/

The mask uses a pin and diffuser system to redistribute the flow of O2 to create a mushroom-shaped cloud of concentrated O2 toward the user’s nose and mouth. The large openings in the mask serve two main purposes. First, they allow room-air entrainment and subsequent dilution of inhaled O2. As with all low-flow devices, inspiratory flow and tidal volume impact air entrainment and subsequent delivered FIO2. Second, the large openings do not retain exhaled air, allowing easy flushing of exhaled carbon dioxide. This eliminates the risk of rebreathing, suffocation, and aspiration.

High-Flow (Fixed-Performance) Devices Several methods exist for controlling FIO2 and ensuring delivery of adequate flow to meet inspiratory demands. High-flow O2 administration devices blend 100% O2 and room air (21% O2) to produce a gas with the desired FIO2 and provide a flow of the gas high enough to prevent the patient from diluting the FIO2 with room air. High-flow O2 delivery devices accomplish this by delivering a flow exceeding any tidal volume, respiratory frequency, or inspiratory flow that the patient might produce. Adult patients with gasping inspirations with flows >40 to 60 L/min and/or sustained respiratory rates >20 breaths/min are potential candidates for high-flow delivery systems. Respiratory Recap Low-Flow Oxygen Delivery Devices ∎ FIO2 is the actual dose of O2 administered. ∎ Low-flow devices provide only a portion of the patient’s tidal volume. ∎ FIO2 of low-flow devices will vary depending on patient breathing patterns as well as the O2 flow delivered. ∎ Low-flow devices are titrated with pulse oximetry or arterial blood gases to achieve acceptable SpO2 and/or PaO2.

The low-flow nasal cannula consists of nasal prongs delivering 1 to 6 L/min in adults, ∎ which provide 0.24–0.40 FIO2 when breathing patterns are normal. ∎ The partial rebreathing mask uses low-flow O2 to achieve higher concentrations with an attached unvalved reservoir bag (0.40–0.70 FIO2). ∎ The nonrebreathing mask uses low-flow O2 to achieve higher concentrations with an attached valved reservoir bag (0.60–0.90 FIO2). ∎ The open O2 mask uses low-flow O2 yet can achieve higher-level concentrations through its unique design (0.24–0.90 FIO2).

Although high-flow O2 administration devices potentially offer a constant FIO2, this goal may not be achieved in all clinical situations. The respiratory therapist must understand the performance characteristics, design, and engineering constraints of each device. For example, if the patient’s inspiratory flow exceeds the flow from the device, the patient will dilute the FIO2 by breathing in additional room air. If this is not recognized, clinicians might be misled into falsely thinking that the patient is receiving a specific concentration of O2. Mixing 100% O2 and 21% O2 (room air) in the right proportions to produce a specific FIO2 is very much like making any solution, except that the solvent and the solute each contain O2. For example, if the respiratory therapist wishes to provide a 40% mixture of O2, each liter of 100% O2 must be diluted with 3 L of 21% room air. Because of quality differences among devices and discrepancies in the calibration of flow meters, it is important to verify any O2 concentration from any high-flow O2 administration device with an O2 analyzer. Air-to-oxygen mix ratios are highly predictable and can be mathematically modeled using relatively simple processes. One strategy is to memorize key mix ratios for common FIO2 levels (Table 14-2). Another strategy is to use a variant of the volume-concentration formula: TABLE 14-2 Air-to-Oxygen Mix Ratios for Various FIO2 Levels FIO2

Mix Ratio (Air:O2 Ratio)

0.24

25:1

0.28

10:1

0.30

8:1

0.35

5:1

0.40

3:1

0.50

1.7:1

0.60

1:1

0.70

0.6:1

0.80

0.3:1

V1 × C1 = V2 × C2 For example, if the respiratory therapist wishes to find the mix ratio for a 0.40 FIO2 high-flow O2 administration device, the calculation will look like this: Air-to-O2 = (100 – O2%)/(O2% – 21):1 Air-to-O2 = (100 – 40)/(40 – 21):1 Air-to-O2 = (60/19):1 Air-to-O2 = 3:1 An O2 analyzer is used to verify the concentration. Another approach to finding the mix ratio is to use an ancient mathematical shortcut, known as the alligation alternate. Figure 14-14

illustrates this approach.

FIGURE 14-14 Magic box (alligation alternative) to determine the oxygen-to-air ratio when mixing O2 and air. Examples are shown for 40% and 60% O2.

Once the mix ratio is known, the respiratory therapist must determine the total gas flow. A total flow of 40 L/min suffices to meet or exceed the inspiratory demands of most adult patients. To obtain the desired FIO2 in sufficient quantities, the respiratory therapist can calculate various 100%

O2 flows, proportionally increasing the air flow to maintain the desired FIO2. Note the increasing sum, as demonstrated in Table 14-3. To reach an acceptable total flow of 40 L/min, the O2 flow must be set at least 10 L/min for an FIO2 of 0.40. TABLE 14-3 Flows of Oxygen, Air, and Total Flow for a 40% O2 Mixing Device Oxygen (L/min)

Air (L/min)

Total Flow (L/min)

1

3

4

2

6

8

3

9

12

4

12

16

10

30

40

The 40-L/min minimum flow guideline assumes that the patient’s minute ventilation will not exceed 10 L/min and the I:E (inspiration-toexpiration) ratio will be 1:3. Some patients may have a higher minute ventilation and, therefore, will require more total gas flow to be certain that the desired FIO2 delivery is provided. A general rule is that more gas flow is better from an FIO2 delivery standpoint. A higher gas flow produces more noise, can be annoying, and may deplete the gas source, however.

Large-Volume Air-Entrainment Nebulizers Large-volume, high-output, all-purpose nebulizers with either cool or heated aerosols have been used in respiratory therapy for many years to provide bland mist therapy with some control of the FIO2 (Figure 14-15).

With these devices, the clinician can adjust FIO2 by manipulating the size of the orifice, which limits air dilution of gas flow from the driving-gas flow meter (usually O2). An adjustable collar below the flow meter connection allows the operator to set the FIO2 in the range of approximately 0.3 to 1.0 (when used with O2). To increase FIO2, the operator sets the collar to a small orifice, which limits entrained as well as the total flow delivered to the system. At the 100% O2 setting, the entrainment orifice is closed, such that the only flow delivered comes from the flow meter itself (typically 15 L/min). The opposite occurs at the low end of FIO2: As more room air is entrained, total flow output increases. At the 35% O2 setting with 15 L/min O2 flow, the total output flow approaches 90 L/min. The large-volume air entrainment nebulizer should be considered a high-flow device only when FIO2 is set at ≤0.4. Most commercial units have a driving-gas inlet orifice diameter that limits flow to 12 to 15 L/min (at 50 psig). When the O2 input flow is 15 L/min, the total flows at FIO2 of 0.6, 0.7, and 1.0 are 30, 25, and 15 L/min, respectively.

FIGURE 14-15 (A) Large-volume air entrainment nebulizer. (B) Commercially available largevolume nebulizer. (A) Modified from Cohen N, Fink J. Humidity and aerosols. In: Eubanks DH, Bone RC, eds. Principles and Applications of Cardiorespiratory Care Equipment. Mosby; St. Louis, 1994. (B) Courtesy of Teleflex Incorporated. Unauthorized use prohibited.

The limited inlet flows may prevent the air-entrainment system flows from meeting the flow demand of tachypneic patients, who often are also hypoxemic and need the high FIO2 settings. Another concern is aerosol droplet deposition, which may cause water to collect in dependent portions of corrugated delivery tubing. This can increase resistance to gas flow, which causes backpressure to build within the nebulizing chamber and limit air entrainment. Gas flow can also become completely blocked, so that gas flows exit via the entrainment port. Respiratory therapists should be alert to patients who, when using an entrainment aerosol system, experience an increased inspiratory flow demand as a result of clinical deterioration. In such circumstances, an alternative system should be considered that ensures the required FIO2

with higher flow capability. One approach is to use two nebulizers in tandem (Figure 14-16). Another strategy is to use a gas injection nebulizer (GIN), in which an additional flow is added downstream from the nebulizer output (Figure 14-17). Yet another option is to employ specially designed high-flow air-entrainment nebulizers, which offer larger-diameter gas inlet orifices to facilitate higher flows at a higher FIO2.

FIGURE 14-16 High-flow nebulizers used in tandem.

FIGURE 14-17 An injection nebulizer, in which additional flow is injected at the outlet of the nebulizer.

Nebulizer systems can direct gas flow to the patient’s face or an

artificial airway with a variety of appliances. The aerosol mask, tracheostomy collar, face tent, and T-piece or Briggs adapter (Figure 1418) are all attached to the large-volume nebulizer by large-bore 22-mm corrugated tubing. Each of these interfaces provides an open system that freely vents inspiratory and expiratory gases around the patient’s face or out of the mask hole openings or through the distal port of a Briggs adapter. Such an open-ended system also can lead to considerable secondary dilution of the FO2. Because these nebulizers produce an aerosol, respiratory therapists can use that as a visual clue to whether total gas flow is matching patient’s inspiratory flow demand. Additional flow may be required if the aerosol exiting the interface disappears during inspiration. Providing adequate flow is especially important if a patient’s oxygenation status is poor or deteriorating, as such patients frequently dramatically increase their inspiratory flow and minute ventilation.

FIGURE 14-18 (A) Aerosol mask. (B) T-piece and reservoir. (C) Face tent. (D) Tracheostomy mask. (A-D) Adapted from Fink JR, Hunt GE. Clinical Practice of Respiratory Care. Lippincott Williams & Wilkins; Philadelphia, 1999.

Stop and Think You are asked to assess a recently extubated patient. Following extubation, she was placed on a face mask with large-volume air-entrainment nebulizer at 40% dilution and an O2 flow of 14 L/min. The SpO2 was 88% just prior to your arrival. The physician increased the O2

setting to 60%, and the SpO2 is now 84%. When you increase the nebulizer dilution setting to 80%, the SpO2 decreases to 82%. How can you explain this response, and what would you do next?

Air-Entrainment Masks An air-entrainment mask comprises a single-patient-use disposable mask with a jet nozzle and entrainment ports. The jet nozzle delivers 100% O2, increasing the flow’s velocity. Moving at high velocity, this gas entrains (or slipstreams) ambient air into the mask because of the viscous shearing forces between the gas traveling through the nozzle and the stagnant ambient air. The FIO2 achieved depends on the nozzle size and the size of the entrainment ports. Commercially available systems use interchangeable jets, adjustable entrainment ports, or a combination of these (Figure 14-19 and Table 14-4).

FIGURE 14-19 (A) Air-entrainment mask. (B) Commercially available air-entrainment mask. (C) Changes in air entrainment by changing jet size or changing size of the entrainment port.

TABLE 14-4 FIO2, Minimum Flow Requirements, Outputs, and Entrainment Ratios for an Air-Entrainment Mask

Description Data from Branson RD. The nuts and bolts of increasing arterial oxygenation: devices and techniques. Respir Care 1993;3(8):672–686.

FIO2 levels will increase if the patient’s hands or bed sheets obstruct the entrainment ports. The patient should be encouraged to keep the mask on the face constantly. A notable limitation of this device is that patients often do not keep the mask on their face while speaking, eating, or drinking. Air-entrainment masks represent a reasonable choice for patients whose hypoxemia cannot be controlled on lower-FIO2 devices such as the cannula (because of changes in breathing pattern). Patients who hypoventilate with a moderate FIO2 are also candidates for the airentrainment mask.

Philips WhisperFlow and Downs Flow Generator High-flow adaptations of the classic air-entrainment device that provides gas mixing include Philips Respironics’ WhisperFlow and WhisperFlow 2 (Figure 14-20). These compact, high-performance Venturi tubes are designed to provide high gas flows in situations in which downstream

resistance occurs, such as with CPAP systems.40 In contrast, the airentrainment nebulizer systems discussed earlier can provide high flows only in low-FIO2 situations and are affected by downstream resistance. The high-flow generators provide gas flows (>100 L/min) sufficient to meet high inspiratory flow demand of tachypneic patients over a full FIO2 range (0.3 to 1).

FIGURE 14-20 (A) WhisperFlow fixed and variable high-flow generators. (B) WhisperFlow 2 variable high-flow generator. Reproduced with the permission of Koninklijke Philips N.V. All rights reserved.

The Downs flow generator increases the FIO2 by redirecting the O2 inlet flow in increasing amounts away from the jet. As greater proportions of the 100% O2 shift away from the jet, less room air is entrained and the FIO2 increases. The higher flow of O2 (which directly enters the device’s output gas flow) compensates for lesser amounts of entrained room air; thus, the FIO2 increases and total device output flow is maintained. The needle valve at the top of the tube controls the total amount of source O2 that enters the system and can be adjusted to supply the appropriate total flow of mixed gas. Disadvantages of the Downs high-flow generator include high gas consumption and noise levels. A bacterial filter can be fitted over the air inlet port to reduce noise.

Air–Oxygen Blending Using Dual Flow Meters Dual flow meters are the simplest and most economical method of delivering a specific FIO2 and total flow. Two flow meters—one for air and one for O2—can be used to mix and deliver precise O2 concentrations (Figure 14-21). These kinds of high-flow flow meters (0 to 75 L/min) can replace the standard 0 to 16 L/min Thorpe tube clinical flow meters in many applications. The gas flow delivered to the patient through largebore corrugated tubing is the sum of the flows from the two flow meters. Equation 14-2 provides a sample calculation using algebra and the previously mentioned volume × concentration relationship. Once the gases are mixed, they are humidified before being delivered to the patient. The patient interface can take the form of the standard aerosol mask, tent, tracheostomy mask, or Briggs adapter with tubing reservoir.33

FIGURE 14-21 High-flow oxygen delivery system using two flow meters, with an oxygen analyzer, humidifier, and tracheostomy mask.

EQUATION 14-2 High-Flow Dual Flow Meter System Problem How should the O2 and airflow meters be set to achieve 80 L/min and FIO2 of 0.7?

Solution

where desired flow of 80 L/min; flow; 3 = air flow; and C represents concentrations (i.e., fractions of O2): C1 = 0.7; C2 = 1.0; C3 = 0.21. Mixing equation adapted for mixing O2 and air: tot desired × FIO2 desired = Insert the known data, and note the two unknowns:

Air–Oxygen Blenders (Proportioners) Air–oxygen blenders, sometimes referred to as mixers or proportioners (Figure 14-22), provide a convenient, compact device for dialing in a specific FIO2; however, they are expensive compared with dual flow meter manual techniques. The principal component of the blender is a proportioning module, in which a 50-psig source of air and O2 are mixed in the appropriate proportions to produce the required FIO2. The blender outlet usually produces 50 psig of the mixed gas; this flow can be directly attached to devices via a flow meter.

FIGURE 14-22 (A) Air–oxygen blender or proportioner. (B) Commercially available air–oxygen blender. (A) Modified from Ward JJ. Equipment for mixed gas and oxygen therapy. In: Barnes TA, editor. Core Textbook of Respiratory Care Practice. 2nd ed. Mosby; Philadelphia, 1994; (B) Reproduced with permission from CareFusion.

Air–O2 proportioners receive each gas separately from a pipeline or compressed gas cylinder. Ideally, the supply pressures of both gases are nearly equal, usually 50 psig. In clinical practice, this does not always occur, so blenders have internal pressure-regulating systems. Once the pressures for air and O2 are sufficiently similar, a dual-orifice needle valve controls the amount of each gas flowing out of the orifices. For higher concentrations, the valve would simultaneously open for more O2 flow as it decreases the airflow. Blender manufacturers provide built-in alarm systems and sometimes pressure gauges that allow the respiratory therapist to confirm the proper inlet pressures. Aside from imbalances in the inlet gas pressure supply lines, another common problem is contamination of one gas supply by another because of retrograde flow. The higher-pressure gas (usually O2) can flow into the medical air gas lines if inlet check valves are defective. When blenders are not in use, the path of least resistance for the higher-pressure O2 travels through the piped air system. Contaminants from gas lines can prevent these pressure valves from sealing properly. Corrosion due to moisture and particulate matter can build up and restrict flow or prevent sealing of check valves. To prevent these problems, routine inspection and cleaning twice a year are recommended. Replacement of inlet sintered metal filters and use of water trap filters should also reduce this issue. More serious cases may require the installation of more complex filter systems. Manufacturers have found it difficult to build blenders with the desired accuracy over the complete range of flows needed in the clinical setting. Low-flow blenders are most accurate for low-flow applications, less than about 20 L/min. High-flow blenders must accurately provide controlled FIO2 levels at flows in the 80- to 100-L/min range. High-flow blenders tend to be more inaccurate at low flows and low-flow blenders at high flows. Evaluations of commercially available medical air–O2 blenders have found that all blenders are quite accurate when both inlet pressures are

50 psig. Given the technical challenges in ensuring the accuracy of air–O2 blenders, all blenders should be calibrated initially and then their accuracy verified periodically by O2 analyzers. Although the devices are relatively reliable and the air–O2 mixing equations are valid, inaccurately calibrated equipment and calculation errors may affect the delivered FIO2. To avoid potentially lethal medical mistakes, all fixed-performance devices and air–O2 blender systems should always have the FIO2 confirmed by direct O2 analysis. Respiratory Recap High-Flow Oxygen Delivery Devices ∎ High-flow, fixed-performance O2 administration devices deliver a predictable FIO2. ∎ Mix ratios can be calculated or memorized. ∎ FIO2 and flow affect the delivered FIO2; in some devices, they can be controlled independently. ∎ FIO2 is reduced if the patient’s inspiratory flow exceeds the device’s total flow output. ∎ The minimum flow is 3 to 4 times the minute ventilation. ∎ The minimum total flow is 4 to 6 L/min for infants and 40 L/min for adults. ∎ Large-volume nebulizers use an air-entrainment mechanism for FIO2 mixing. ∎ Air-entrainment masks deliver a precise flow when low FIO2 is specified but have limited ability to provide flows for FIO2 > 0.4. ∎ High-flow generators are engineered to maintain accurate FIO2 at high levels of flow. ∎ Dual flow meters can be used to accurately mix O2 and air and to adjust flows. ∎ Air–O2 blenders require 50-psig sources of both air and O2.

Oxygen Enclosures Placing the patient into an O2-enriched environment was one of the earliest methods of O2 administration. Adult oxygen tents, infant incubators, and pediatric croup tents were all introduced between the mid-1920s and the 1940s. The adult tent was widely used for both O2 administration and high-humidity therapy through the 1960s. Today, such enclosures are used primarily in infant and pediatric applications; they

include hoods, incubators, and croup tents. O2 and aerosol tents, even for children, have been essentially abandoned. Although some facilities continue to use infant oxygen hoods, infant nasal cannulas are favored. The hood covers only the head, allowing access to the infant’s lower body while still permitting use of a standard incubator or radiant warmer. The O2 hood (Figure 14-23) is a round or rectangular, bottomless, clear rigid plastic device with a half-moon cutout; the cutout allows the hood to be placed over an infant’s neck to enclose the entire head. O2 is delivered to the hood through either a blender with a heated humidifier or a heated air-entrainment nebulizer. A minimum flow of 6 to 8 L/min is necessary to prevent the accumulation of CO2. Clinicians should perform frequent or continuous monitoring of the O2 concentration and internal hood temperature when this device is used.

FIGURE 14-23 Oxygen hood. © Steve Lovegrove/Shutterstock.

Hyperbaric Oxygen Therapy Hyperbaric oxygen (HBO) therapy involves administration of gas at an increased atmospheric pressure; its use in medicine has varied over the years. Patients receiving HBO are placed inside an airtight chamber that can be pressurized to several times the normal atmospheric pressure of

760 mm Hg. The goal of HBO is to dissolve more gas (particularly O2) into the patient’s blood and body tissues. The increased O2 concentration in the blood and body tissues facilitates metabolism in the absence of HbO2 (when used for CO poisoning) and exposes anaerobic bacteria to a fatal level of O2 (for treatment of wounds with Clostridium infections, such as gas gangrene). Hyperbaric chambers can hold several patients and caretakers, or they can be designed to accommodate a single patient, with the care personnel remaining outside. Smaller HBO apparatuses designed to enclose individual affected limbs are also in use. Conventional O2 therapy and HBO therapy differ in many significant ways, so specialized training of respiratory therapy personnel involved with HBO is required. For example, gas volumes differ in relation to the chamber pressure, and O2 toxicity occurs in both pulmonary and cerebral forms that evolve much more rapidly under HBO conditions. Because hyperbaric treatment is indicated for clinical situations arising from recreational or occupational diving accidents, many of the available HBO chambers are found in coastal areas or on rescue ships. Divers are trained to incrementally gas-off by ascending slowly or in stages. When they surface too rapidly, they may develop decompression sickness and air embolisms. In such cases, the affected divers are returned to their lowest depth pressure and decompressed more slowly in the chamber. Because of the frequent use of HBO equipment in diving accidents, gauges are calibrated in feet of seawater (fsw): 33 fsw = 1 atm = 10 msw. Treatment of recreational or occupational decompression sickness does not necessarily involve the use of supplemental O2. HBO treatment is indicated for carbon monoxide poisoning,41 Clostridium myonecrosis (gas gangrene), air embolism (the bends), decompression sickness (N2 narcosis, rapture of the deep), and accelerating healing of selected wounds, grafts, burns, or infections. Because of the biochemical complexity of CO poisoning, the advantages of HBO therapy in comparison to normobaric, ambient 100% O2 therapy continue to be debated. HBO treatment for decompression sickness (the bends; nitrogen coming out of solution in the joints of the body), however, remains the standard of care.

Respiratory Recap Oxygen Enclosures ∎ O2 enclosures include O2 tents and hoods. ∎ HBO therapy is currently indicated for treatment of carbon monoxide poisoning, wounds (especially those infected by anaerobic bacteria), air embolism, and decompression sickness.

Monitoring the Physiologic Effects of Oxygen O2 therapy is often initiated in response to patient complaints of shortness of breath. The actual symptoms of hypoxia, however, are cognitive impairment, cardiac rhythm and conduction dysfunction, and renal dysfunction. Signs of hypoxia may include high respiratory frequency, cyanosis, chest pain, low PaO2, and low SaO2. Effective O2 treatment of these conditions requires careful monitoring.

Blood Gases and Oximetry Assessment of patients’ clinical signs and the results of arterial blood gas analysis are the gold standards for documenting physiologic indices of oxygenation, ventilation, and acid–base balance. Knowledge of the actual or best estimate of delivered FIO2 is helpful to provide a baseline against which to evaluate the physiologic response to supplemental O2 therapy. Measurements of PaO2, SpO2, Hb, and cardiovascular function (pulse, ECG, and blood pressure) are also useful to develop an informed differential diagnosis of the cause(s) of hypoxemia and/or hypoxia. Patients’ conditions can rapidly change, however, and intermittent measurements may not reflect the status of dynamic patients. Continuous pulse oximetry monitoring is appropriate in unstable patients. Pulse oximetry has become the most common form of continuously monitoring SpO2 and is the standard of care in the operating room, postanesthesia care unit, pulmonary function or sleep laboratory, intensive care unit, emergency room, and other clinical areas throughout the hospital. Its noninvasive approach, ease of use, and real-time feedback have led to its widespread acceptance in titrating O2 levels in ventilated and spontaneously breathing patients. This technology may be used either to spot check or to continuously monitor patients’ condition. Pulse oximetry has some limitations, however. Most clinical oximeters use only two wavelength measurements, which cannot identify carboxyhemoglobinemia or other abnormal hemoglobins. More important, the pulse oximeter is a poor monitor of ventilation. If patients are

breathing supplemental O2, reliance on pulse oximetry can further delay detection of elevated carbon dioxide levels and provide a false sense of security even when patients are in hypercapnic respiratory failure.42 Stop and Think The hospital where you work is opening a new critical care wing. You are asked to verify the function of the air and O2 outlets. How would you approach this task?

Oxygen Analysis Oxygen analyzers are used to measure the concentration of O2 (O2%) administered to patients (Figure 14-24). Such analysis is routinely performed in conjunction with infant O2 hoods, incubators, mechanical ventilators, anesthetic circuits, and some fixed-performance O2 administration devices (e.g., an aerosol-entrainment T-piece). Clinicians should check dual air–O2 flow meters and blenders to confirm the desired O2 concentrations. Monitoring can consist of spot samples, periodic checks, or continuous monitoring with high–low limit alarms.

FIGURE 14-24 Oxygen analyzer. Courtesy of Amvex Corporation.

Polarographic analyzers use a Clark electrode to measure O2. Galvanic cell analyzers, like polarographic analyzers, rely on an electrochemical principle. Although both types of analyzers actually measure PO2, they display the results as O2%. Analyzers used at high altitudes therefore require recalibration. Calibration is usually accomplished by exposing the electrode to room air (21% O2) and then to 100% O2. The O2 analyzer is adjusted to read the two calibrating gas concentrations correctly. Inability to calibrate the analyzer usually means that the electrolyte in the electrode needs to be changed. O2 analyzers should be checked relatively frequently for calibration and should be

repaired if they are unable to read within ±2%. Respiratory Recap Evaluation of Oxygen Therapy ∎ Arterial blood gas measurements are the best way of evaluating hypoxemia. ∎ Pulse oximetry provides a real-time, noninvasive estimate of oxygenation. ∎ O2 analyzers are used to measure the O2 concentration of a gas mixture.

Clinical Application of Oxygen Therapy Respiratory therapists are frequently asked to integrate patient information and recommend a medical gas therapy. This process begins with patient assessment and is usually based on clinical circumstances or specific signs or symptoms that suggest hypoxemia or hypoxia. Sometimes laboratory data (e.g., blood gases) reveal an unnoticed problem. After determining that the patient has a problem that O2 or other gas therapy may treat, the many factors related to O2 transport may complicate the decision process. For instance, patients may be experiencing problems with ventilation, O2 content of arterial blood, or perfusion. Figure 14-25 shows factors to be considered in the decisionmaking process for O2 therapy.

FIGURE 14-25 Oxygen administration guide.

Description A complete history and laboratory profile are often unavailable when a patient has an acute problem requiring medical gas therapy, so the clinician may have to rely on clinical signs and symptoms as the only guides. As a general guideline, it is usually safer to provide liberal flows and concentrations than to restrict O2. There are always exceptions, but side effects of O2 therapy are usually less significant than the brain damage that occurs secondary to hypoxia. In the past, many sources inappropriately emphasized withholding O2 because of the relatively small numbers of patients with COPD and chronic hypercarbia who may hypoventilate when they receive O2 therapy. The initial assessment may

also provide information about the cause of the patient’s dyspnea or hypoxemia. Following the initial assessment, the clinician should determine whether the patient requires hyperbaric O2 therapy or traditional ambient medical gas therapy. Severe carbon monoxide poisoning can be treated with hyperbaric therapy if immediate access to HBO is available. The next decision is the initial concentration of O2 and appropriate O2 therapy device (Table 14-5). Respiratory therapists often apply O2 based on bedside assessment and clinical judgment. Many patients find an O2 mask more uncomfortable than a nasal cannula, but a mask may be more appropriate if the patient has a high O2 requirement. A room-air blood gas analysis can be valuable—if it can be obtained without significant delay—to assist with diagnosis and guide selection of the level of O2 concentration needed. An O2 therapy system should be selected based on the patient’s FIO2 and inspiratory flow requirements. High-flow devices provide more consistent O2 levels for patients who have rapid respiratory rates and those who require a high FIO2. Inspired O2 is then titrated to achieve a PaO2 greater than 60 mm Hg or an SpO2 greater than 90%. Pulse oximetry can be useful for the initial O2 titration. TABLE 14-5 Oxygen Delivery Devices for Adult Applications

Description Be aware that O2 therapy alone may not correct hypoxemia in all patients. In particular, patients with hypercapnia and hypoxemia frequently require ventilatory support. For patients with a large right-to-left shunt, O2 therapy will not result in improvements in PaO2 or SpO2 regardless of the FIO2 applied. Respiratory therapists should be conservative when reducing FIO2 and liberal when increasing it. A common guideline is to reduce the FIO2 in decrements of 0.05, monitoring PaO2 or SpO2 as the FIO2 is decreased and allowing at least 20 minutes before making another adjustment to reflect the actual physiologic response to any FIO2. Patients with severe lung diseases may take even longer to equilibrate to changes in FIO2. When increasing FIO2, it is always wise to overshoot or exceed the predicted PaO2 or SpO2 and then titrate down. Therapist-driven protocols and clinical pathways (Figure 14-26) allow clinicians to apply O2 therapy by following a predetermined decisionmaking algorithm. Each patient must be considered as a special case, however, and clinicians should not be bound by guidelines if the clinical situation dictates an alternative approach.

FIGURE 14-26 Oxygen therapy for acutely ill medical patients. Data from O’Driscoll BR, Howard LS, Earis J, et al. British Thoracic Society Guideline for oxygen use in adults in healthcare and emergency settings. BMJ Open Resp Res 2017; 4(1):e000170; and Siemieniuk RA, Chu DK, Kim LA, et al. Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ 2018;k4169.

Description

Helium–Oxygen Therapy Since Barach established the value of low-density gas therapy in 1934, helium–O2 mixtures have had a notable, if limited, role in respiratory care. Beyond their use in industry and deep-sea diving, patients may breathe these heliox mixtures for a number of medical reasons. Heliox is used clinically because of its low density—the only gas with a lower density than helium is hydrogen. Unlike hydrogen, helium is an inert gas and, therefore, nonreactive. Helium is relatively insoluble in body fluids. Because it does not support life, for clinical applications helium must always be delivered in a gas mixture containing at least 20% O2. In addition to its use for diagnostic purposes, such as measurement of lung volumes (e.g., functional residual capacity), heliox may have therapeutic applications in patients with obstructive lung diseases—specifically, to decrease their overall work of breathing and PaCO2.43–53 However, recent evidence suggests that heliox has a minimal impact on overall dynamic hyperinflation in COPD and asthmatic patients during mechanical ventilation.50 Notably, the world’s helium stores are becoming depleted. Although the need for heliox in patient treatment is relatively small, helium is essential for some medical applications, such as cooling of MRI equipment. The physical properties of helium differ from those of air or O2 (Table 14-6). These physical properties of helium affect its flow through airways of the lungs (Equation 14-3). Because turbulent flow is density dependent whereas laminar flow is density independent, use of heliox is expected to have a greater effect on turbulent flow. Its lower density means that heliox produces a lower Reynolds number and has a greater tendency to induce laminar flow. Laminar flow is desirable because it is more energy efficient than turbulent flow. Based on the Reynolds number, it appears that gas flow tends to be laminar in small peripheral airways of the lungs and turbulent in larger central airways. Thus, heliox may have limited benefit for diseases affecting small airways (e.g., emphysema, asthma) but may be useful for diseases affecting larger airways (e.g., postextubation stridor, croup). When gas flows through an orifice (i.e., axial acceleration), the flow through that orifice (e.g., a constricted

airway) will increase if the density of the gas (e.g., heliox) decreases. Because of the Bernoulli principle, less pressure is required to produce flow with heliox than with air or O2. According to Graham’s law, heliox (80% helium/20% O2) diffuses at a rate 1.8 times greater than O2. EQUATION 14-3 Physical Principles That Explain the Benefits of Heliox Therapy For turbulent flow, the Hagen-Poiseuille equation predicts that flow is affected by the radius of the conducting tube, the pressure gradient, the density of the gas (ρ), and the length of the conducting tube (l) as follows:

where is flow and ΔP is the pressure gradient. Whether flow is laminar or turbulent is determined by the Reynolds number (Re), as follows: Re = Inertial forces/Viscous forces = (vrρ)/η where v is the velocity of gas movement, r is the radius, and η is viscosity. A low Reynolds number causes flow to be laminar. For gas flow through an orifice (e.g., axial acceleration), flow has only a weak dependence on the Reynolds number and is affected by density as follows:

In other words, flow through an orifice (e.g., a constricted airway) will increase if the density of the gas (e.g., heliox) decreases. The Bernoulli principle states that the pressure required to produce flow is affected by the mass of the gas as follows:

where (P1 − P2) = pressure required to produce flow, (v22 − v12) = difference in velocity between P1 and P2, and m = mass of the gas. In other words, less pressure is required to produce flow with heliox than with air or oxygen. Graham’s law states that the rate of diffusion is inversely related to the square root of gas density. Thus, heliox (80% He/20% O2) will diffuse at a rate 1.8 times faster than oxygen, which explains why the flow of heliox through an oxygen flow meter is 1.8 times faster than the indicated flow. According to wave speed theory, flow through an airway cannot be greater than the flow at which gas velocity equals wave speed. Wave speed is the speed at which a small disturbance travels in a compliant tube filled with a fluid. The wave speed C2 in an airway depends on the cross-sectional area of the airway (A), the density of the fluid, and the slope of the pressure–area curve of the airway (dP/dA), as follows:

Note that maximal flow ( max) is the product of the fluid velocity at wave speed and the airway area (cA). If max = cA, then the following relationship occurs:

According to wave speed theory, max increases as gas density decreases. Wave speed theory is useful only when gas flow is density dependent, however. In small airways, and particularly at low lung volumes, gas flow is density independent, and viscous flow limitation becomes more important than wave speed.

TABLE 14-6 Physical Properties of Oxygen, Air, and Helium

Description Helium is available premixed with O2 in several standard mixtures in large compressed gas cylinders. The most popular mixtures are 80%/20% and 70%/30% helium–O2. These mixtures are, respectively, 1.805 and 1.586 less dense than pure O2. In any heliox breathing system, a tightly sealed closed system is required because helium will easily leak through small holes. To avoid administration of a hypoxic gas mixture, 20% O2/80% He should be mixed with O2 to provide the desired helium concentration and FIO2. The FIO2 requirement limits the helium concentration that can be administered. If an FIO2 greater than 0.40 is required, the limited concentration of helium is unlikely to produce a clinical benefit. The FIO2 requirement may decrease if heliox therapy is effective, however.

Heliox has been used as a temporary measure for patients with stridor and for patients with airway obstruction, such as those with lifethreatening asthma. The benefit of heliox for postextubation stridor is anecdotal. Although it may improve the symptoms related to stridor, aggressive treatment of the underlying problem must occur concurrently. In spontaneously breathing patients with asthma, heliox has been reported to decrease PaCO2, increase peak flow, and decrease pulsus paradoxus. The reduction in pulsus paradoxus may be particularly important because it reflects a reduction in inspiratory muscle work. Heliox has also been used with intubated and mechanically ventilated asthmatic patients, in whom it produces a reduction in PaCO2 with a lower peak airway pressure and an improvement in oxygenation. The role of heliox in the treatment of COPD remains unclear, however. COPD is a disease of the small airways—a region of the lungs in which flow is density independent. Nonintubated patients may receive heliox therapy via a well-fitting simple mask or a mask with a reservoir bag (Figure 14-27). A Y-piece attached to the mask allows concurrent delivery of aerosolized medications. Sufficient flow—often 12 to 15 L/min—is required to keep the reservoir bag inflated, which may necessitate use of three to six Hsize cylinders per day. Using an O2-calibrated flow meter for heliox therapy causes the flow of heliox (80% helium/20% O2) to be 1.8 times greater than the indicated flow. Great precision in achieving the desired flow is not required when administering heliox; instead, the objective when using a reservoir bag and mask is to keep the reservoir bag nearly full at all times.

FIGURE 14-27 Equipment for heliox administration to spontaneously breathing patients.

In the past, heliox administration during mechanical ventilation has been problematic, but today several commercially available ventilators can be used to administer heliox. Traditionally, ventilators have been designed to deliver a mixture of air and O2 only. The density, viscosity, and thermal conductivity of helium can affect the delivered tidal volume and the measurement of exhaled tidal volume. With some ventilators, no reliable tidal volume is delivered with heliox. Use of other ventilators may result in a much higher delivered tidal volume than desired. Several studies reported improved aerosol penetration and deposition in the lungs with a nebulizer powered with heliox rather than air, but

others failed to find a benefit with the use of heliox-driven nebulizer therapy.48 Heliox can affect nebulizer function, resulting in a smaller particle size, reduced output, and longer nebulization time.54 When heliox (rather than air or O2) is used to power the nebulizer, the flow should be increased by 50% to 100% to ensure adequate output from the nebulizer. Respiratory Recap Heliox ∎ The therapeutic benefits of heliox are related to the gas’s low density. ∎ Use of heliox is beneficial in some patients with partial upper airway obstruction or asthma. ∎ Heliox adversely affects the function of equipment such as flow meters, nebulizers, and ventilators.

In patients with COPD, heliox might reduce PaCO2, dyspnea, and work of breathing to a greater extent than does O2 therapy alone. Outcome studies have not shown an improvement in patient outcomes when using a combination of noninvasive ventilation and heliox, however.

Carbon Dioxide Therapy Therapeutic applications of carbon dioxide are either quite limited or controversial. Such therapy has several dangerous side effects, and its efficacy remains unproven in many of the proposed applications. Historically, increasing inspired CO2 levels was envisioned as a way to treat hysterical hyperventilation (anxiety attacks) by lessening syncopal attacks due to hypocarbia. The typical approach used 5% CO2 in O2 (carbogen) or rebreathing into a paper bag or tubing reservoir. Breathing into a paper bag might relieve anxiety attacks, but current treatment standards recommend treating most cases with anxiolytic medications. In the past, carbogen was also used to stimulate spontaneous breathing in postoperative patients with the goal of hastening the removal of volatile anesthetics and preventing atelectasis, but this practice has since been abandoned. Treatment of hiccoughs (singultus) with carbogen or by rebreathing exhaled CO2 is occasionally successful, but the mechanisms by which this treatment works remain unknown. Carbogen has also been used to terminate seizures (petit mal) by the mechanism of decreasing brain excitability. In the past, CO2 was administered as a treatment for stroke, as it was believed to improve regional blood flow by dilating vessels in the brain. More recently, carbogen has been used to encourage ophthalmic artery blood flow. Because expired air normally contains approximately 5% CO2, rebreathing that gas can provide CO2 gas therapy. The paper bag is the simplest device; the Adler rebreather and Dale-Schwartz tube are commercial adaptations of this principle. Premixed high-pressure gas cylinders can provide for administration of specific mixtures of carbon dioxide. The regulators that attach to the cylinder valves are specific to the concentration used. The most commonly used mixtures are 5% CO2/95% O2 and 7% CO2/93% O2—more than 5% CO2 is rarely used. CO2 concentrations greater than 10% are not recommended because of the risk of rapidly developing side effects. A nonrebreathing mask is used to deliver the CO2/O2 gas therapy to the patient. Administration times are generally limited to fairly short

periods, in the range of 5 to 15 minutes. Patients on carbogen therapy must be carefully monitored for pulse, respiratory rate, blood pressure, and mental state. Pulse rate, minute ventilation, and blood pressure usually increase somewhat when carbogen treatments are administered, but significant changes in any of these measurements should prompt discontinuance of the therapy. Carbogen therapy may also depress the patient’s mental state and can result in convulsions, coma, and ultimately death.

Nitric Oxide Therapy In 1987, researchers found that nitric oxide (NO) is normally biosynthesized in vascular endothelial cells and is an important mediator of several physiologic functions, including vasodilation, neurotransmission, long-term memory, and immunologic defense. The NO molecule is highly diffusible and lipid soluble. Its half-life ranges from 3 to 50 seconds, as it converts to nitrates, nitrites, and higher oxides of nitrogen. Nitric oxide is a ubiquitous, highly reactive, gaseous, diatomic radical that is important physiologically at low concentrations (Box 14-1). Atmospheric concentrations of NO usually range from 10 to 100 ppb. BOX 14-1 Typical Expression of Concentration of Nitric Oxide and Nitrogen Dioxide Concentrations of nitric oxide and nitrogen dioxide are usually expressed in parts per million (ppm) or parts per billion (ppb). % = 1:100 ppm = 1:1,000,000 10,000 ppm = 1% 1000 ppb = 1 ppm

L-Arginine acts as the substrate for NO synthesis in biologic systems.

NO is produced in the presence of nitric oxide synthase (NOS). The lipophilic NO molecule readily diffuses across cell membranes to adjacent cells, allowing it to serve as a local messenger molecule. It typically diffuses from its cell of origin to a neighboring cell, where it binds with guanylate cyclase. Activation of guanylate cyclase results in the production of cyclic guanosine 3′,5′-monophosphate (cGMP) from guanosine triphosphate (GTP), which produces a biological effect within the cell (e.g., smooth muscle relaxation). The term selective pulmonary vasodilation is used to indicate two physiologic phenomena (Figure 14-28).53 First, selective pulmonary vasodilators reduce pulmonary vascular resistance without affecting systemic vascular resistance. Second, they affect vascular resistance only near ventilated alveoli. Inspired vasodilators are delivered to those

lung units that are ventilated. Although not a selective pulmonary vasodilator, NO becomes one when inhaled. Inhaled NO selectively improves blood flow to ventilated alveoli and reduces intrapulmonary shunt and improved arterial oxygenation. The selective pulmonary vasodilation demonstrated by inhaled NO is due to hemoglobin’s high affinity for NO, which is approximately 106 times as great as its affinity for O2. In contrast to inhaled NO, intravenous vasodilators (e.g., sodium nitroprusside, nitroglycerin, prostacyclin) are not selective. Although intravenous vasodilators lower pulmonary artery pressure, they also lower systemic blood pressure. These agents increase blood flow to both ventilated and unventilated lung units, resulting in an increased intrapulmonary shunt and a lower PaO2.

FIGURE 14-28 Inhaled nitric oxide is a selective pulmonary vasodilator because vasodilation occurs primarily in parts of the lungs that are ventilated and because systemic vasodilation does not occur.

Multicenter, randomized, double-blind, placebo-controlled studies of inhaled NO for persistent pulmonary hypertension of the newborn (PPHN) have reported improvements in PaO2 and a reduction in the requirement for extracorporeal life support with the use of inhaled NO.55–57 These studies established a role for inhaled NO in term infants with PPHN and prompted the FDA to approve use of inhaled NO in 1999 for the following indication:

INOmax, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.

This is the only FDA-approved indication for inhaled NO—all other uses are off-label. Nitric oxide should not be used for hypoxemic newborns with congenital cardiac defects who are dependent on right-to-left shunt. The usual starting dose of inhaled NO is 20 ppm. This dose is then weaned to the lowest effective dose (e.g., 5 ppm) and continued until the neonate’s condition improves. Inhaled NO produces an initial improvement in PaO2 for patients with ARDS, but this effect is lost after several days. Prolonged use of NO appears to have a dose-dependent effect on renal function: Prolonged and high-dose NO therapy increases the risk of renal dysfunction, particularly in patients with ARDS.58 Randomized multicenter trials in ARDS failed to report improvements in important patient outcomes such as mortality with the use of inhaled NO.59–62 The toxicity of inhaled NO appears to be low when this gas is administered by clinicians familiar with its use. Nitrogen dioxide (NO2) is produced spontaneously from NO and O2. The conversion rate of NO to NO2 is determined by the O2 concentration, NO concentration, and the residence time of NO with O2. The Occupational Safety and Health Administration (OSHA) has set safety limits for NO2 at 5 ppm, but airway reactivity and parenchymal lung injury have been reported with inhalation of even 2 ppm NO2 or less. Methemoglobin production after NO exposure is uncommon at the NO doses used for therapeutic inhalation (20 ppm or less). Inhibition of platelet adhesion, aggregation, and agglutination has been reported with inhaled NO. At high doses (40 to 80 ppm), inhaled NO reportedly decreases pulmonary vascular resistance and increases pulmonary capillary wedge pressure in some patients with severe left ventricular dysfunction. Withdrawal of inhaled NO can be problematic for some patients. In some cases, the degree of hypoxemia and pulmonary hypertension increases after discontinuation of NO compared to baseline, leading to hemodynamic instability. Reinstitution of NO inhalation promptly corrects the hemodynamic instability, and NO withdrawal is postponed until the

patient is less severely ill. The reasons for rebound are not known but may relate to feedback inhibition of NOS activity. The following guidelines may prevent the deleterious effects of rebound during withdrawal of inhaled NO: 1. Use the lowest effective NO dose (5 ppm or less). 2. Do not withdraw inhaled NO until the patient’s clinical status has improved sufficiently. 3. Set the NO dose at 1 ppm for a short time (30 minutes to 1 hour) before discontinuing NO. 4. Increase the FIO2 before withdrawing inhaled NO therapy, and prepare to support the patient’s hemodynamics if necessary. The INOmax DS and the INOblender devices (Figure 14-29) allow for operator-determined concentrations of inhaled NO without excessive inhaled NO2. These devices can be used with neonatal ventilators, adult ventilators, and anesthesia machines, as well as with spontaneously breathing patients. The system is configured to deliver 0 to 80 ppm when used in conjunction with an 800-ppm NO source cylinder. The D size or size 88 (1963 L at 2000 psig) NO cylinders are constructed of aluminum alloy and have threaded connections specific for NO (CGA 626). NO is stored as nitrogen gas.

FIGURE 14-29 INOmax DS. Courtesy of IKARIA.

To use the INOvent, the operator inserts the injection module into the inspiratory circuit at the outlet of the ventilator. The injection module consists of a hot-film flow sensor and a gas injection tube. Flow in the ventilator circuit is precisely measured, and NO is injected proportional to that flow to provide the desired NO dose. The delivery system includes

gas monitoring of O2, NO, and NO2 downstream from the point of injection. Age-Specific Angle The only FDA-approved indication for inhaled nitric oxide is hypoxic respiratory failure of the newborn.

Respiratory Recap Inhaled Nitric Oxide ∎ Inhaled nitric oxide is a selective pulmonary vasodilator. ∎ Inhaled nitric oxide is an FDA-approved treatment for hypoxic respiratory failure of the newborn. ∎ NO has low toxicity at the usual clinical doses. ∎ Inhaled NO is administered via a specially designed delivery system.

Key Points Supplemental O2 is indicated to treat hypoxemia as determined by scenario, clinical exam, pulse oximetry, or arterial blood analysis. O2 therapy is used for COPD, ARDS, CPR, pulmonary edema, and CO poisoning. O2 is not explosive, but it does increase the combustibility of other flammable materials. Supplemental O2 is a relatively benign drug. However, complications of O2 therapy include O2 toxicity, hyperoxemia, nitrogen washout atelectasis, O2-induced hypoventilation, retinopathy of prematurity, and failure of ductus closure in infants with congenital heart disease. O2 may be of limited usefulness for patients with anemia, low cardiac output, or right-to-left shunt >10%. Flow control devices include flow restrictors, Bourdon gauges, and Thorpe tubes. Backpressure-compensated Thorpe tubes are accurate regardless of downstream resistance when powered by 50-psig sources. Nasal cannulas, simple masks, partial rebreathing masks, and nonrebreathing masks are low-flow O2 delivery devices. When these devices are used, delivered FIO2 can vary with the patient’s breathing patterns. The FIO2 from a low-flow O2 delivery device is determined by the O2 flow, reservoir volume, and inspiratory flow of the patient. High-flow O2 delivery systems provide more consistent FIO2 levels and can better meet the entire and changing inspiratory needs of the patient. Hoods, incubators, and tents are oxygen enclosure devices. Hyperbaric O2 therapy is currently indicated for treatment of carbon monoxide poisoning, wounds (especially those infected by anaerobic bacteria), air embolism, and decompression sickness. O2 analyzers use polarography or galvanic cells to measure oxygen partial pressure, which they report as O2 concentration (O2%). Heliox is used clinically because of its low density and ability to

prevent turbulent flow. Therapeutic applications of CO2 therapy are limited or controversial. Inhaled nitric oxide is a selective pulmonary vasodilator.

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CHAPTER

15 Humidity and Aerosol Therapy Dean R. Hess

© Andriy Rabchun/Shutterstock

OUTLINE Humidity Devices Used for Humidification Bland Aerosol Therapy Humidification to Tracheostomy Device Selection for Humidity Therapy Aerosol Drug Administration Aerosol Generators Aerosol Delivery During Invasive Mechanical Ventilation Aerosol Delivery During Noninvasive Ventilation Aerosol Delivery by Tracheostomy Aerosol Delivery by High-Flow Cannula Selection of an Aerosol Delivery Device Aerosol Delivery for Systemic Disease

OBJECTIVES 1. 2. 3. 4. 5.

Describe the normal gas warming and humidification functions of the upper airway. List the goals of aerosol and humidity therapy. Compare active and passive humidifiers. Compare heated and unheated humidifiers. Compare jet nebulizers, ultrasonic nebulizers, and mesh nebulizers.

6. Compare nebulizers, pressurized metered-dose inhalers, and dry powder inhalers for aerosol drug administration. 7. Distinguish between spacers and valved holding chambers. 8. Discuss issues involved in the selection of a device for aerosol delivery. 9. Discuss issues pertinent to aerosol drug delivery during mechanical ventilation.

KEY TERMS active humidifier aerosol artificial nose bland aerosol therapy bubble humidifier dry powder inhaler (DPI) geometric standard deviation (GSD) gravitational sedimentation humidity therapy isothermic saturation boundary (ISB) jet nebulizer large-volume nebulizer mass median aerodynamic diameter (MMAD) mesh nebulizer nebulizer passive humidifier passover humidifier pressurized metered-dose inhaler (pMDI) Respimat Soft Mist Inhaler spacer ultrasonic nebulizer valved holding chamber

Introduction Administration of humidity and aerosol therapy is a common task for the respiratory therapist. Humidification of inspired gas is particularly important in the care of mechanically ventilated patients, and many respiratory drugs are administered as aerosols. The selection of appropriate devices for humidity and aerosol production has important implications for patient outcome.

Humidity The interface between the atmosphere and the lungs is mediated through the fluid lining of the airways. Humidity in inspired gas is essential to a healthy respiratory tract. Breathing a dry, cold gas through the upper airway can change the balance of the fluid lining the airways and may result in either short-term or irreversible structural damage of the airway.1,2 Exposure of the airways to cold, dry gas from the ambient environment increases mucous production and thickening of secretions, reduces the motility of the cilia, and increases airway irritability. In addition, administration of dry gases via an endotracheal tube can damage the tracheal epithelium and tube occlusion. Humidity therapy is the addition of water to the gas delivered to the airways. The nose, which adds heat and humidity to the inspired gas, is an efficient humidifier. The respiratory mucosa lining the sinuses, trachea, and bronchi also assists in heating and humidifying inspired gas. This respiratory mucosa is covered by secretions produced by mucous glands, goblet cells, and transudation of fluid through cell walls (Figure 15-1). Heat is transferred from capillary beds close to the surface of the mucosa. The nasal mucosa is particularly well suited for this function, having the highest concentration of mucous glands in the airway and a rich vascular bed close to the surface that provides heat and water. The turbinates and conchae provide a convoluted path through which gas must travel, creating turbulent flow and a large surface area for contact with respiratory gases. This large surface area gives up heat and moisture to inspired gas but efficiently recovers heat and water on exhalation.

FIGURE 15-1 The cellular, aqueous, and mucous components of the airway mucosa. Adapted from Williams R, Rankin N, Smith T, Galler D, Seakins P. Relationship between humidity and temperature of inspired gas and the function of the airway mucosa. Crit Care Med 1996;24(11):1920–1929.

Normal Heat and Moisture Exchange When inspired gas reaches the lung parenchyma, it is fully saturated with water vapor at body temperature (44 mg/L at 37° C) (Figure 15-2). The point at which this occurs, called the isothermic saturation boundary (ISB), is approximately 5 cm distal to the carina at the level of the thirdgeneration airways. Proximal to the ISB, temperature and humidity fall during inspiration and rise during exhalation. Distal to the ISB, temperature and relative humidity do not fluctuate. A drop in environmental temperature and humidity, mouth breathing, an increase in tidal volume, or endotracheal intubation (which bypasses the upper airway) moves the ISB deeper into the lungs, although it never reaches the level of the respiratory bronchioles or alveoli.

FIGURE 15-2 Normal temperature and humidity of gas at various points along the respiratory tract.

Description At the end of inspiration, the temperature of the nasal mucosa is 31° C or lower because of heat loss caused by turbulent convection and loss of the latent heat of vaporization. As inspired gas warms, water vapor is transferred by evaporation from the mucosal lining through the latent heat of vaporization. Warming and humidification continue until the inspired

gas is fully saturated at body temperature. Although the latent heat of vaporization remains present as water vapor and does not contribute to warming of gases, the loss of latent heat of vaporization causes the mucosa to cool. During exhalation, heat is transferred from the exhaled gas to the cooler tracheal and nasal mucosa by convection. As these gases cool, their capacity for water vapor diminishes, and condensation occurs. The condensate water accumulates on the tracheal surfaces, where the mucus reabsorbs it. Heat is transferred back to the mucosa, resulting in warming and rehydration. The latent heat and water are held until the next inspiration, when the cycle begins again. With mouth breathing, flow is more laminar, requiring heat transfer by radiation. Because air is a poor heat conductor, the mouth is less efficient than the nose at heating inspired air. The temperature of the water vapor at the oropharynx during oral and nasal breathing of room air is approximately 22° C, with a relative humidity (RH) of 15% to 39%. At the pharynx, the temperature difference between inspired and expired gas is 4° C during nose breathing and 7° C during mouth breathing. The inspired gas temperature increases 5° C during mouth breathing and 9° C during nose breathing. The RH is 95% at the oropharynx during inspiration with nose breathing, and 75% during mouth breathing. On exhalation, the RH is nearly 95% at the pharynx and 90% at the airway opening. This difference suggests that the normal airway can condition inspired gas so as to add humidity with either nose or mouth breathing. Nevertheless, more heat and moisture are lost with exhalation with mouth breathing than with nose breathing. Even with mouth breathing, the ISB is usually not lower than the third generation of the bronchi. Heat and moisture normally are lost from the mucosa above the ISB, from a surface area of approximately 300 cm2 that is covered by 240 µL of airway lining fluid 8 µm deep. With normal tidal volume for an adult male, 22 µL of water and 61 J of heat are required to condition each breath from normal ambient conditions to 100% RH at body temperature. The water and heat losses per breath are 15 µL and 42 J, respectively. Over 24 hours, these losses total 250 mL of water and 726 kJ of heat. When inhaling dry, cold gases, the ISB shifts deeper into the respiratory tract, and ciliary function and mucous production become compromised. Bypassing the upper airway eliminates the normally

efficient mechanisms used to retain heat and humidity in the lungs. Recruitment of airways that are less efficient for humidification changes their mucosal characteristics. The lower distal gas temperature reduces ciliary activity within 10 minutes. Once compromised, ciliary function can take weeks to recover. Respiratory secretions become thicker, contributing to the development of mucous plugs and inability to maintain normal bronchopulmonary hygiene. When absolute humidity drops to less than 24 mg/L in the inhaled gas, the beat frequency of the cilia decreases.

Goals of Humidity Therapy Humidity therapy seeks to maintain normal physiologic conditions by providing adequate heat and humidity to inspired gas so as to approximate normal inspiratory conditions (CPG 15-1). Some also advocate administration of heat and humidity, albeit with less data, for the treatment of hypothermia, reactive airway response to cold air, and thickened secretions. CLINICAL PRACTICE GUIDELINE 15-1 Recommendations for Humidification During Invasive and Noninvasive Mechanical Ventilation 1. Humidification is recommended for every patient receiving invasive mechanical ventilation. 2. Active humidification is suggested for noninvasive mechanical ventilation, as it may improve adherence and comfort. 3. When providing active humidification to patients who are invasively ventilated, it is suggested that the device provide a humidity level between 33 mg H2O/L and 44 mg H2O/L and a gas temperature between 34° C and 41° C at the circuit Y piece, with a relative humidity of 100%. 4. When providing passive humidification to patients undergoing invasive mechanical ventilation, it is suggested that the heat and moisture exchanger (HME) provide a minimum of 30 mg H2O/L. 5. Passive humidification is not recommended for noninvasive mechanical ventilation. 6. When providing humidification to patients with low tidal volumes, such as when lungprotective ventilation strategies are used, HMEs are not recommended because they contribute additional dead space, which can increase the ventilation requirement and

PaCO2. 7. HMEs are not recommended as a prevention strategy for ventilator-associated pneumonia. Reproduced from Restrepo RD, Walsh BK. Humidification during invasive and noninvasive mechanical ventilation: 2012. Respir Care 2012:57(5):782–788.

Medical gases are anhydrous, so they require addition of humidity before they are administered to patients. When delivered to the nose and mouth, gas should be heated and humidified to normal ambient room air conditions (22° C at 50% RH or an absolute humidity of 10 mg/L). For gas delivered to the trachea through an endotracheal or tracheotomy tube, heat and humidity should ideally be at least 32° to 35° C at 100% RH (absolute humidity of 36 to 40 mg/L). For newborns, healthcare providers should ensure a neutral thermal environment, with adequate warmth and humidity to minimize insensible heat and water loss. Low-birth-weight infants, when provided with adequate heat and humidity, have a reduced morbidity rate compared with infants breathing colder and drier inspired gas. For hypothermic patients, the respiratory therapist can facilitate rewarming and minimize further heat loss by heating the inspired gases. However, this technique is less useful than other warming treatments (e.g., wrapping the patient in blankets and warming intravenous solutions). Individuals with reactive airways may develop increased airway resistance when they breathe cold air. This response can be diminished by warming the inspired gases and providing gas humidified with at least 20 mg/L of water at 23° C. Heated humidity has been used in the treatment of patients with thick, tenacious secretions. In contrast, the use of external humidifiers does not appear to improve the mobilization of thick secretions. Most patients with an artificial airway require humidification of inspired gas to prevent the formation of thick, tenacious secretions, but evidence is lacking to support the use of humidity therapy (i.e., cool mist or heated aerosol) for patients with an intact upper airway. Cooler-than-room-temperature humidified gases and aerosols commonly are used in the treatment of upper airway inflammation caused by croup, epiglottitis, and swelling resulting from extubation. The cold gas promotes localized vasoconstriction, thereby reducing swelling and relieving the discomfort associated with upper airway inflammation.

Excessive humidity is defined as a level greater than 100% RH at body temperature. The water volume of a vapor stream is 20 to 50 µL of water per liter of air and is unlikely to cause over-humidification. To exceed that water volume, gas temperatures would have to be grossly in excess of body temperature. Humidification of inspired gas reduces insensible water loss from the airway but is unlikely to add significant water to the body. Inspired gas warmer than 45° C may cause thermal injury to the airway. Respiratory Recap Goals of Humidity Therapy ∎ To provide adequate heat and humidity ∎ To treat hypothermia ∎ To prevent airway response to cold air ∎ To aid removal of thick secretions

Stop and Think A hypothermic patient arrives in your emergency department. You are asked to provide warm, humidified gas to speed rewarming. How effective do you think that treatment will be?

Devices Used for Humidification A humidifier adds molecular water to gas.3–8 An active humidifier adds water or heat, or both, to the inspired gas. A nebulizer produces an aerosol, a suspension of particles in gas. A passive humidifier uses exhaled heat and moisture to humidify inspired gas. The American National Standards Institute (ANSI) recommends that heated humidifiers have a water output of at least 30 mg/L (100% RH at 30° C). This is considered the minimum level of humidity to avoid mucosal damage and inspissation of secretions for patients who have a bypassed upper airway (i.e., an endotracheal or tracheostomy tube). The Emergency Care Research Institute (ECRI) recommends that active humidifiers have an output of 37 mg of water per liter of inspired gas (85% RH at body temperature or 100% RH at 34° C). Active heated humidifiers are often the devices of choice for patients with artificial airways. ANSI recommends a water output of 10 mg/L for unheated humidifiers; this provides approximately 50% RH at 22° C ambient conditions, which enhances the dissipation of static electricity to prevent fires. This humidity level is thought to be the lowest acceptable level to minimize mucosal damage to the upper airway in a variety of environments. Stop and Think A patient receiving low-flow oxygen therapy by cannula complains of nasal drying. Do you think a bubble humidifier will help? What other options might you suggest?

Active Humidifiers A passover humidifier directs gas over the surface of water (Figure 153A and Figure 15-3B). A passover wick humidifier incorporates a wick of absorbent paper or cloth that draws water from the reservoir and becomes saturated; the wick comes in contact with the gas stream. A passover barrier humidifier uses a hydrophobic barrier that allows water molecules, but not droplets, to cross from the water reservoir into the gas

stream.

FIGURE 15-3 (A) Passover humidifier. (B) Heated passover humidifier. (C) Bubble humidifier. (D) Heated bubble humidifier. Adapted from Peterson BD. Heated humidifiers. Respir Care Clin North Am 1998;4(2):243–260.

In a bubble humidifier, dry gas is directed toward the bottom of a water-filled reservoir, where the stream of gas is broken up (diffused) into bubbles, which gain humidity as they rise through the water (Figure 153C). This type of humidifier has a tube with small holes along its length or a tube attached to a diffuser made of plastic foam, sintered metal, or mesh that breaks the stream of gas into small bubbles. Bubble humidifiers typically are unheated and used with simple oxygen delivery devices. The higher the flow through a bubble humidifier, the lower the water vapor content and temperature of the gas leaving the device. Commercially available bubble humidifiers are capable of humidifying dry medical gas to an absolute humidity of 10 to 20 mg/L at flows of 2 to 10 L/min, although these humidifiers are most efficient at flows of 5 L/min or less. When flows greater than 10 L/min are required, other humidifying options should be considered. At flows less than 10 L/min, bubble humidifiers are safe for extended single-patient use without risk of infection. Heating the reservoir improves the efficiency of these humidifiers. However, the small-bore tubing used to connect the humidifier to the administration appliance is easily obstructed by condensate as the humidified gas cools en route to the patient. Low-flow, unheated bubble humidifiers typically have a gravity or spring-loaded pressure-relief valve to protect against obstructed or kinked tubing and an alarm that sounds when a pressure of 2 psi or higher develops in the humidifier. The addition of humidity to low-flow medical gas is not an evidencebased practice, and eliminating the use of humidifiers for low-flow oxygen reduces the cost of routine oxygen administration. Humidification of the inspired gas should be considered for patients who complain of discomfort associated with nasal dryness or irritation. Other devices may accomplish this more efficiently than simple bubble humidifiers. In addition, topical application of water-based lubricants to the nostrils may be a reasonable response to complaints of dryness. Heated bubble humidifiers (Figure 15-3D) accommodate flows of 10 to 120 L/min and use tubing with a 22-mm inside diameter (ID). These devices use corrugated 22-mm ID tubing between the humidifier and the patient. At high flows, bubble humidifiers produce aerosols that may transmit bacteria from the humidifier’s reservoir to the patient. Heated passover humidifiers are used most commonly during mechanical

ventilation (Figure 15-4).

FIGURE 15-4 Commercially available heated humidifiers used during mechanical ventilation. (A) Courtesy of Fisher & Paykel Healthcare; (B) Courtesy of Teleflex Incorporated. Unauthorized use prohibited.

A jet nebulizer (Figure 15-5) uses compressed gas that passes through a restricted orifice, creating a low-pressure area near the tip of a narrow tube. Fluid is drawn from a reservoir and sheared or shattered into droplets by the airstream. Jet nebulizers incorporate baffles to minimize the size of the aerosol exiting particles and use the aerosol in the device to maximize surface contact with the gas. Because bacteria might potentially colonize the reservoir, jet nebulizers pose an infection risk. To minimize this risk, healthcare providers should always fill the jet nebulizer with sterile fluids and discard any residual fluids before refilling.

FIGURE 15-5 (A) Schematic drawing of large-volume jet nebulizer. (B) Commercially available large-volume nebulizers. (A) Modified from Cohen N, Fink J. Humidity and aerosols. In: Eubanks DH, Bone RC, eds. Principles and Applications of Cardiorespiratory Care Equipment. St. Louis, Mosby; 1994; (B) courtesy of Cardinal Health.

Systems used to replace the water in the humidifier should ensure continuity of therapy and minimize disruption of gas flow to the patient. In continuous-feed systems (the most desirable option), the water is replenished without operator intervention or interruption of gas flow to the patient. These systems often rely on gravity, usually consisting of a mounted reservoir external to the humidifier mechanism and most commonly with flotation controls and level-compensated reservoirs. Continuous-feed systems maintain a constant compressible volume, which is important when they are used in a ventilator circuit. Intermittent-fill systems have several disadvantages compared with continuous-feed systems. Changing the water level in a fixed-volume container changes the compressible volume in the circuit as well, resulting in fluctuations in delivered tidal volume. This issue poses a risk for mechanically ventilated newborns and pediatric patients. Open intermittent-fill systems are more susceptible to contamination of the reservoir. With humidifiers that do not have alerts for low water levels, respiratory therapists must regularly check the humidifier chamber to ensure that it does not become empty. Humidifier heaters most commonly use controllers to regulate electrical power to the heater element. The most basic units do not monitor the temperature of the heater, providing power to the heating element based on the setting of the temperature control knob rather than the patient’s airway temperature. Active humidifiers use a heating plate located under the reservoir, a curved element wrapped around the humidifier chamber, a yoke or collar between the water reservoir and the active mechanism of the nebulizer, a plate or rod immersed in the water reservoir, or a set of wires or elements that heat an absorbent wick or tubes containing water. Servo-controlled humidifiers monitor the temperature of gas delivered to the patient, adjusting the power to the heating elements according to the temperature detected by a thermistor probe placed downstream from

the humidifier, near the patient’s airway connection. When the temperature at the patient’s airway is lower than desired, the controller supplies more power to the heater. As this distal temperature nears or exceeds the set temperature, the servo reduces the power to the heating system. Thermistor probes are best placed in the inspiratory limb of the ventilator circuit, far enough from the patient that the temperature of the exhaled gas is not detected. The sensor probe in the inspiratory limb must be located outside the heated environment to allow the heated-wire controller to maintain the desired temperature and water content of inspired gases (Figure 15-6).

FIGURE 15-6 Position of temperature probe outside of incubator when using heated humidification system. Adapted from Peterson BD. Heated humidifiers. Structure and Function. Respir Care Clin North Am 1998;4(2):243–260.

Age-Specific Angle

The temperature probe of a humidifier should not be placed inside an incubator or under a radiant heater because the surrounding air temperature affects humidifier function.

As heated and humidified gas cools, its water content declines and condensation (rain out) occurs. The amount of condensate is affected by the ambient temperature, the gas flow, and the length, diameter, and thermal mass of the tubing between the humidifier and the patient. In a traditional ventilator circuit, the humidifier is heated to 50° C or higher, and the saturated gas contains more than 80 mg of water per liter. As the gas cools to 35° C en route to the patient, it can hold only 40 mg of water per liter; as a result, water condenses in the tubing. The circuit must be drained frequently to prevent pooling condensate from obstructing the gas flow or inadvertently pouring into the patient’s airway. The ventilator circuit, and subsequently condensate, becomes contaminated with bacteria from the patient within the first hour of use. The tubing should be positioned such that drainage moves away from the patient’s airway to avoid accidental lavage of the airway. Condensate presents a risk to the staff as well as to the patient; thus, it must be disposed as contaminated waste. Water traps placed in dependent positions in both the inspiratory and expiratory limbs will drain condensate from the ventilator circuit, reducing the obstruction to gas flow. These water traps should minimize changes in circuit compliance and allow the trap to be emptied without disrupting ventilation of the patient. Techniques used to reduce the formation of condensate include increasing the thermal mass of the circuit, using a coaxial circuit with the inspiratory limb surrounded by the expiratory limb, and adding heated wires to the circuit. Increasing the passive thermal mass of the circuit with thick tubing or wrapping the tubing with insulating material insulates the gas inside the tubing from ambient air. Surrounding the inspiratory limb of the circuit with the expiratory limb in a coaxial manner uses the patient’s exhaled gas as a heated air bath surrounding the inspiratory limb. Placing heated wires in the inspiratory and expiratory tubing of the ventilator circuit heats the gas in the circuit, reducing the temperature differential between the humidifier and the patient. Notably, a humidifier with heated-wire circuits operates at a lower temperature than does a similar device with conventional circuits. The humidifier’s RH control

regulates the temperature differential between the humidifier and the circuit temperature. When the humidifier is cooler than the gas in the inspiratory limb, the absolute humidity remains the same but the relative humidity is decreased, and the circuit has no condensate (Figure 15-7). An increase in inlet chamber temperature induced by high ambient temperature reduces the performance of heated-wire humidifiers, leading to a risk of endotracheal tube occlusion (Figure 15-8).6

FIGURE 15-7 (A) Appropriate settings for a heated-wire circuit will ensure that gas is delivered to the patient at 100% body humidity. (B) Settings too low for a heated-wire circuit mean that the gas delivered to the patient is too dry.

FIGURE 15-8 The temperature regulation system of a heated humidifier with a heated circuit. The heated humidifier outlet temperature is regulated through the heater plate. When the inlet temperature is low, the heater heats the water and evaporation occurs, ensuring sufficient humidification. When the inlet temperature is high, the water may not be warmed, and consequently the gas may remain dry.

When inlet chamber temperature is high, the humidifier plate stops heating.9 The water contained in the chamber remains too cold for evaporation to occur, leading to low levels of humidity. The inlet chamber temperature is influenced by both the ambient temperature and the ventilator output temperature. A high ambient temperature prevents the gas from cooling in the circuit between the ventilator output and the humidification chamber. Minute ventilation also affects ventilator output

gas temperature. To avoid over-humidification, the temperature of gas delivered under conditions of induced hypoventilation should be set to the patient’s core body temperature.10 When no condensate is visible in the inspiratory limb of the ventilator circuit, it is impossible to know whether the gas is being humidified without making direct humidity measurements. To ensure humidification of the inspired gas, the clinician should adjust the temperature differential to the point at which condensation forms near the patient’s airway—the most reliable indicator that gas is fully saturated. If no condensate is visible, the relative humidity could be anything from zero to 99%, and the clinician has no way of determining it other than using a hygrometer. If the humidity control is set incorrectly, dry gas can be delivered to the patient’s airway, resulting in mucous obstruction of the airway (refer to Figure 15-7).

Passive Humidifiers A heat and moisture exchanger (HME), also called an artificial nose, is a passive humidifier.7,8 The HME captures exhaled heat and moisture and transfers part of that heat and humidity to the next inspired breath (Figure 15-9). The ideal HME should add minimal dead space, weight, and resistance to the airway; should incorporate standard connections; and should operate at 70% efficiency or higher. Efficiency is the ratio of the humidity of exhaled gas to the humidity returned to the patient by the HME.

FIGURE 15-9 (A) Function of heat and moisture exchanger. (B) Commercially available heat and moisture exchanger. (B) © 2010 Kimberly-Clark Worldwide, Inc. Used with permission.

HMEs include condensers, hygroscopic condensers, and hygrophobic condensers. Condenser humidifiers are constructed of metallic gauze, corrugated metal, or parallel metal tubes that provide high thermal conductivity. The condenser cools to room temperature during inspiration. During exhalation, saturated gas cools as it contacts the condenser, water condenses and collects on the elements of the condenser, and the temperature of the condenser core rises. On the next inspiration, air is warmed and humidified by the condenser through evaporation of water from the surface. The efficiency of condenser humidifiers is only about 50%. Hygroscopic condenser humidifiers contain materials of low thermal conductivity (meaning that heat from conduction and the latent heat of condensation are not dissipated), such as paper, wool, or foam, which are impregnated with a hygroscopic chemical such as calcium chloride or lithium chloride. During exhalation, warm saturated gas precipitates water on the cool condenser element, whereas water molecules in the hygroscopic chemical bind to the salt without transitioning from a vapor to a liquid state. During inspiration, the lower water vapor pressure in the inspired gas liberates water molecules from the hygroscopic compound without any decrease in temperature from vaporization. The efficiency of these devices can be as high as 70%. Hydrophobic condenser humidifiers use a repellent-water element with a large surface area and low thermal conductivity. During exhalation, the condenser temperature rises to approximately 25° C. On inspiration, the cool gas and the process of evaporation cool the condenser to approximately 10° C. This large temperature shift results in more water condensation in the humidifier on exhalation, with this water then being used to humidify the next inspiration. These devices are about 70% efficient. Hydrophobic humidifiers can also serve as efficient microbiological filters. The efficiency of HMEs declines as the tidal volume, inspiratory flow, or fraction of inspired oxygen (FIO2) increases. Resistance through the HME increases as the water load of the device increases. When the HME is dry, resistance across the device is minimal. After several hours of use, however, resistance may increase as water is absorbed onto a hygroscopic HME. The increased work imposed by HMEs may not be well tolerated by patients. HMEs also increase mechanical dead space—

a particularly problematic concern for patients receiving lung-protective mechanical ventilation, as the lower tidal volume coupled with the additional mechanical dead space can result in hypercapnia.11–14 Although the HME forms a barrier between the patient and the ventilator circuit, the value of such devices as a filter, in terms of patient outcomes and the safety of the healthcare provider, remains unclear.15 Figure 15-10 presents a clinical algorithm to guide the use of HMEs. Although some manufacturers recommend that these devices be changed daily, current evidence suggests that HMEs can be safely used for at least 48 hours.16

FIGURE 15-10 Clinical algorithm for use of heat and moisture exchanger. Adapted from Branson RD, Campbell RS. Humidification in the intensive care unit. Respir Care Clin North Am 1998;4(2):305–320.

Description The choice of HME should be based on efficiency, dead space, weight, and cost. The humidity efficiency of the devices ranges from 40% to 90%. HMEs that deliver gas with an absolute humidity greater than 30 mg H2O/L have a low risk of tracheal tube occlusions, whereas those providing absolute humidity less than 25 mg H2O/L are associated with an increase in tracheal tube occlusion and should be avoided.16 The resistance through HMEs varies from 0.4 cm H2O/L/s to 4 cm H2O/L/s, and the dead space ranges from about 20 mL to almost 100 mL. It is important to appreciate the heterogeneity of HMEs’ humidification performance: Put simply, some perform much better than others. HMEs are an inexpensive alternative to active humidifiers, but cost alone should not be the determining factor in the decision to use these devices. Contraindications for HME use include the presence of thick, copious,

or bloody secretions; a large leak, such as might occur with a large bronchopleural fistula, a leak around the endotracheal tube cuff, or a leak around the interface with noninvasive ventilation; a body temperature less than 32° C; and a minute ventilation greater than 10 L/min. Of concern is the fact that the dead space of the HME can result in an increase in PaCO2 or ventilatory requirements, or both, in a patient with a low tidal volume as part of a lung-protective ventilation strategy. Hazards associated with the use of HMEs include impaction of pulmonary secretions, higher resistive work of breathing, mucous plugging, hypercapnia, and hypothermia. During aerosol administration, the HME must be removed or bypassed. When an HME is used, the circuit remains dry. Moreover, some HMEs are effective filters. These benefits have led some to recommend use of an HME as part of a ventilator-associated pneumonia (VAP) prevention program. Recent studies, however, have not found that HME use is more effective in preventing VAP than is active humidification.17,18 Stop and Think A mechanically ventilated patient has respiratory acidosis. How might an HME contribute to this problem?

Respiratory Recap Assessment of Adequate Humidity Delivery The delivered relative humidity is 100% if condensate is seen in the delivery tubing near the patient’s airway.

Respiratory Recap Heat and Moisture Exchangers ∎ Efficiency declines as the tidal volume, inspiratory flow, and FIO2 increase. ∎ HMEs increase dead space and resistive work of breathing. ∎ HMEs do not need to be changed more often than every 48 hours.

Bland Aerosol Therapy Bland aerosol therapy provides humidification with solutions such as saline for therapeutic and diagnostic purposes. Large-volume pneumatic nebulizers and ultrasonic nebulizers are commonly used for these purposes. Large-volume pneumatic nebulizers, which have reservoir volumes greater than 100 mL, are often used to aerosolize solutions such as normal saline (0.9% NaCl), half normal saline (0.45% NaCl), and distilled water for prolonged periods. They are primarily used to provide humidification of medical gases for patients with bypassed upper airways, as treatment of upper airway inflammation with cold mist for local vasoconstriction, to prevent occlusion of airway stents, and to induce sputum production for diagnostic purposes. Little evidence supports the use of bland aerosols to hydrate lower respiratory tract secretions. For humidification of inspired gases, a large-volume nebulizer offers little advantage over alternative methods such as heated humidifiers.

Humidification to Tracheostomy Heated humidity, bland aerosol, or HME can provide humidification of the inspired gas in patients with a tracheostomy who are breathing spontaneously. In patients who are not hospitalized, HMEs might be more convenient. The configuration of HMEs for tracheostomized patients with spontaneous breathing differs from applications for mechanically ventilated patients. Specifically, these devices typically have less dead space than the devices used with mechanical ventilation. Some HMEs have a port for delivering oxygen to hypoxemic patients, which may decrease the temperature and absolute humidity of inspired gas. Although the respiratory rate does not affect the absolute humidity, it can be affected by tidal volume and oxygen supplementation. With 3 L/min of oxygen supplied through HMEs equipped with oxygen ports, absolute humidity may be inadequate.19 As a general rule, heated humidity is superior to HME for spontaneously breathing patients with tracheostomy.20

Device Selection for Humidity Therapy Table 15-1 compares the relative attributes of common humidification systems. The authors of a Cochrane Review concluded that HMEs and active heated humidifiers differ little in terms of their overall effectiveness.21 To select the most appropriate humidification device, the clinician should consider the following questions: TABLE 15-1 Comparison of Common Humidification Systems

Description What source, temperature, and humidity of gas is the patient breathing? What is the point of entry of gas into the airway? What is the inspiratory flow, tidal volume, and minute volume? Does the patient have an intact or a bypassed upper airway? Does the patient have normal or diseased lungs? Is there evidence of increased, thick secretions or a humidity deficit?

Are special needs imposed by dead space or the patient’s size, age, ability to tolerate administration, or sensitivity to changes in the work of breathing?

Aerosol Drug Administration Aerosol drug therapy has a number of advantages over other routes of administration: A smaller dose can be targeted to the site of action, the onset of action occurs more quickly, and the therapeutic effect is achieved with fewer systemic side effects.22–26 Delivering aerosolized drugs directly to the airways limits their systemic absorption, minimizes systemic side effects, and achieves a high therapeutic index compared with systemic administration. In contrast, a variety of medications, including peptides and other macromolecules, can be targeted to the lung parenchyma for systemic administration across the alveolar-capillary membrane into the pulmonary vascular bed. Aerosol devices can deliver a wide variety of medications, and many types of devices are used for this purpose, including nebulizers, pressurized metered-dose inhalers, and dry powder inhalers. For medical use, aerosol generators produce particles with a mass median aerodynamic diameter of 1 to 5 µm.

Basic Concepts of Aerosol Therapy An aerosol is composed of particles suspended in air. The time for which particles remain suspended depends on their low terminal settling velocity (vt), or the velocity at which the aerosol particles fall in air because of gravity, a value related to particle size and density. The deposition of inhaled aerosols onto airway surfaces varies with the size of the particles. For example, the vt of a 5-µm water droplet is 0.074 cm/s, almost 22 times greater than that of a 1-µm water droplet but one-fourth that of a 10-µm water droplet. The geometric size of the particles is commonly expressed as the mass median aerodynamic diameter (MMAD). Half the mass of particles in an aerosol is less than the MMAD, and the other half of the mass is greater. Relatively few particles make up the mass above the MMAD, with a much greater number of particles less than the median particle diameter required to reach a comparable mass. Geometric standard deviation (GSD) is a measure of the variation of particle size distribution. A monodisperse aerosol, in which all particles are basically

the same size, has a GSD less than 1.2, whereas a heterodisperse aerosol, with a wider range of particle sizes, has a GSD of more than 1.2. Most therapeutic aerosols are heterodisperse. Respiratory Recap Characterization of Aerosols ∎ Mass median aerodynamic diameter (MMAD) ∎ Geometric standard deviation (GSD)

Inertia is the tendency of an object with mass, once in motion, to travel in a straight line. The greater the mass and velocity of a particle, the greater is the inertia that keeps it in motion. Inertial impaction is the primary mechanism of deposition of aerosol particles 5 µm or larger and an important mechanism for particles as small as 2 µm. As aerosol is inhaled and the stream of gas enters the airway, particles tend to continue along their initial trajectory, impacting and depositing on the airway. The higher the inspiratory flow, the greater the velocity and inertia of the particles, which increases the tendency of smaller particles to impact and become deposited in airways. Turbulent flow, complex passageways, bifurcation of the airways, and inspiratory flows greater than 30 L/min increase the impaction of particles larger than 2 µm in larger airways. Gravitational sedimentation occurs when aerosol particles settle out of suspension because of gravity. The greater the mass of the particle, the faster it settles. Very small particles (those less than 0.5 µm in diameter) do not settle at all. Breath holding for 4 to 10 seconds after inhalation of an aerosol lengthens the residence time for particles in the lungs, increasing the time for deposition through gravitational sedimentation, especially in the last six generations of the airway. Breath holding increases deposition of aerosol by as much as 10%, with up to a fourfold increase in peripheral distribution. This marginal increase in deposition explains why breath holding has not been demonstrated to significantly improve the clinical response to aerosolized medications conducted to targeted airways. Diffusion, or Brownian movement, is the primary mechanism of deposition of particles less than 3 µm in the airway. As gas reaches the

distal regions of the lungs, its flow stops. Aerosol particles bouncing against both air molecules and each other are deposited on contact with the airway surfaces. Preferential deposition for particles 0.5 to 3 µm occurs in both the central and peripheral airways. Coalescence, the attraction of particles to each other, occurs when particles come within a distance 25 times or less their diameter. Aerosol droplets in the respirable range (1 to 5 µm) are more likely to become deposited in the lower respiratory tract than are larger or smaller particles. For particles larger than 0.5 µm, the depth of penetration into the lungs is inversely proportional to the particle size. Particles between 0.1 and 1 µm are so small that a significant proportion of those that enter the lungs may be exhaled. Particles larger than 5 µm more likely impact the upper airway. Respiratory Recap Primary Factors Affecting Aerosol Delivery ∎ Deposition ∎ Inertia ∎ Gravity ∎ Diffusion

Aerosol Deposition, Targeting, and Translocation Once an aerosol settles in the airway, it must move across the mucous barrier and retain its bioactivity to be effective as a therapeutic agent. The optimal site of action depends on the agent administered. Bronchodilators and steroids must reach the epithelium to be effective. Aerosolized antibiotics and mucokinetic agents are most effective when dispersed in infected airway secretions at sites of maximum airway obstruction. Particle charge, solubility, size, and the biophysical properties of secretions all affect the ability of an aerosol to penetrate the mucous barrier. Turbulent flow and airway obstruction affect the airway deposition pattern. Other factors that limit efficacy, especially of macromolecules, include binding to constituents of mucus, including mucin and

deoxyribonucleic acid (DNA), and the breakdown of bioactive molecules by proteases and other enzymes. Molecular weight and particle diffusion through mucus are inversely related. The antibiotic diffusion barrier represented by mucin may be significant in vitro, particularly for aerosol antibiotics. Translocation of macromolecules can be further compromised by the hypersecretions that accompany inflammation and chronic pulmonary disease. These secretions can act as a barrier to the penetration of an aerosol. Factors that promote translocation of medicated aerosols to the airway include an effective surfactant layer and increased particle retention time. Mucous breaks along the airway assist with particle deposition and translocation. Surfactant promotes the displacement of some particles from air to the aqueous phase.

Factors Affecting Drug Dose Distribution Dosing of aerosolized medication is imprecise. Indeed, clinicians may not be able to determine how much drug is delivered to targeted areas of the lungs in patients with progressive disease states and during exacerbations—both of these factors reduce aerosol deposition in the respiratory tract. A firm relationship between tidal volume and aerosol effectiveness has not been established. Theoretically, larger breaths should capture more aerosol, but this relationship has not been shown clinically. High inspiratory flow increases aerosol impaction in larger airways, whereas low inspiratory flow may result in reduced delivery of medication from a dry powder inhaler. Humidity also influences the delivery of aerosol medications. Droplets of solution may either evaporate or grow, depending on the water content and temperature of the gas, and powder particles can clump together or aggregate in high humidity. Drug formulations dictate, in part, which aerosol delivery options are available for a specific medication. Most solutions can be nebulized if the medication is soluble, but the physical characteristics of the solution (or suspension) can affect particle size and nebulizer output. Furthermore, some macromolecules may not enter suspension well and can be shattered into non-bioactive forms by the force of air required to generate an aerosol.

Aerosol Generators Jet Nebulizers Pneumatic jet nebulizers use the Bernoulli principle to drive a highpressure gas through a restricted orifice across the top of a capillary tube, with the bottom of the tube being immersed in the solution (Figure 15-11). An aerosol forms when the jet stream shears fluid from the capillary tube and drives the particles against a solid or liquid surface that acts as a baffle. Impaction against a baffle removes larger particles from suspension, allowing them to return to the reservoir. In contrast, smaller particles remain suspended in the gas and travel from the nebulizer. A number of factors affect the delivery of aerosols by nebulizer (Box 15-1). Box 15-2 describes the technique for using a medication nebulizer.

FIGURE 15-11 (A) Small-volume jet nebulizer for drug delivery. (B) Schematic drawing of smallvolume jet nebulizer.

BOX 15-1 Factors That Affect Aerosol Delivery by Nebulizer

Technical factors Manufacturer Gas flow Fill volume Solution characteristics Characteristics of the driving gas Designs to enhance output Continuous versus intermittent delivery Patient factors Breathing pattern Nose versus mouth breathing Characteristics of gas Airway obstruction Positive pressure delivery Artificial airway and mechanical ventilation

BOX 15-2 Technique for Use of a Jet Nebulizer 1. Assemble the tubing, nebulizer cup, and mouthpiece (or mask). 2. Place the medicine into the nebulizer cup; use a fill volume of 4 to 5 mL. 3. The patient should be seated in an upright position. 4. Connect to a power source; use a flow of 6 to 8 L/min or a compressor. 5. Have the patient breathe normally with occasional deep breaths until sputter or no more aerosol is produced. 6. Keep the nebulizer vertical during treatment. 7. Rinse the nebulizer with sterile water and allow it to air dry.

An effective small-volume pneumatic nebulizer should deliver more than 50% of its total dose as aerosol in the respirable range (1 to 5 µm) in 10 minutes or less of nebulization time. Nebulizer performance varies with fill volume, flow, gas density, and nebulizer model.27,28 The amount of drug nebulized increases as the fill volume increases. The residual volume of solution (dead volume) that remains in commercial smallvolume nebulizers varies from 0.5 to 1.5 mL, depending on the device. Increasing the fill volume therefore allows a greater proportion of the medication to be nebulized. For example, with a 1-mL residual volume, a fill of 2 mL provides only 50% of the nebulizer charge available for nebulization. By comparison, a fill of 4 mL makes 3 mL, or 75%, of the medication available for nebulization. Droplet size and nebulization time vary inversely with flow. Within the design limits of the nebulizer, the

higher the flow to the nebulizer, the smaller the particle size generated and the shorter the time required to nebulize the full dose. Most nebulizers function best at a flow of 6 to 8 L/min, although some are designed for lower flows, such as those for continuous aerosol therapy. Gas density affects both aerosol generation and delivery of aerosol to the lungs. This effect is most evident with low-density helium–oxygen mixtures (heliox).29 A carrier gas of lower density produces less turbulent flow, reducing aerosol impaction losses during inspiration and improving delivery of aerosol to the lungs. By comparison, when heliox drives the jet nebulizer, aerosol output is reduced, requiring a twofold increase in flow to produce a comparable respirable aerosol output per minute.30 This issue can be overcome by use of a mesh nebulizer. The benefit of heliox for aerosol delivery in patients with acute asthma is unclear, with some studies indicating a benefit from this apporach31 and others reporting no benefit.32,33 Available evidence does not support routine use of heliox for aerosol delivery, but it might have a role in the treatment of patients with severe acute asthma. Humidity and temperature affect the particle size and concentration of drug remaining in the nebulizer. Evaporation of water and adiabatic expansion of gas can reduce the temperature of the aerosol to more than 5° C (41° F) below the ambient temperature. Aerosol particles entrained into a warm and water-saturated gas stream may increase in size. These larger particles tend to coalesce, increasing the MMAD. Some positive expiratory pressure (PEP) devices allow concomitant administration of aerosols by nebulizer. Devices that obstruct the aerosol pathway produce a significantly smaller particle size aerosol and a significant decrease of patient dose.34 Unless the device has been designed for compatibility with a nebulizer (e.g., Monaghan Aerobika), the nebulizer should be placed between the device and the patient’s airway.35 Clinicians and patients often tap a nebulizer periodically to shake droplets of medication from the walls of the nebulizer into the reservoir. Drug delivery from the nebulizer effectively stops with the onset of sputtering. Thus, the point of initial jet nebulizer sputter should indicate an end of the treatment. Because the nebulizer selected affects the reliability of aerosol delivery, the chosen device should be matched to the specific medication prescribed to the patient. When a compressor is used

to power the nebulizer, the performance of the compressor also factors into this decision. Operation of the nebulizer throughout the patient’s respiratory cycle, though a common practice, wastes the aerosol produced during the expiratory phase. A typical inspiration-to-expiration ratio of 1:3 results in 75% of the aerosol emitted from the nebulizer being lost to the atmosphere. This loss is a major factor in the poor efficiency associated with pneumatic nebulizers. If 50% of the nominal dose is emitted, 50% is in the respirable range, and 25% of that is inhaled by the patient, then 12.5% of the nominal dose is inhaled by the patient and 20% is exhaled. This results in the 10% deposition observed with in vivo measurements. A reservoir on the expiratory limb of the nebulizer conserves drugs by collecting some of the nebulizer output that otherwise would be wasted to the atmosphere. To create such a reservoir, 15 cm of aerosol tubing can be placed on the expiratory side of the nebulizer. As an alternative, commercial devices such as simple bag reservoirs (Figure 15-12) provide a greater volume reservoir in which the smaller aerosol particles remain in suspension for inhalation and larger particles rain out.

FIGURE 15-12 Nebulizer with reservoir bag to capture aerosol during the expiratory phase.

Vented breath-enhanced nebulizer systems (Figure 15-13) allow the

patient to inhale additional air through the nebulizer, thereby increasing drug delivery on inspiration. The inlet vent closes on exhalation, and aerosol exits via a one-way valve in the mouthpiece. This design reduces aerosol waste and increases the inhaled dose by as much as 50% without increasing the treatment time.

FIGURE 15-13 (A) Vented breath-enhanced nebulizer. (B) Schematic drawing of a vented breathenhanced nebulizer.

Breath-actuated nebulization synchronizes aerosol generation with inspiration, increasing the amount of drug available for inspiration. The inhaled aerosol per breath is similar, but the amount of drug inhaled and the treatment time increase by a factor of 4. Inspiratory phase nebulization can be accomplished with a thumb control port that allows the patient to manually direct gas to the nebulizer only on inspiration. This improves the efficiency of the nebulizer if the patient has good hand–breath coordination. More effective systems do not require hand– breath coordination and instead synchronize aerosol production to the patient’s inspiratory phase. The Monaghan AeroEclipse (Figure 15-14) is a pneumatic breath-actuated nebulizer that responds to the patient’s inspiratory flow, producing aerosol during inspiration and ending nebulization when the inspiratory flow drops below a threshold.36–38

FIGURE 15-14 Breath-actuated nebulizer.

The I-Neb system uses a microprocessor and pneumotachometer to regulate nebulization during the first half of inspiration. Applying a technique called adaptive aerosol delivery (AAD), it monitors the inspiratory time of the first three breaths and creates a template for nebulization during inspiration of subsequent breaths (Figure 15-15). Some nebulizers are valved devices and have expiratory filters (Figure 15-16); these are designed specifically for the delivery of pentamidine. The filter minimizes ambient contamination with the aerosol and the patient’s exhaled gases. These nebulizers also produce very small particles to enhance parenchymal deposition.

FIGURE 15-15 Adaptive aerosol delivery system. Courtesy of Philips Respironics.

FIGURE 15-16 (A) Respirgard nebulizer for pentamidine administration (Marquest). (B) Schematic drawing of Respirgard nebulizer.

The performance of single-patient-use plastic nebulizers may begin to degrade after many uses. Between treatments, nebulizers should be rinsed with sterile water and air dried or replaced. Contamination of nebulizer solutions can occur with storage of multiple-dose solutions at room temperature and reuse of syringes to measure the solution. Refrigerating solutions and disposing of syringes every 24 hours eliminate bacterial contamination. For patients who cannot use a mouthpiece, the nebulizer can be fitted to a mask. The clinical response to medication delivery via a mouthpiece versus a close-fitting mask shows no differences. Patient compliance and preference, therefore, should guide selection of the device. If a mask is used, care should be taken to avoid inadvertent aerosol delivery into the eyes (Figure 15-17).39–42 A mouthpiece enhances medication delivery to the airways in adults.

FIGURE 15-17 Unilateral left dilated pupil, which does not react to light, caused by the inadvertent aerosolization of ipratropium bromide into the eye.

Crying consists of a long exhalation preceded by a very short and rapid inhalation. This pattern prevents lower airway deposition of an aerosol. Thus, aerosols should not be administered to a crying child. Instead, it is more efficient to deliver medication by close-fitting mask when the child is asleep. The blow-by technique, in which the clinician directs the aerosol from the nebulizer toward the patient’s nose and mouth, is usually ineffective due to the incremental aerosol drop-off with increasing distances from the face.43,44 At a distance of 4 cm from the face, however, blow-by can be an effective means of drug delivery with the appropriate nebulizer system.45

The small particle aerosol generator (SPAG) is a jet-type aerosol generator used to administer ribavirin (Figure 15-18). It uses a secondary drying chamber that reduces the MMAD to 1.2 µm with a GSD of 1.4. The SPAG reduces the 50 psi of line-pressure medical gas to 26 psi; it is connected to two flow meters that control flow to the nebulizer and the drying chamber. The aerosol generated in the medication reservoir enters the long cylindrical drying chamber, where additional flow of dry gas reduces the size of the aerosol particles through evaporation. The flow to the nebulizer is adjusted to a maximum of 7 L/min, with a total flow from both flow meters of 15 L/min.

FIGURE 15-18 (A) Small particle aerosol generator (SPAG) for ribavirin administration. (B) Schematic drawing of SPAG. (A) Courtesy of Valeant Pharmaceuticals; (B) Adapted from Scanlan CL, Wilkins RL, Stoller JK. Egan’s fundamentals of respiratory care. 7th ed. St. Louis, Mosby; 1999

The administration of ribavirin has highlighted concerns about secondhand exposure of healthcare workers to aerosol. To protect clinical staff, open-air administration should be avoided; instead, ribavirin administration should be limited to a negative-pressure, single-patient room with six air exchanges per hour. Procedures used to reduce the release of ribavirin into the environment include containment of the aerosol with a canopy over the delivery device (Figure 15-19), use of a scavenging system, and filtering of the expiratory limb of the circuit of a mechanically ventilated patient. Practices that reduce caregiver exposure include turning off the nebulizer 5 minutes before opening the tent or 1 minute before disconnecting the ventilator and using personal protective equipment including goggles, a respirator, gown, and gloves. Administrative policies should prevent pregnant or lactating women and staff members who have had reactions to the drug from coming into contact with ribavirin.

FIGURE 15-19 Scavenging system for ribavirin administration. Modified from Kacmarek RM, Kratohvil J. Evaluation of a double-enclosure double-vacuum unit scavenging system for ribavirin administration. Respir Care 1992;37(1):37–45. Reprinted with permission.

When ribavirin is administered during mechanical ventilation, the drug has a tendency to occlude filters, valves, and endotracheal tubes. Tandem filters placed in series in the expiratory limb of the ventilator can reduce expiratory valve occlusion but require frequent changing. Aerosol from the SPAG is entrained into the ventilator circuit distal to the output of the humidifier through a one-way valve. A high-pressure alarm in the circuit alerts the clinician to an excessive baseline pressure should expiratory occlusion occur. If standard bronchodilator dosing does not relieve the symptoms of a patient with acute asthma, continuous aerosol can be provided at a controlled rate of medication delivery.46–48 Doses of albuterol between 7.5

and 15 mg/h have proved effective in treating acute exacerbations of asthma. One strategy is to use an intravenous infusion pump to deliver a premixed bronchodilator solution into a jet nebulizer (Figure 15-20). Another strategy relies on a large-volume nebulizer that delivers a consistent output of medication at a specific flow. Albuterol solution and saline are mixed in the reservoir, and the nebulizer is operated at a flow recommended by the manufacturer to deliver the desired dose.

FIGURE 15-20 (A) Delivery systems for continuous aerosolized bronchodilator by continuous infusion of medications into a standard small-volume nebulizer. (B) Commercially available nebulizer for continuous aerosol administration. (C) Commercially available nebulizer for continuous aerosol administration. (B) Courtesy of Westmed, Inc. (C) Courtesy of B&B Medical Technologies.

Patients should be taught how to disinfect their nebulizers for home use. After each treatment, the patient should shake the remaining solution from the nebulizer cup. The patient should rinse the nebulizer cup with either sterile or distilled water and let it air dry on an absorbent towel. Once or twice a week, the patient should disassemble the nebulizer, wash it in soapy tap water, and disinfect it with either a 1.25% acetic acid (white vinegar) mixture or a quaternary ammonium compound at a dilution of 1 ounce to 1 gallon of sterile or distilled water. The acetic acid soak should last for at least 1 hour, but a quaternary ammonium compound soak needs only 10 minutes. Although the patient should not reuse acetic acid, quaternary ammonium solution can be reused for up to 1 week. Pneumatic nebulizers function correctly with repeated uses provided that they are cleaned after each use, rinsed, and air dried. Nebulizers for hospital use are disposable, single-patient-use devices and should be changed at the conclusion of the dose, every 24 hours, or when visibly soiled. Nebulizers should not be rinsed with tap water but may be rinsed with sterile water and allowed to dry between treatments. Compressed air or oxygen is needed for jet nebulizers. Compressors are the only available flow source at home and may also be used in the hospital. Although this factor is not commonly considered, the compressor gas flow and pressure can affect nebulizer performance in terms of droplet size distribution and drug output rate. Replacing the nebulizer or compressor with a different brand changes the aerosol characteristics. Thus, clinicians should be cautious when changing out the compressor/nebulizer pairs unless they are aware of the resulting impact on aerosol delivery.49,50 Stop and Think You are asked to instruct a 4-year-old child with asthma, and the child’s parents, on the proper use of a nebulizer and compressor for home therapy. How would you approach this assignment?

Mesh Nebulizers Several manufacturers have developed aerosol devices that use a mesh or plate with multiple apertures to produce an aerosol (Figure 15-21 and Box 15-3).51–53 Mesh nebulizers use a vibrating mesh or a vibrating horn. With the vibrating mesh (e.g., Aerogen Aeroneb, Pari eFlow Technology), contraction and expansion of a vibrational element produce upward and downward movements of a domed aperture plate. The aperture plate contains up to 4000 tapered holes; that is, the holes have a larger cross section on the liquid side and a smaller cross section on the side from which the droplets emerge. The medication is placed in a reservoir above the domed aperture plate. Sound pressure builds up in the vicinity of the membrane, creating a pumping action that extrudes solution through the holes in the plate to produce an aerosol. The exit diameter of the aperture holes determines the aerosol particle size and flow. The size of the holes in the plate can be modified for specific clinical applications. In the vibrating horn system (e.g., Omron), a piezoelectric crystal vibrates at a high frequency when electrical current is applied, with the vibration transmitted to a transducer horn in contact with the solution. Vibration of the transducer horn forces the liquid through the apertures in the plate so that it forms an aerosol.

FIGURE 15-21 Mesh nebulizers. (A) Principle of operation. (B–D) Representative commercially available mesh nebulizers. (E) Holding chamber for mesh nebulizer. (A) Adapted from Hess DR. Aerosol delivery devices in the treatment of asthma. Respir Care 2008;53(6):699–725; (B) Courtesy of Omron Healthcare; (C) Courtesy of Aerogen; (D) Courtesy of eFlow LLC (PARI Pharma GmbH); (E) Courtesy of Aerogen.

BOX 15-3 Technique for Use of a Mesh Nebulizer 1. Correctly assemble the equipment. 2. Pour the solution into the medication reservoir or insert the medication vial. Do not exceed the volume recommended by the manufacturer. 3. Turn on the power. 4. Hold the nebulizer in the position recommended by the manufacturer. 5. Breathe normally. 6. If the treatment must be interrupted, turn off the unit to avoid waste. 7. At the completion of the treatment, clean the unit as recommended by the manufacturer. 8. Be careful not to touch the mesh during cleaning, as this will damage the unit. 9. Once or twice a week, disinfect the nebulizer following the manufacturer’s instructions.

Mesh nebulizers have a fast rate of nebulization and a small dead volume. The fast nebulization rate improves patient satisfaction. The small dead volume means that, compared with a jet nebulizer, a smaller solution volume can be placed into the device. The Aerogen mesh nebulizer can be used with a holding chamber that improves the device’s effectiveness and decreases the loss due to exhalation and aerosol condensation.54,55 The output of a mesh nebulizer depends on the fluid’s characteristics.56,57 These nebulizers may be unsuitable for viscous fluids, which suggests that matching the formulation to the device may be important for these aerosol generators. Mesh technology can be coupled with adaptive aerosol delivery, as in the I-Neb device for delivery of iloprost. Several medications, including the antibiotic aztreonam for cystic fibrosis and the bronchodilator glycopyrrolate for chronic obstructive pulmonary disease (COPD), have specific Food and Drug Administration (FDA)-cleared indications for use with a mesh nebulizer.

Soft Mist Inhaler The Respimat Soft Mist Inhaler delivers a metered dose of medication as a fine mist (Figure 15-22 and Box 15-4).58,59 The medication delivered by the Respimat is stored in a collapsible bag in a sealed plastic container inside the cartridge. With each actuation, the device draws the correct dosage from the inner reservoir, and the flexible bag contracts accordingly. A twist of the inhaler’s base compresses a spring. A tube slides into a canal in the cartridge, and the dose is drawn through the tube into a micropump. When the patient releases the dose-release button, the energy released from the spring forces the solution through the uniblock, causing the release of a slow-moving aerosol. The device’s dose indicator shows how many doses are left.

FIGURE 15-22 (A) Respimat Soft Mist Inhaler. (B) Components of the Respimat. (C) The uniblock, which is the core element of the Respimat. ® 2010 Boehringer Ingelheim International GmbH, Germany. All rights reserved.

BOX 15-4 Technique for Use of Respimat Inhaler First-Time Use 1. With the cap closed, press the safety catch while pulling off the clear base. Be careful not to touch the piercing element located inside the bottom of the clear base. 2. Write the discard date on the label of the inhaler; it is the date 3 months from the date the cartridge is inserted into the inhaler. 3. Take the cartridge out of the box. Push the narrow end of the cartridge into the inhaler. The base of the cartridge will not sit flush with the inhaler; instead, approximately ⅛ inch will remain visible when the cartridge is correctly inserted. The cartridge can be pushed against a firm surface to ensure that it is correctly inserted. Do not remove the cartridge once it has been inserted into the inhaler. 4. Put the clear base back into place. Do not remove the clear base again. The inhaler should not be taken apart after you have inserted the cartridge and put the clear base back.

Prime for First-Time Use The following steps are needed to prime the dosing system and will not affect the number of doses available. After preparation and initial priming, the inhaler will deliver 120 doses. Proper priming is important to ensure that the correct amount of medicine is delivered. 1. Hold the inhaler upright, with the cap closed, to avoid accidental release of the dose. Turn the clear base in the direction of the white arrows on the label until it clicks (halfturn). 2. Flip the cap until it snaps fully open. 3. Point the inhaler downward (away from your face). Press the dose release button. Close the cap. 4. Repeat these steps until a spray is visible. Once the spray is visible, repeat these steps three more times to make sure the inhaler is prepared for use.

Daily Dosing 1. Hold the inhaler upright with the cap closed to avoid accidental release of a dose. Turn the clear base in the direction of the white arrows on the label until it clicks (half-turn). 2. Flip the cap until it snaps fully open. 3. Breathe out slowly and fully. 4. Close your lips around the end of the mouthpiece without covering the air vents. 5. Point the inhaler toward the back of your throat. 6. While taking in a slow, deep breath through your mouth, press the dose release button and continue to breathe in slowly for as long as possible. 7. Hold your breath for 10 seconds or for as long as comfortable.

8. Close the cap until you use the inhaler again. 9. If the inhaler has not been used for more than 3 days, spray 1 puff toward the ground to prepare the inhaler for use. 10. If the inhaler has not been used for more than 21 days, repeat the priming process until a spray is visible. Then repeat three more times to prepare the inhaler for use.

When to Replace the Inhaler The Respimat contains approximately 1 month of medication. The dose indicator shows approximately how much medicine is left. When the pointer enters the red area of the scale, there is enough medicine for 7 days. Discard the inhaler 3 months after insertion of the cartridge into the inhaler, even if all the medicine has not been used, or when the inhaler is locked (empty).

The core element of the Respimat is the fine nozzle system of the uniblock. When the medication solution is forced through the nozzle system, two jets of liquid emerge and converge at an optimized angle, and the impact of these converging jets generates the aerosol. The aerosol produced by the Respimat moves much more slowly and has a more prolonged duration than an aerosol cloud from a pressurized metered-dose inhaler (pMDI).60 Compared with a pMDI, lung deposition is doubled and oropharyngeal deposition reduced. Low deposition on the face, and especially in the eyes, occurs when the Respimat is fired accidentally outside the body or is fired at the same time as the patient exhales.61 Patients have a high level of satisfaction with the Respimat.62 One report described a prototype adapter that would enable use of the Respimat during mechanical ventilation.63

Ultrasonic Nebulizers An ultrasonic nebulizer (USN) uses a piezoelectric crystal that vibrates at a high frequency to convert electricity to sound waves, creating standing waves in the liquid immediately above the transducer and disrupting the liquid’s surface, forming a geyser of droplets (Figure 1523). A disposable medication cup with a flexible diaphragm may be used in this device, with the sound waves communicated through a layer of water acting as a couplant. Alternatively, the solution to be aerosolized can be placed directly on the transducer. The USN is capable of greater aerosol output (0.4 to 5 mL/min) with greater aerosol density than is possible with conventional jet nebulizers. The frequency determines the

particle size, and the amplitude of the signal determines the output. Within limits, the particle size is inversely proportional to the frequency and cannot be adjusted by the user. USNs can operate at different frequencies (1.24 to 2.25 MHz), producing a range of MMAD (2.5 to 6 µm).

FIGURE 15-23 Schematic drawing of ultrasonic nebulizer. Adapted from Cohen N, Fink J. Humidity and aerosols. In: Eubanks DH, Borne RC, eds. Principles and Applications of Cardiorespiratory Care Equipment. St. Louis, Mosby; 1994.

The large-volume USN, which is used for bland aerosol therapy or sputum induction, incorporates an air blower to carry the mist to the patient. An inverse relationship exists between the aerosol density emitted by the USN and the flow of gas through the nebulizer. Because of the energy required to operate the device, the temperature of the solution in a USN increases by as much as 15° C (59° F) over 15 minutes. As the temperature rises, the drug concentration also rises, increasing the likelihood of undesirable side effects such as denaturing of proteins. Small-volume USNs are available for aerosol drug delivery (Figure 15-24). These systems may or may not use a water-filled couplant compartment, with the medication placed in a cup or directly onto the

transducer connected to a battery-powered power source. The patient’s inspiratory flow draws aerosol from the nebulizer into the lungs. As the USN operates, the aerosol remains in the medication cup or chamber until a flow of gas pushes or pulls the aerosol from the nebulizer. If a USN creates aerosol continuously, the patient draws aerosol from the nebulizer during inspiration and clears aerosol from the chamber during exhalation, with aerosol collecting in the chamber between end expiration and through inspiration. Diverting exhalation away from the medication chamber can ensure minimal waste to the atmosphere and more drug available for inhalation.

FIGURE 15-24 (A) Minibreeze ultrasonic nebulizer. (B) Lumiscope ultrasonic nebulizer. (A) Courtesy of Briggs Healthcare; (B) Courtesy of GF Health Products, Inc.

Small-volume USNs may have less dead volume than traditional small-volume nebulizers. The portable power source provided within the USN provides for both greater convenience and mobility. These advantages may be offset by USN’s relatively high cost compared to standard jet nebulizers. USNs have been used for administration of a

wide variety of formulations, ranging from bronchodilators to antiinflammatory agents and antibiotics, but they are less effective than other delivery devices, especially with suspensions. The Tyvaso Inhalation System (Optineb) (Figure 15-25) uses an ultrasonic nebulizer to deliver a treprostinil inhalation solution for the treatment of pulmonary arterial hypertension. It incorporates filters to minimize ambient contamination with the drug and prompts the patient to use correct inhalation technique.

FIGURE 15-25 The Tyvaso Inhalation System (Optineb) uses an ultrasonic nebulizer to deliver a treprostinil inhalation solution for the treatment of pulmonary arterial hypertension. Courtesy of United Therapeutics Corporation.

Overhydration has been associated with prolonged bland aerosol treatment by USN in children and patients with renal insufficiency. The high-density aerosol from the USN may precipitate bronchospasm. An acoustic power output greater than 50 watts/cm2 has been associated with disruption of the structure of some molecules. USNs have attracted attention as a possible option for administering aerosols during mechanical ventilation because they do not require the addition of a

driving gas flow to the circuit. Disadvantages of the USN in the ventilator circuit include its weight, its position dependency, a tendency to heat medications, and the need for water couplants.

Pressurized Metered-Dose Inhalers The pressurized metered-dose inhaler (Figure 15-26) is a commonly prescribed method for aerosol delivery.24,64 A pMDI consists of a pressurized canister containing a drug in the form of a micronized powder or solution that is suspended with a mixture of propellants, surfactant, preservatives, flavoring agents, and dispersing agents. The concentrations of the dispersing agents are equal to or greater than that of the medication, and these dispersing agents may be associated with coughing and wheezing. The active drug accounts for approximately 1% of the contents of the pMDI. As much as 80% by weight of the spray from the pMDI consists of the propellant, which in the past was a chlorofluorocarbon (CFC). Because of international agreements to ban CFCs, pMDIs now use hydrofluoroalkanes (HFAs), such as HFA133a, as the propellant.65,66 As of December 31, 2013, all pMDIs using CFCs were removed from the U.S. market. The cost of these pMDIs is higher than the previously marketed CFC formulations, but this might change as generics become available.

FIGURE 15-26 (A) Schematic drawing of metered-dose inhaler. (B) Commercially available metered-dose inhaler. (A) Adapted from Rau JL Jr. Respiratory Care Pharmacology. 5th ed. St. Louis, Mosby; 1998; (B) © M. Dykstra/Shutterstock.

In a pMDI, the mixture is released from the canister through a metering valve and stem that fit into an actuator boot, and the device is designed and tested by the manufacturer to work with a specific medication formulation. Even small changes in the actuator’s design can dramatically change the characteristics and output of the aerosol. The metering valve volume varies from 30 to 100 µL and contains 20 µg to 5 mg of drug. The volume emitted by the pMDI is 15 to 20 mL after volatilization of the propellant. Lung deposition ranges from 10% to 25% of the nominal dose in adults, with intersubject variability largely dependent on the technique employed. HFA steroid inhalers were engineered to generate aerosol particles with an average size of 1.2 µm; particles of this size can more effectively reach the lower respiratory tract and have less oropharyngeal deposition, thereby improving clinical outcomes.67 Each puff of Proventil HFA releases 4 µL of ethanol, which may be of concern for patients who abstain from alcohol. A breath alcohol level of up to 35 µg per 100 mL may be detected for up to 5 minutes after two puffs of Proventil HFA.68 ProAir HFA and Xopenex HFA also contain ethanol. HFA propellant may cause false-positive readings in gas-monitoring systems, because the infrared spectra of HFAs overlap with common anesthetic gases.69 Ventolin HFA contains no excipients other than the propellant but has a greater affinity for moisture than other HFA inhalers; in consequence, it is packaged in a moisture-resistant protective pouch that contains a desiccant and has a limited shelf life once it is removed from the pouch. Clogging of HFA pMDI albuterol actuators has been reported.70 Patients should clean these devices at least once a week by removing the metal canister, running warm water through the plastic actuator for 30 seconds, shaking the actuator to remove water, and then allowing it to air dry. The actuator should be cleaned more frequently if a reduction in the force of emitted spray is noted. The amount of albuterol exiting the actuator nozzle of a pMDI is 100 µg with each actuation, or 90 µg from the opening of the actuator boot;

this is how pMDI aerosol actuations are characterized in the United States. Thus, a dose of 2 to 4 actuations (200 to 400 µg nominal dose) is typically used. In ambulatory patients, 10% deposition may deliver a dose of 20 to 40 µg for an effective bronchodilation response. Effective use of the pMDI depends on proper technique. Many patients who use pMDIs and health professionals who teach pMDI use do not perform this procedure properly, which can lead to poor outcomes.71–78 Box 15-5 lists the steps for administering a bronchodilator with a pMDI. The optimal inspiratory flow is slow (20 L/min). Good patient instruction can take 10 to 30 minutes of the clinician’s time and should include demonstration, practice, and confirmation of the patient’s performance. Demonstration placebo units are available for this purpose. Repeated instruction improves performance. Infants, young children, the elderly, and patients in acute distress may not be able to use a pMDI effectively. BOX 15-5 Technique for Use of a Pressurized Metered-Dose Inhaler 1. Hold the pressurized metered-dose inhaler (pMDI) in your hand to warm it. 2. Remove the mouthpiece cover. 3. Inspect the mouthpiece for foreign objects. 4. Hold the pMDI in a vertical position. 5. Shake the pMDI. 6. If the pMDI is new or has not been used recently, prime it by shaking and pressing the canister to deliver a dose into the room. Repeat several times. 7. Breathe out normally. 8. Open your mouth and keep your tongue from obstructing the mouthpiece. 9. Hold the pMDI in a vertical position, with the mouthpiece aimed at your mouth. 10. Place the mouthpiece between your lips or position it two finger breadths from your mouth. 11. Breathe in slowly and press the pMDI canister down once at the beginning of inhalation. 12. Continue to inhale until your lungs are full. 13. Move the mouthpiece away from your mouth, and hold your breath for 10 seconds (or as long as you comfortably can). 14. Wait at least 30 seconds between doses. 15. Repeat for the prescribed number of doses. 16. Recap the mouthpiece.

17. Rinse your mouth if using inhaled steroids. 18. Keep count of the number of uses so that you know when the canister is empty. 19. Clean the pMDI once a week and as needed.

Age-Specific Angle Infants, young children, the elderly, and patients in acute distress may not be able to use a pMDI effectively.

Stop and Think You are caring for a patient in the emergency department who has severe acute asthma. Albuterol administration by pMDI has been prescribed, but the patient is demonstrating difficulty using the device effectively. What would you do to improve this patient’s care?

The pMDI can be used as often as every 30 seconds without affecting its performance. A new pMDI or one that has not been used recently should be actuated several times before use to prime the metering chamber properly. Priming requirements vary among devices—for example, four priming actuations are needed for albuterol and fluticasone and two priming actuations for ipratropium and budesonide. The pMDI should always be stored with the cap on, both to prevent foreign objects from entering the boot and to reduce humidity and microbial contamination. pMDIs should always be discarded when empty to avoid administration of propellant without medication. Although many pMDIs contain more than the labeled number of doses, drug delivery per actuation may be very inconsistent and unpredictable subsequent to the labeled number of actuations. Beyond the labeled number of actuations, propellant can release an aerosol plume that contains little or no drug, a phenomenon called tail-off. A practical problem for patients who use pMDIs is the difficulty of determining the number of doses remaining in the device. Ideally, the patient will know the number of doses in a full pMDI and keep track of how many actuations have been used. Many patients are unaware of the number of doses in a full pMDI, however, and most do not know how to determine when their pMDI is empty. Floating the canister in water has

been suggested as a way to determine when it is depleted, but this method is unreliable and should not be used.79 The FDA now recommends that manufacturers integrate a dose-counting device into new pMDIs, and most pMDIs have integrated dose counters. Add-on devices can also be used that count down the number of puffs released from a pMDI (Figure 15-27).

FIGURE 15-27 (A) Dose counter on a hydrofluoroalkane (HFA) pressurized metered-dose inhaler (Ventolin HFA). (B) Doser. (A) © GlaxoSmithKline. Used with permission; (B) Courtesy of Doser-MediTrack Products.

The QVAR RediHaler is a breath-actuated pMDI. The dose is ready for inhalation when the cap is opened. When the patient breathes in through the mouthpiece, a dose of beclomethasone is delivered. The cap must be closed to prepare the next dose. This device should not be shaken, and there is no need for priming. Stop and Think You are asked to help a patient who is having difficulty using her pMDI. What would you do to help her improve her inhaling technique?

Spacers and Valved Holding Chambers Spacers and valved holding chambers (Figure 15-28) are accessory devices that reduce oropharyngeal deposition of drugs, ameliorate the bad taste of some medications, eliminate the cold Freon effect, and, in the case of valved holding chambers, reduce the need for hand–breath coordination. These devices reduce the pharyngeal dose of aerosol from the pMDI 10-fold to 15-fold. This reduces the total body dose from swallowed medications, which is an important consideration with steroid administration. For very young patients, very old patients, and others unable to use the device with a mouthpiece, a face mask can be used (Figure 15-29).

FIGURE 15-28 Spacers and valved holding chambers. (A) Courtesy of Philips Respironics; (B) © Rob Byron/Shutterstock; (D) © Robert Byron/Dreamstime.com.

FIGURE 15-29 Valved holding chamber with face mask. © Jones & Bartlett Learning. Courtesy of MIEMSS.

A spacer is a simple open-ended tube or bag that, with sufficiently large device volume, provides space for the pMDI plume to expand by allowing the propellant to evaporate. To perform this function, a spacer must have an internal volume of more than 100 mL and provide a distance of 10 to 13 cm between the pMDI nozzle and the first wall or baffle. Smaller, inefficient spacers can reduce the respiratory dose by 60% and offer no protection against poor coordination of actuation and breathing pattern. Spacers with internal volumes greater than 100 mL generally provide some protection against early firing of the pMDI, although exhalation immediately after the actuation clears most of the aerosol from the device, wasting the dose. A valved holding chamber (VHC; usually 140 to 750 mL in volume) allows the plume from the pMDI to expand and incorporates a one-way

valve that permits the aerosol to be drawn from the chamber during inhalation only, diverting the exhaled gas to the atmosphere and not disturbing the remaining aerosol suspended in the chamber. Patients with small tidal volumes may empty the aerosol from the chamber with five to six breaths, except in the case of a device with an exceptionally large dead space. A VHC can also incorporate a mask for use with an infant, a child, or a patient who is unable to use a mouthpiece because of size, age, coordination, or mental status. With infants, these masks must have minimal dead space and must be comfortable on the child’s face, and the chamber must have a valve that opens or closes with the low inspiratory flow generated by the patient. Box 15-6 describes the optimal technique for use of a VHC. The high oropharyngeal drug deposition that occurs with steroid pMDIs can increase the risk of oral yeast infections (thrush). Rinsing the mouth after steroid use can reduce this problem, but most pMDI steroid aerosol impaction occurs deeper in the pharynx, which is not easily rinsed away. For this reason, steroid pMDIs should always be used in combination with a VHC. BOX 15-6 Technique for Use of a Pressurized Metered-Dose Inhaler with a Spacer or Valved Holding Chamber 1. Hold the pressurized metered-dose inhaler (pMDI) in your hand to warm it. 2. Assemble the apparatus and check for foreign objects. 3. Remove the mouthpiece cover. 4. Shake the pMDI. 5. If the pMDI is new or has not been used recently, prime the device by shaking it and pressing the canister to deliver a dose into the room. 6. Repeat several times. 7. Hold the canister in a vertical position. 8. Breathe out normally. 9. Open your mouth and keep your tongue from obstructing the mouthpiece. 10. Place the mouthpiece into your mouth (or place the mask completely over your nose and mouth). 11. Breathe in slowly through your mouth, and press the pMDI canister once at the beginning of inspiration. 12. If the device produces a whistle, your inspiration is too rapid. 13. Allow 15 seconds between puffs. 14. Move the mouthpiece away from your mouth, and hold your breath for 10 seconds (or

as long as you comfortably can). The technique is slightly different for a device with a collapsible bag: 1. Open the bag to its full size. 2. Remove the canister from the pMDI mouthpiece and insert it into the mouthpiece attached to the collapsible bag. 3. Press the pMDI canister immediately before inhalation, and inhale until the bag is completely collapsed (if you have difficulty emptying the bag, you can breathe in and out of the bag several times to evacuate the medication). The following recommendations apply for both techniques: 1. Rinse your mouth if using inhaled steroids. 2. Clean the holding chamber every 2 weeks and as needed. 3. Keep count of the number of uses so that you know when the canister is empty.

Electrostatic charge acquired by the aerosol when it is generated, or present on the surface of the inhaler or add-on device, decreases aerosol delivery from VHCs.80–82 Electrostatic charge may be particularly important with a delay in aerosol inhalation after actuation. VHCs made from readily conducting materials, such as stainless steel or aluminum, avoid this problem. Priming by firing 20 doses into a new spacer coats the inner surface with surfactant and minimizes static charge, although this step is not practical because it wastes more than 10% of the dose in a new pMDI canister. Washing a nonconducting VHC with detergent is a commonly used method to reduce surface electrostatic charge, and detergent washing is now incorporated in most manufacturer instructions. Detergent washing greatly improves drug delivery and is easy for the patient to perform. After washing, the VHC should not be towel dried, which could impart electrostatic charge; instead, the device should be allowed to drip dry in ambient air. The FDA requires manufacturers of add-on devices to recommend that patients rinse them in clean water after washing in detergent, so as to avoid patient contact with detergentcoated surfaces, which could result in contact dermatitis. VHCs manufactured from transparent, charge-dissipative polymers, as an alternative to opaque conducting materials such as stainless steel or aluminum, are commonly used. Accessory devices either use the manufacturer-designed boot that comes with the pMDI or incorporate a universal canister adapter to fire the pMDI canister. Different formulations of pMDI drugs operate at different pressures and have different-sized orifices in the boot designed

by the manufacturer for use exclusively with that pMDI. The output characteristics of a pMDI change with the use of an adapter with a different-sized orifice. For this reason, spacers or holding chambers with universal canister adapters should be avoided, and patients should use only those with a universal boot adapter. Particularly in young children, use of a VHC requires a face mask. When using a face mask, the patient (or parent) should ensure an adequate seal, and the patient should take five to six breaths through the chamber to deliver the full dose. Drug delivery decreases when dead space increases, whereas it increases with smaller VHC volume and lower tidal volume. Rigid masks with a large dead space volume might not be not suitable for use in children, especially if discomfort from the stiff mask makes its use less acceptable to the child.83 Age-Specific Angle When using holding chambers with children, consideration should be given to mask fit and dead space volume.

Dry Powder Inhalers Dry powder inhalers (DPIs) create aerosols by drawing air through a dose of powdered medication.84,85 The powder contains micronized drug particles (less than 5 µm MMAD), with larger lactose or glucose particles (more than 30 µm in diameter) or micronized drug particles being bound into loose aggregates. Micronized particles adhere strongly to each other and to most surfaces. Adding the larger particles of the carrier diminishes cohesive forces in the micronized drug powder so that separation into individual respirable particles (deaggregation) occurs more readily. In this way, the carrier particles aid the flow of the drug powder from the device. Carriers also act as fillers by adding bulk to the powder when the unit dose of a drug is very small. The drug particles, which are usually loosely bound to the carrier, are stripped from the carrier by the energy provided by the patient’s inhalation (Figure 15-30). The release of respirable particles of the drug requires inspiration at relatively high flow. Although the optimal inspiratory flow varies among devices (Table 15-2), it is typically greater than the requirement for pMDI. The high inspiratory flow

results in pharyngeal impaction of the larger carrier particles that make up the bulk of the aerosol. The oropharyngeal impaction of carrier particles gives the patient the sensation of having inhaled a dose.

FIGURE 15-30 (A) Aerosolization of dry powder. (B) Component parts of Flexhaler. (C) Component parts of Diskus. (A) Modified from Dhand R, Fink JB. Dry powder inhalers. Respir Care 1999;44(8):940–951. Reprinted with permission; (B) Republished with permission of Blackwell Science. From Crompton GK. Delivery systems. In: Kay AB, ed. Allergy and Allergic Diseases. London: Blackwell Science;1997:1440–1450. Permission conveyed through Copyright Clearance Center, Inc.

Description TABLE 15-2 Recommended Inspiratory Flows for Common Dry Powder

Inhalers Device

Optimal Inspiratory Flow (L/min)

Breezhaler

50

Diskus

60

Ellipta

60

Flexhaler

60

HandiHaler

40

Neohaler

90

RespiClick

60

Commercially available DPIs are either multidose (i.e., the device contains a month’s prescription; Figure 15-31) or single-dose units (i.e., the patient loads a single-dose capsule prior to each use; Figure 15-32). With single-dose devices, the patient must understand that the capsules should not be ingested; they should be administered only via inhalation, with the appropriate delivery device. Moreover, the capsules should be used only in the intended device and should not be administered in another device. The powder should never be dumped from the capsule into a nebulizer for administration. Currently available DPIs are all passive systems, meaning that the patient must provide the energy to disperse the powder from the device. A primary advantage of DPIs is coordination of actuation with inspiration, because these devices are breath actuated. A primary disadvantage of unit-dose DPIs is the time needed to load a dose for each use. Another disadvantage of DPIs is that each model operates differently from the others in loading and priming. Pharyngeal deposition also presents a problem due to the high inspiratory flow required to operate DPIs.

FIGURE 15-31 Multiple-dose dry powder inhalers. (A) Diskus. (B) Flexhaler. (C) Diskhaler. (D) Ellipta. (E) RespiClick. (B) © 2019 AstraZeneca; (C) © Marjanneke de Jong/Shutterstock; (D) © GlaxoSmithKline. Used; (E) ©2017 Teva Respiratory, LLC.

FIGURE 15-32 Single-dose dry powder inhalers. (A) Handihaler. (B) Podhaler. (C) Neohaler. (D) Breezhaler. (A) © mayer kleinostheim/Shutterstock; (B) Courtesy of Novartis Pharmaceuticals Corporation; (C) Courtesy of Novartis Pharmaceuticals Corporation; (D) © Sunovion Pharmaceuticals Inc. All rights reserved.

The internal geometry of the DPI device influences the resistance offered to inspiration and the inspiratory flow required to deaggregate the medication. Devices with higher resistance require a higher inspiratory flow to produce a dose. Inhalation through high-resistance DPIs may improve drug delivery to the lower respiratory tract compared with pMDIs, provided the patient can reliably generate the required flow. Highresistance devices have not been shown to improve either deposition or bronchodilation compared with low-resistance DPIs. DPIs with several components require correct assembly of the apparatus and priming of the device to ensure aerosolization of the dry powder. DPIs produce aerosols in which most of the drug particles are in the respirable range, although the distribution of particle sizes differs significantly among various DPIs. High ambient humidity may cause the dry powder to clump, creating larger particles that are not as effectively aerosolized. Air with high moisture content is less efficient at deaggregating particles of dry powder than is dry air, such that high ambient humidity increases the size of drug particles in the aerosol and may reduce drug delivery to the lungs. High ambient humidity also can result from exhalation into a DPI; from bringing a DPI into a warm indoor environment from the cold outdoors or a cold car, causing condensation to form inside the device; or from using a DPI in a warm, humid environment. Newer DPIs contain individual doses that are better protected from humidity. Nevertheless, humidity can accumulate if the DPI is stored with the cap off. Because the energy from the patient’s inspiratory flow disperses the drug powder, the magnitude and duration of the patient’s inspiratory effort influence aerosol generation from a DPI. Failure to perform inhalation at a sufficiently fast inspiratory flow reduces the dose of the drug emitted by the DPI and increases the distribution of particle sizes within the aerosol. Because of the high oropharyngeal deposition that occurs due to the high inspiratory flow required, patients should be instructed to rinse the mouth and pharynx after use. Breath coordination is also important during use of a DPI. Exhalation into a DPI blows out the powder from the device and reduces drug delivery. Moreover, the humidity in the exhaled air reduces subsequent aerosol generation. For these reasons, patients must be instructed not to exhale into a DPI. Because DPIs are breath-actuated devices, they reduce the problem

of coordinating inspiration with actuation. Indeed, using a DPI (Box 15-7) differs in important respects from the technique used to inhale drugs from a pMDI. DPIs are critically dependent on inspiratory flow to generate the aerosol; therefore, they should be used with caution, if at all, in very young or ill children, weak individuals, elderly persons, and those with altered mental status. Patients may need repeated instruction before they can master the use of a DPI, and periodic assessment is necessary to ensure that patients continue to use the optimal technique. BOX 15-7 Technique for Use of Dry Powder Inhalers 1. Lift or take the cap or cover off. 2. Follow the dose preparation instructions in the package insert. a. Ellipta: Slide the cover until it clicks. b. Diskus: Slide the cover, and put the tab forward. c. Handihaler, Neohaler, Breezhaler, and Podhaler: Remove the cover and mouthpiece, insert the capsule, replace the mouthpiece, and press the button(s) to puncture the capsule. d. Flexhaler: Remove the cover. Holding the DPI upright, turn the base until it stops, and then turn it back to its original position. e. Twisthaler: Holding the DPI upright, twist cap counter clockwise. f. RespiClick: Open the cap all the way until a click is heard. Close and reopen the cap if more than one inhalation of drug is needed. 3. Do not point the mouthpiece downward once a dose has been prepared for inhalation because the dose may fall out. 4. Exhale slowly away from the mouthpiece to empty the lungs. Do not blow into the mouthpiece. 5. Place the lips firmly around the mouthpiece, with the tongue under the mouthpiece. 6. Inhale forcefully through the mouth. Do not gradually build up the speed of inhalation. a. The capsule should be heard spinning for the Handihaler, Neohaler, and Breezhaler. b. For RespiClick, do not block the vent above the mouthpiece. 7. Continue inhaling until the lungs are full. 8. At the end of the inhalation, take the inhaler out of the mouth and close the lips. 9. Hold the breath for 5–10 seconds, and exhale normally. a. Take a few normal breaths, and then breathe in through the device a second time for the Handihaler, Neohaler, Breezhaler, and Podhaler. 10. Rinse or otherwise clean mouth and pharynx after each dose. 11. Except for the mouthpiece, do not clean DPIs.

Respiratory Recap Aerosol Medication Delivery Devices ∎ Jet nebulizer ∎ Mesh nebulizer ∎ Soft mist inhaler ∎ Ultrasonic nebulizer (USN) ∎ Pressurized metered-dose inhaler (pMDI) ∎ Metered-dose inhaler with spacer or holding chamber ∎ Dry powder inhaler (DPI)

Aerosol Delivery During Invasive Mechanical Ventilation Aerosolized drugs are administered to mechanically ventilated patients using a nebulizer or pMDI.86–88 DPIs cannot be used in intubated mechanically ventilated patients. A number of factors affect aerosol delivery during mechanical ventilation (Figure 15-33). Box 15-8 and Box 15-9 present the techniques used to deliver aerosolized bronchodilators during mechanical ventilation by jet nebulizer and pMDI, respectively.

FIGURE 15-33 Summary of factors affecting delivery of aerosols during mechanical ventilation. Adapted from Dhand R, Jubran A, Tobin MJ. Bronchodilator delivery by metered-dose inhaler in ventilator supported patients. Eur Respir J 1996;9(6):585–595.

Description

BOX 15-8 Technique for Aerosol Delivery by Jet Nebulizer During Mechanical Ventilation 1. Fill the nebulizer with the drug solution to the optimum fill volume.

2. Place the nebulizer in the inspiratory line at least 30 cm from the patient’s Y piece. 3. Ensure that the flow through the nebulizer is 6 to 8 L/min. Continuous gas flow from an external source or the nebulizer control of the ventilator can be used to power the nebulizer. 4. The nebulizer may be operated either continuously or only during inhalation. Some ventilators provide inspiratory gas flow to the nebulizer. 5. Adjust the tidal volume as necessary. 6. Turn off the bias flow on the ventilator if possible, and remove (or bypass) the heat and moisture exchanger if present. 7. Check the nebulizer for adequate aerosol generation throughout its use. 8. Disconnect the nebulizer when all the medication has been nebulized or when no more aerosol is being produced. Store the nebulizer under aseptic conditions. 9. Reconnect the ventilator circuit and reinstate the original ventilator settings.

BOX 15-9 Technique for Use of a Pressurized Metered-Dose Inhaler During Mechanical Ventilation 1. Place a spacer on the inspiratory limb of the ventilator circuit. Ideally, the spacer will remain in the ventilator circuit so that the circuit need not be disconnected for each bronchodilator treatment. 2. Shake the pressurized metered-dose inhaler (pMDI) canister vigorously. 3. Actuate the pMDI to synchronize with the precise onset of inspiration by the ventilator. Actuate the pMDI once only. 4. Repeat actuations at 30-second intervals until the total dose has been delivered.

Ventilator circuits both warm and humidify the inspired gas. Humidity, however, can increase the particle size of the aerosol and reduce its deposition during mechanical ventilation. Humidification of inhaled gas reduces aerosol deposition by approximately 40%, probably because of an increase in particle loss in the ventilator circuit. For this reason, some clinicians recommend bypassing the humidifier during aerosol administration. Nebulizers require as long as 30 minutes to complete aerosolization, however, and inhalation of dry gas for this length of time can damage the airway. In addition, disconnection of the ventilator circuit, which is required to bypass the humidifier, interrupts ventilation and may increase the risk of ventilator-associated pneumonia.15 Placement of a jet nebulizer 30 cm from the endotracheal tube is more efficient than placement of this device between the inspiratory limb and the patient Y piece, because the inspiratory ventilator tubing acts as

a spacer that allows the aerosol to accumulate during the expiratory phase. Operating the nebulizer only during inspiration (breath actuated) is more efficient for aerosol delivery than is continuous aerosol generation. The gas flow driving the nebulizer produces additional flow in the ventilator circuit, requiring adjustment of tidal volume and inspiratory flow when the nebulizer is in use. When patients are unable to trigger the ventilator (because of the additional nebulizer gas flow), hypoventilation can result. Longer inspiratory times allow a higher proportion of the aerosol generated by the nebulizer to be inhaled with each breath. Because nebulizers generate aerosol over the course of several minutes, longer inspiratory times have a cumulative effect in improving aerosol delivery. Nebulizers placed in-line in the ventilator circuit can become contaminated with bacteria, with the bacteria then being carried as microaerosols directly to the lower respiratory tract; this pathway represents a potential source of ventilator-associated pneumonia. The pMDI cannot be used in the ventilator circuit with the actuator designed by the manufacturer, so a third-party actuator is required (Figure 15-34). The size, shape, and design of these actuators affect the amount of respirable drug available to the patient and may vary with different pMDI formulations. A pMDI with a spacer in the inspiratory limb of the ventilator circuit produces a fourfold to sixfold greater delivery of aerosol compared to a pMDI connector that lacks a chamber. When pMDIs are used with a collapsible cylindric spacer, the ventilator circuit need not be disconnected with each treatment. Leaving a pMDI noncollapsible chamber device in-line is not practical because it adds compressible volume to the circuit. The selection of pMDI adapter design makes a major difference in the actual delivered dose,89 and incorporating the pMDI adapter into the design of a closed suction system is discouraged.

FIGURE 15-34 Devices to adapt a metered-dose inhaler to a ventilator circuit. (A) Inline device. (B) Elbow device. (C) Collapsible chamber device. (D) Chamber device. (E) Chamber device in which aerosol is directed retrograde into the ventilator circuit. Reproduced from Dhand R, Jubran A, Tobin MJ. Bronchodilator delivery by metered-dose inhaler in ventilator supported patients. Eur Respir J 1996;9(6):585–595. Reproduced with permission of the European Respiratory Society.

Actuation of the pMDI out of phase with inspiratory flow delivers very little aerosol to the patient. Unlike with nebulizers, dose delivery from a pMDI remains relatively constant regardless of ventilator settings.90 With use of pMDI during mechanical ventilation, delivery of a large tidal volume, use of an end-inspiratory pause, and use of a slow inspiratory flow have little effect on aerosol delivery and deposition.91–93 Although some HMEs are compatible with aerosol delivery,94 most must be removed or a specially designed HME used that allows for bypassing the HME during aerosol therapy (Figure 15-35).95 No studies have demonstrated contamination problems with administration of an aerosol from a pMDI during mechanical ventilation.

FIGURE 15-35 Devices that allow a heat and moisture exchanger to be bypassed during aerosol delivery. (A) Courtesy of Teleflex Incorporated. Unauthorized use prohibited; (B) Courtesy of Smiths Medical; (C) AirLife Bypass HME Technology. © 2019 Vyaire Medical, Inc. Used with Permissions.

Depending on the FIO2 and the propellant gas volume, an inline pMDI actuation theoretically may result in a hypoxic gas mixture to an infant receiving a tidal volume less than 100 mL. The large dead space volume of a spacer or chamber at the end of the endotracheal tube must also be considered during administration of pMDI medications to an infant. Stable mechanically ventilated patients with COPD achieve nearmaximum bronchodilation after administration of four puffs of albuterol with a pMDI or 2.5 mg albuterol with a nebulizer. When proper technique is ensured, nebulizers and pMDIs will produce similar therapeutic effects in mechanically ventilated patients. Aerosol delivery by pMDI is easy to administer, involves less personnel time, provides a reliable dose of the drug, is free of the risk of bacterial contamination, and adds no extra flow to the circuit. The mesh nebulizer overcomes some of the issues associated with the jet nebulizer because it adds no gas flow into the circuit and the device can remain in the circuit between treatments. This device is placed between the ventilator and the humidifier (Figure 15-36). Aerosol delivery is more efficient with the mesh nebulizer compared to the jet nebulizer. Because of the cost of HFA pMDI formulations, the vibrating mesh nebulizer is being used increasingly during mechanical ventilation.

FIGURE 15-36 Mesh nebulizer at inlet of humidifier in ventilator circuit.

Respiratory Recap Aerosol Delivery During Mechanical Ventilation ∎ Either a pMDI or a nebulizer can be used. ∎ Careful attention to technique is important.

Stop and Think

You are asked if inhalers are better than nebulizers in mechanically ventilated patients. What would be your response?

Aerosol Delivery During Noninvasive Ventilation Aerosol therapy during noninvasive ventilation (NIV) can be delivered effectively by pressurized metered-dose inhaler with a spacer or nebulizer.96–98 Alternatively, the patient can be removed from NIV and the inhaled medication administered in the usual manner, although this approach has the disadvantage of interrupting NIV. A number of factors affect aerosol delivery during NIV, including the type of ventilator, mode of ventilation, circuit conditions, type of interface, type of aerosol generator, drug-related factors, breathing parameters, and patient-related factors (Figure 15-37). When a critical care ventilator is used for NIV, factors affecting aerosol delivery are much the same as the factors affecting aerosol delivery with invasive ventilation. Despite the impediments to efficient aerosol delivery with a bilevel ventilator due to the continuous gas flow and potential for leaks, therapeutic effects are achieved after inhaled bronchodilator administration to patients with asthma and COPD. Careful attention to the technique of drug administration is required to optimize therapeutic effects of inhaled drugs during NIV. The nebulizer should be placed near the mask rather than at the outlet of the ventilator during NIV (Figure 15-38).98 A metered-dose inhaler should be used with a spacer. A mesh nebulizer can be incorporated directly into the mask for NIV (Figure 15-39).99,100 Care must be taken to ensure an adequate mask fit so that aerosol is not directed into the eyes of the patient.

FIGURE 15-37 Factors influencing aerosol delivery during noninvasive ventilation. Data from Dhand R. Aerosol therapy in patients receiving noninvasive positive pressure ventilation. J Aerosol Med Pulm Drug Deliv 2012;25:63–78. The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers.

FIGURE 15-38 Insertion site for nebulizer and inhaler for use with a bilevel ventilator during noninvasive ventilation.

FIGURE 15-39 Noninvasive ventilation mask incorporating mesh nebulizer. Reproduced with the permission of Koninklijke Philips N.V. All rights reserved.

Aerosol Delivery by Tracheostomy Inhaled albuterol is occasionally used in spontaneously breathing patients with a tracheostomy tube.101–104 A measurable amount of albuterol aerosol can be delivered through the tracheostomy tube during spontaneous breathing, whether a nebulizer or a pMDI with spacer is used. Delivery of albuterol aerosol into a high gas flow is inefficient for the nebulizer, however, and use of a T piece for albuterol delivery is more effective than use of a tracheostomy mask. A pMDI with valved holding chamber offers better efficiency than does a nebulizer, although the pMDI is most efficient when a valved T piece is used and the valve is placed proximal rather than distal to the spacer. Figure 15-40 shows the proper equipment for aerosol delivery by nebulizer and pMDI for spontaneously breathing patients with a tracheostomy. Aerosol delivery through a tracheostomy tube may be improved with assisted ventilation compared to spontaneous breathing. The use of a manual resuscitation bag for aerosol delivery in spontaneously breathing patients with tracheostomy is not a standard practice, however.

FIGURE 15-40 Equipment for aerosol delivery to tracheostomy. (A) Nebulizer. (B) Spacer for pMDI delivery by tracheostomy.

Aerosol Delivery by High-Flow Nasal Cannula Use of aerosol delivery with a high-flow nasal cannula (HFNC) is attracting increasing interest.98 This can be accomplished with either a jet nebulizer or a mesh nebulizer (Figure 15-41). The mesh nebulizer is positioned before the humidifier, whereas the jet nebulizer can be positioned closer to the nasal cannula. The delivered dose of aerosol when used with HFNC is low but appears to be sufficient to create a physiologic response.105-111

FIGURE 15-41 Aerosol delivery with high-flow nasal cannula. (A) Mesh nebulizer. (B) Jet nebulizer. (B) From Bräunlich J, Wirtz H. Oral versus nasal high-flow bronchodilator inhalation in chronic obstructive pulmonary disease. J Aerosol Med Pulm Drug Deliv 2018;31(4):248–254.

Selection of an Aerosol Delivery Device Each type of aerosol delivery device has both advantages and disadvantages (Table 15-3).24,78,112–114 Evidence-based recommendations for selection of an aerosol delivery device have been published (CPG 152),114 but the choice of device often is determined by patient preference or clinician bias. In some cases, the choice of device is dictated by the drug to be delivered (e.g., antibiotics are available only for nebulizer delivery). In other cases, the FDA has cleared drugs for use with a specific nebulizer (Table 15-4). Whenever possible, patients should use only one type of aerosol delivery device. Each device requires use of a different technique, and repeated instruction is necessary to ensure that the patient uses the device appropriately. Using different devices can be confusing for patients and may reduce their compliance with therapy. When patients must use different devices, it is important to teach the proper inspiratory flow with each. A commercially available device can be used to facilitate this teaching (Figure 15-42).

FIGURE 15-42 In-Check DIAL inhaler technique training and assessment device. This device enables clinicians to train patients in the proper inspiratory technique considering force and flow

rate to achieve optimal deposition of the medication being inhaled into the lungs. Courtesy of Haag-Streit.

TABLE 15-3 Advantages and Disadvantages of Various Aerosol Delivery Devices Device

Advantages

Disadvantages

Jet nebulizer

Patient coordination is not required Effective with tidal breathing High doses can be given Dose modification is possible Can be used with supplemental O2 Can deliver combination therapies if drugs are compatible Some are breath actuated

Expense Device is not portable Pressurized gas source is required Lengthy treatment time Contamination is possible Device preparation required Not all medications are available in solution form Performance variability

Mesh nebulizer

Patient coordination is not required Effective with tidal breathing High doses can be given Dose modification is possible Small dead volume Quiet Faster delivery than with a jet nebulizer Less drug is lost during exhalation Battery operated Portable and compact Can be used with holding chamber

Expense Contamination is possible Device preparation is required Not all medications are available in solution form

Respimat Soft Mist Inhaler

Low velocity of emitted aerosol No propellant Dose counter

Expense Some patients find it difficult to use this device Limited medications available

Ultrasonic nebulizer

Patient coordination is not required High doses are possible Small dead volume Quiet Faster delivery than with a jet nebulizer Less drug is lost during exhalation

Expense Need for electrical power Potential for contamination Prone to malfunction Possible drug degradation Does not nebulize suspensions well Device preparation is required Potential for airway irritation exists Not all medications are available in

solution form Pressurized metered-dose inhaler (pMDI)

Portable and compact No drug preparation is required Dose reproducibility is high Device is difficult to contaminate Treatment time is short Most have a dose counter Some are breath-actuated

Patient coordination is essential Patient actuation is required Large pharyngeal deposition occurs High doses are difficult to deliver Not all medications are available in pMDI form

Metered-dose inhaler with holding chamber

Less patient coordination is required Less pharyngeal deposition occurs

More complex for some patients More expensive than a pMDI alone Less portable than a pMDI

Dry powder inhaler (DPI)

Less patient coordination is required Propellant is not required Breath activated Small and portable Short treatment time

Requires moderate to high inspiratory flow Some units are single dose High pharyngeal deposition is possible Not all medications are available in DPI form High doses are difficult to deliver

CFC, chlorofluorocarbon. Adapted from AARC consensus statement: aerosols and delivery devices. Respir Care 2000;45:589–595; and Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, et al. Device selection and outcomes of aerosol therapy: evidence-based guidelines. Chest 2005;127(1):335–371.

TABLE 15-4 Approved Devices for Specific Drug Formulations Formulation

FDA-Approved Device

Tobramycin (TOBI)

Pari LC

Dornase alfa (Pulmozyme)

Hudson T Up-draft II, Marquest Acorn II, Pari LC, Durable Sidestream, Pari Baby

Pentamidine (NebuPent)

Marquest Respirgard II

Ribavirin (Virazole)

Small Particle Aerosol Generator (SPAG)

Iloprost (Ventavis)

I-Neb Adaptive Aerosol Delivery (AAD)

Aztreonam (Cayston)

Altera

Treprostinil (Tyvaso)

Optineb

Glycopyrrolate (Lonhala)

Magnair

Liposomal amikacin (Arikayce)

Lamira

CLINICAL PRACTICE GUIDELINE 15-2 Recommendations Related to Selection of Aerosol Delivery Device 1. Select the appropriate aerosol generator and interface based on the patient’s age, physical and cognitive ability, cost, and availability of the prescribed drug for use with a specific device. 2. Nebulizers and pressurized metered-dose inhalers (pMDIs) with valved holding chambers are suggested for use with children younger than 4 years of age and adults who cannot coordinate the use of a pMDI or dry powder inhaler (DPI). 3. Restrict administration of aerosols with DPIs to patients older than 4 years of age who can demonstrate sufficient flow for the specific inhaler. 4. For patients who cannot correctly use a mouthpiece, aerosol masks are suggested as the interface of choice. 5. It is suggested that blow-by not be used for aerosol administration. 6. It is suggested that aerosol therapy be administered with a relaxed and nondistressed breathing pattern. 7. Unit dose medications are suggested to reduce the risk of infection. 8. It is suggested that nebulizer/drug combinations should be used as approved by the FDA. 9. Healthcare providers should understand how to use aerosol generators correctly; they should teach and periodically reteach patients about how to use aerosol devices correctly. 10. It is suggested that intermittent positive pressure breathing should not be used for aerosol therapy. 11. It is recommended that either a nebulizer or a pMDI can be used for aerosol delivery during noninvasive ventilation. Modified from Ari A, Restrepo RD. Aerosol delivery device selection for spontaneously breathing patients: 2012. Respir Care 2012;57(4):613–626.

Each of the aerosol delivery devices can work equally well provided that patients can use them correctly. When selecting an aerosol delivery device, the following questions should be considered:114

In which devices is the desired drug available? Which device is the patient likely to be able to use properly, given the patient’s age and the clinical setting? For which device and drug combination is reimbursement available? Which devices are the least costly? Can all types of inhaled asthma/COPD drugs that are prescribed for the patient be delivered with the same type of device? Using the same type of device for all inhaled drugs may facilitate patient teaching and decrease the chance that the patient may become confused about the different inhalation techniques required for different devices. Which devices are the most convenient for the patient, family (outpatient use), or medical staff (acute care setting) to use, given the time required for drug administration and device cleaning and the portability of the device? How durable is the device? Does the patient or clinician have any specific device preferences? Proper patient education is critical. Respiratory therapists, physicians, and nurses caring for patients with respiratory diseases should be familiar with issues related to performance and with the correct use of aerosol delivery devices. If the selected delivery device should fail to provide satisfactory treatment, another option should be considered. To improve adherence, aerosol therapy should be administered with some easily remembered activity of daily living. For twice-daily administration, medications can be kept with the toothbrush and inhaled just before tooth brushing. With young patients, it is always best to avoid regular use of medication at school, because the inconvenience can significantly reduce compliance and may be an embarrassment to some children. Rescue medication must be available at school, at the daycare center, or in the caretaker’s home. It helps to prepare written guidelines for use of the medication, and the guidelines must be distributed to all places where the child stays, such as home, school, or the residences of both parents in cases of divorce or separation. Lack of response to inhaled asthma medication can be related to a number of factors, including incorrect inhalation technique, inhalation

from an empty canister, failure to take preventive medications as prescribed, a change in the patient’s environment, or perhaps misdiagnosis. For example, children who have aspirated a foreign body or who have gastroesophageal reflux disease or psychogenic wheeze may demonstrate a poor response to asthma therapy. Infants with tracheomalacia or bronchopulmonary dysplasia may even worsen after inhaling a bronchodilator aerosol because of increased dynamic airway collapse.

Aerosol Delivery for Systemic Disease Aerosols are usually inhaled for treatment of pulmonary disease; however, some interest has arisen regarding use of the lungs to deliver inhaled drugs to the systemic circulation. One example is inhaled insulin. Afrezza is rapid-acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes mellitus; it is taken at the beginning of a meal. It is not recommended for patients who smoke or those with lung disease. The Afrezza inhaler (Figure 15-43) is available in two strengths: 4 units (blue cartridge) and 8 units (green cartridge). The manufacturer provides a conversion table to allow the clinician and the patient to determine the number of Afrezza cartridges equivalent to injected mealtime insulin. As many as three cartridges might be required. Box 15-10 describes the steps for Afrezza use.

FIGURE 15-43 The Afrezza inhaler. Courtesy of MannKind Corporation.

BOX 15-10 Technique for Use of Afrezza Inhaler 1. Select the correct number of Afrezza cartridges for the dose. Remove a cartridge from the strip by pressing on the clear side to push the cartridge out. Remove the correct number of cartridges for the dose. Pushing on the cup will not damage the cartridge. Afrezza cartridges in an opened strip must be used within 3 days. 2. Hold the inhaler level in one hand with the white mouthpiece on the top and the purple base on the bottom. Open the inhaler by lifting the white mouthpiece to a vertical position. Before placing the cartridge into the inhaler, make sure it has been at room temperature for 10 minutes (cartridges are stored in a refrigerator). Hold the cartridge with the cup facing down. The pointed end of the cartridge should line up with the pointed end in the inhaler. Place the cartridge into the inhaler, ensuring that the cartridge lies flat in the inhaler. Lower the mouthpiece to close the inhaler, which will open the drug cartridge. Once the cartridge is loaded, it should be held level to avoid loss of the powder. Close the inhaler; a snap signals that it is secured.

3. Remove the mouthpiece cover. Hold the inhaler away from the mouth and exhale. Place the mouthpiece into the mouth, and tilt the inhaler down toward the chin. Close the lips around the mouthpiece to form a seal. Tilt the inhaler downward while keeping the head level. Inhale deeply through the inhaler. Breath hold as long as comfortable, and remove the inhaler from the mouth. After the breath hold, resume normal breathing. 4. Place the purple mouthpiece cover back onto the inhaler. Open the inhaler by lifting up the white mouthpiece, and remove the cartridge from the purple base. Discard the used cartridge. Repeat steps 2 through 4 for each Afrezza cartridge needed for the prescribed dose. Use one inhaler at a time. Discard the inhaler after 15 days.

Inbrija, a levodopa inhalation powder (Figure 15-44), is a prescription medicine used on an as-needed basis in adults with Parkinson disease treated with regular carbidopa/levodopa medicine; it does not replace regular carbidopa/levodopa medicine. As Parkinson disease progresses, patients experience off periods, which are characterized by the return of symptoms. Many people with Parkinson disease fluctuate between on periods, during which symptoms are controlled, and off periods, in which symptoms return due to low levels of dopamine between doses of treatment. Of the approximately 1 million persons with Parkinson disease, nearly 40% experience off periods. Because of the risk of bronchospasm, use of Inbrija in patients with asthma, COPD, or another chronic underlying lung disease is not recommended. Box 15-11 describes the steps for using the Inbrija inhaler.

FIGURE 15-44 The Inbrija inhaler. © 2019 Acorda Therapeutics, Inc.

BOX 15-11 Technique for Use of Inbrija Inhaler 1. Gather the necessary supplies—the inhaler and a package of two capsules. Check the expiration date. 2. Pull the cap straight off, and place it to the side. 3. Twist and pull off the mouthpiece to separate it from the handle. Place the mouthpiece and inhaler on a clean and dry surface. 4. Carefully peel back the foil, and take out one capsule. Remove only one capsule at a time, just before use. 5. Hold the inhaler upright using the handle, and drop one capsule into the opening of the capsule chamber. 6. Line up the white arrows on the handle and mouthpiece, and firmly push the mouthpiece and handle together until you hear a click. This punctures the capsule. Release the mouthpiece; it will spring back and stay attached. 7. Hold the inhaler level and away from your mouth and breathe out completely. Do not breathe into the mouthpiece. 8. While keeping the inhaler level, close your lips firmly around the mouthpiece. Take in a deep, comfortable breath over several seconds until your lungs feel full. As you breathe in, you will hear and feel the capsule spin. 9. Take the inhaler out of your mouth, hold your breath for 5 seconds, and then breathe out. 10. Twist and pull off the mouthpiece, and remove the used capsule.

11. Repeat with the second capsule to finish the full dose. 12. Throw out used capsules in the household trash. 13. Make sure there are no capsules in the inhaler before you store it. Attach the mouthpiece to the handle by pushing until you hear a click. Attach the cap over the mouthpiece. The inhaler is now ready to store.

Key Points The upper airway is an efficient humidifier. The primary goal of humidity therapy is to maintain normal physiologic conditions by providing heat and humidity in the inspired gas. Humidifiers can provide active or passive humidification. Active humidifiers may be heated or unheated. Heated circuits can be used to maintain heat and humidity in gas delivery. The humidity delivery device should be assessed for condensate near the patient. Use of HMEs is limited by their effectiveness and their dead space. Bland aerosol therapy is used for therapeutic and diagnostic purposes. The particle size of aerosols for medical purposes should be in the range of 1 to 5 µm. Devices used to deliver therapeutic aerosols include jet nebulizers, ultrasonic nebulizers, metered-dose inhalers, metered-dose inhalers with a spacer or holding chamber, and dry powder inhalers. Nebulizers and pMDIs can be used effectively in patients receiving mechanical ventilation and in spontaneously breathing patients with a tracheostomy. Aerosol can be delivered using a nebulizer with high flow nasal cannula. Either a nebulizer, a pMDI, a pMDI with a spacer or valved holding chamber, or a DPI can be used effectively if the patient uses good technique.

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CHAPTER

16 Airway Clearance and Lung Expansion Therapy Dean R. Hess

© Andriy Rabchun/Shutterstock

OUTLINE Normal Mechanisms of Mucociliary Transport Airway Clearance Sputum Collection Lung Expansion Therapy

OBJECTIVES 1. Describe the mechanism of normal mucus transport in the lungs. 2. Demonstrate the techniques of mechanical insufflation–exsufflation, postural drainage, manually assisted coughing, active cycle of breathing, autogenic drainage, nasotracheal suctioning, incentive spirometry, intermittent positive pressure breathing, positive expiratory pressure, oscillatory positive expiratory pressure, and high-frequency techniques. 3. List indications, contraindications, hazards, and precautions for mechanical insufflation– exsufflation, postural drainage, manually assisted coughing, active cycle of breathing, autogenic drainage, nasotracheal suctioning, incentive spirometry, intermittent positive pressure breathing, positive expiratory pressure, oscillatory positive expiratory pressure, and high-frequency techniques. 4. Compare the advantages and disadvantages of various airway clearance techniques.

5. Compare the following methods of sputum collection: cough, induced sputum, tracheal aspiration, bronchoscopy, mini-bronchoalveolar lavage, transtracheal aspiration. 6. Compare techniques of lung inflation therapy.

KEY TERMS active cycle of breathing autogenic drainage chest physiotherapy (CPT) forced expiratory technique (FET) high-frequency chest wall compression (HFCWC) high-frequency chest wall oscillation (HFCWO) huff coughing incentive spirometry (IS) intermittent positive pressure breathing (IPPB) intrapulmonary percussive ventilation (IPV) mechanical insufflation–exsufflation mini-bronchoalveolar lavage (mini-BAL) nasotracheal suctioning percussion therapy positive expiratory pressure (PEP) postural drainage (PD) sputum induction vibration therapy

Introduction Many acute and chronic respiratory diseases are associated with retained airway secretions due to increased mucous production, impaired mucociliary transport, or a weak cough. In normal lungs, mucociliary activity, breathing, and coughing are the primary mechanisms used to remove secretions. With disease, changes in volume and character of secretions, dyskinesia of the cilia, and instability of the airway reduce the ability to clear secretions. Difficulty with airway clearance commonly occurs at the end of life.1 A variety of breathing maneuvers and mechanical devices are used to assist patients in mobilizing airway secretions. This chapter describes these maneuvers and devices.

Normal Mechanisms of Mucociliary Transport Secretions from the submucosal glands and surface secretory cells cover the ciliated epithelium of the airway (Figure 16-1). The relatively thin and watery sol layer, through which the cilia normally beat, arises from serous cell secretions. The thicker, superficial gel layer is formed from the more viscous secretions contributed by mucous cells and surface goblet cells, possibly enriched by components from the sol layer as water evaporates. This gel layer traps dust, pollens, contaminants, and microorganisms. In the central airways, the majority of the secretory capacity is attributed to the submucosal glands rather than the surface secretory cells.

FIGURE 16-1 (A) Surface of a typical ciliated epithelium. (B) Cilla at each phase of beat cycle. (C) Cephalad airflow bias. With normal mucociliary function, greater energy is applied to the mucous layer during expiration than during inspiration because of airway narrowing during expiration. (C) Reproduced from Fink JB. Forced expiratory technique, directed cough, and autogenic

drainage. Respir Care 2007;52(9):1210–1223. Reprinted with permission.

Description Cilia beat in a coordinated wavelike motion through the sol layer, with their tips extending to the gel layer, propelling it toward the pharynx during the forward power stroke. This action is followed by a return recovery stroke in which the cilia return to their starting position, closer to the cell surface and at a slower speed.1 The normal respiratory tract produces approximately 100 mL of mucus per day, some of which is absorbed as the secretions converge on the trachea, with the remainder expelled from the respiratory tract and swallowed. This process serves as a first-line defense protecting the lower respiratory tract. With airway mucus hypersecretion, the amount of mucus is pathologic and no longer protective. Mucus hypersecretion is characterized by submucosal gland hypertrophy, goblet cell hyperplasia, and increased mucin synthesis, along with plasma exudation, decreased mucociliary transport, mucostasis, and mucous plugs (Figure 16-2).

FIGURE 16-2 Airway mucus secretion and hypersecretion. (Left) In healthy airways, mucus forms a bilayer over the epithelium, with surfactant separating the gel and sol layers. Mucins secreted by goblet cells and submucosal glands confer viscoelasticity on the mucus, which facilitates mucociliary clearance of inhaled particles and irritants. Mucus hydration is regulated by salt (and hence water) flux across the epithelium. The glands also secrete water. Plasma proteins exuded from the tracheobronchial microvasculature bathe the submucosa and contribute to the formation of mucus. These processes are under the control of nerves and regulatory mediators. (Right) Airway inflammation (in asthma, chronic obstructive pulmonary disease [COPD], and possibly cystic fibrosis [CF]) induces changes associated with a mucus hypersecretory phenotype, including increased plasma exudation (more predominant in asthma than in COPD or CF), goblet

cell hyperplasia via differentiation from basal cells and associated increased mucus synthesis and secretion, and submucosal gland hypertrophy (with associated increased mucus production), leading to increased luminal mucus (and airway obstruction). Adapted from Rogers DF. Physiology of airway mucus secretion and pathophysiology of hypersecretion. Respir Care 2007;52(9):1134–1149.

Description Mucociliary transport depends on the rheologic properties of mucus. The interaction of mucus and airflow can alter these properties. Mucous gel properties primarily reflect the concentration and molecular characteristics of the mucous glycoproteins (mucins). Deoxyribonucleic acid (DNA) and actin fibers resulting from infection and inflammation can contribute additional cross-linking to the mucous gel. Notably, the purulent sputum from adult patients with cystic fibrosis (CF) has higher elasticity and viscosity than the nonpurulent sputum from individuals without CF. Cough and other high-airflow maneuvers reduce the cross-linking of mucous when airflow linear velocities are high enough (3 L/s in the trachea) to cause wave formation in the mucus layer. Reduced mucus viscosity during the cough maneuver may improve sputum clearance. Mucus acts as a low-viscosity fluid during the short time of the rapidly changing, turbulent airflow associated with effective cough but resumes its high-viscosity character after cessation of the cough and does not flow backward under the influence of gravity. Airflows associated with tidal breathing have no effect on mucus viscoelasticity. Cephalad airflow bias is responsible for the movement of mucus in airways during normal ventilation.2,3 Airway diameters normally increase on inspiration and narrow on expiration. The narrowing of airways on exhalation increases the velocity and shearing forces in the airway, creating a cephalad airflow bias with tidal breathing. This bias becomes amplified during coughing, when increased transmural pressure causes the airways to fold and constrict, increasing airflow velocity even further. During mechanical ventilation, a peak expiratory flow greater than peak inspiratory flow favors mucus transport toward the airway opening (Figure 16-3).2,3

FIGURE 16-3 Method of determining expiratory–inspiratory flow difference and ratio. The upper panel displays an example of a flow pattern that gives a positive value for the expiratory– inspiratory flow difference (i.e., B – A > 0) and the expiratory–inspiratory flow ratio (B/A > 1), which would create an expiratory flow bias and therefore tend to expel mucus. In this example, intrinsic positive end-expiratory pressure might be generated by the ventilator settings. The lower panel shows a flow pattern in which B – A < 0 and B/A < 1, which favors mucus retention because of inspiratory flow bias and increased expiratory resistance. In this example, intrinsic positive endexpiratory pressure is generated by impedance, as in chronic obstructive pulmonary disease. Reproduced from Volpe MS, et al. Ventilation patterns influence airway secretion movement. Respir Care 2008(10);53:1287–1294. Reprinted with permission.

In healthy individuals, the mucociliary escalator serves as the primary

mechanism of mucus clearance from the lungs. In contrast, in patients with acute airway diseases leading to ciliary dysfunction and/or mucus hypersecretion, cough is the primary mechanism for mucus clearance from the central airways, and cephalad airflow makes an increasingly greater contribution to peripheral airway clearance. In patients with chronic airway diseases involving mucus hypersecretion, these latter mechanisms become the major mechanisms responsible for keeping the airways patent. Gravity is not a primary mechanism for normal mucociliary transport because the viscosity of the normal mucous blanket is sufficient to resist flow of mucus into gravity-dependent terminal bronchioles. Cough is one of the most common respiratory symptoms for which patients seek medical attention.4 During a normal cough, the expiratory airflow rises to a maximum along with narrowing of the intrathoracic airways. The narrowing of the airways is a product of high airflows and pressure differentials across the lung. Airflow velocity varies inversely with the cross-sectional area of the airways, creating high linear velocities, increased turbulence, high shearing forces within the airway, and high kinetic energy. These forces shear secretions and debris from the airway walls, propelling them toward the central and upper airway, where they are expectorated or swallowed. A rapid series of coughs improves airway clearance. Excessive cough is associated with a number of complications (Table 16-1).5 In chronic obstructive pulmonary disease (COPD), narrowing airways may close prematurely, trapping gas, reducing expiratory flows, and limiting the effectiveness of the cough. There is an important balance between compression and collapse of airways: Collapse of the airway inhibits clearance. TABLE 16-1 Complications of Excessive Cough Cardiovascular

Arterial hypotension; bradyarrhythmias and tachyarrhythmias; dislodgment/malfunctioning of intravascular catheters; loss of consciousness; rupture of subconjunctival, nasal, and anal veins; and massive intraocular suprachoroidal hemorrhage during pars plana vitrectomy

Constitutional

Excessive sweating, anorexia, exhaustion

symptoms Gastrointestinal

Gastroesophageal reflux events; gastric hemorrhage following percutaneous endoscopic gastrostomy; hepatic cyst rupture; herniations (e.g., inguinal, through abdominal wall, small bowel through laparoscopic trocar site); malfunction of gastrostomy button; Mallory-Weiss tear; splenic rupture

Genitourinary

Inversion of bladder through urethra; urinary incontinence

Musculoskeletal

Range from asymptomatic elevations of serum creatine phosphokinase to rupture of rectus abdominus muscles; diaphragmatic rupture; rib fractures; sternal wound dehiscence

Neurologic

Acute cervical radiculopathy; cerebral air embolism; cerebral spinal fluid rhinorrhea; cervical epidural hematoma associated with oral anticoagulation; cough syncope; dizziness; headache; malfunctioning ventriculoatrial shunts; seizures; stroke due to vertebral artery dissection

Ophthalmologic

Spontaneous compressive orbital emphysema of rhinogenic origin

Psychosocial

Fear of serious disease; lifestyle changes; self-consciousness

Quality of life

Decreased

Respiratory

Exacerbation of asthma; herniations of the lung (e.g., intercostal, supraclavicular); hydrothorax in peritoneal dialysis; laryngeal trauma (e.g., laryngeal edema, hoarseness); pulmonary interstitial emphysema, with potential risk of pneumatosis intestinalis, pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum, pneumothorax, and subcutaneous emphysema; tracheobronchial trauma (e.g., bronchitis, bronchial rupture)

Skin

Petechiae and purpura; disruption of surgical wounds

Reproduced from Irwin RS. Complications of cough: ACCP evidence-based clinical practice guidelines. Chest 2006;129(1 suppl):54S–58S, with permission from the American College of Chest Physicians.

Cough peak flow is greater than 400 L/min in normal individuals.6 Cough peak flow greater than 160 L/min is necessary for adequate airway clearance, whereas cough peak less than 60 L/min has been associated with risk of reintubation.7 A cough peak flow greater than 270 L/min decreases the risk of pneumonia in patients with neuromuscular disease.

Airway Clearance Deep Breathing and Coughing The normal mechanism for lung expansion and bronchial hygiene is spontaneous deep breathing (including yawn and sigh maneuvers) and an effective cough. Instructing and encouraging the patient to take sustained deep breaths is among the safest, most effective, and least expensive strategies to keep the lungs expanded and secretions moving.8 The negative intrathoracic pressure generated during spontaneous deep breathing tends to better inflate the less compliant, gravity-dependent areas of the lung than mechanical methods relying on lung inflation by application of positive airway pressure. A deep breath is a key component of a normal effective cough. An effective cough is the most important component of bronchial hygiene therapy (Box 16-1). A normal cough involves a deep breath, closure of the glottis, and compression of abdominal and thoracic muscles generating pressures in excess of 80 mm Hg (110 cm H2O), followed by an explosive release of gas as the glottis opens (Figure 164). In addition to mobilizing and expelling secretions, the high inspiratory volume generated during a cough may have an important role in reexpanding lung tissue. Coughing is associated with a number of untoward effects (refer to Table 16-1). In the patient with unstable airways, high pleural pressures cause dynamic compression of airways, trapping gas and secretions and rendering the cough ineffective. A variety of breathing techniques enhance cephalad airflow bias.

FIGURE 16-4 The cough reflex. (A) Irritation. (B) Inspiration. (C) Compression. (D) Expulsion.

BOX 16-1 Procedure for Directed Cough 1. Explain to the patient that deep breathing and coughing will help to keep the lungs expanded and clear of secretions. 2. Assist the patient to a sitting position or to a semi-Fowler position if a sitting position is not possible. 3. Directed cough procedure: a. Instruct the patient to take a deep breath; then hold the breath, using abdominal muscles to force air against a closed glottis; and then cough with a single exhalation. b. Have the patient take several relaxed breaths before the next cough effort. c. Document the teaching accomplished, the procedures performed, and the patient response in the patient record. 4. Huff cough procedure (forced expiratory technique): a. Instruct the patient to take three to five slow, deep breaths by inhaling through the nose and exhaling through pursed lips, using diaphragmatic breathing. Have the patient take a deep breath and hold it for 1 to 3 seconds. b. Instruct the patient to exhale from the mid to low lung volume (to clear secretions from peripheral airways). Have the patient take a normal breath in and then squeeze it out by contracting the abdominal and chest wall muscles, with the mouth (and glottis) open during exhalation. Repeat several times. c. As secretions enter the larger airways, have the patient exhale from the high to mid lung volume to clear secretions from more proximal airways. Repeat this maneuver two to three times. d. Instruct the patient to take several relaxed diaphragmatic breaths before the next

cough effort. e. Document the teaching accomplished, the procedures performed, and the patient response in the patient record. 5. Modified directed cough procedures: a. Patients who have had abdominal or thoracic surgery: Instruct the patient to place a hand or a pillow over the incision site and apply gentle pressure while coughing. The caregiver may assist with incision support during coughing. Support chest tubes as necessary. b. Quadriplegic patients: The clinician places palms on the patient’s abdomen, below the diaphragm, and instructs the patient to take three deep breaths. On exhalation of the third breath, the clinician pushes forcefully inward and upward as the patient coughs.

Forced Expiratory Technique For patients who are unable to generate an effective cough, sharp forced exhalations without glottis closure (huff coughing) may be the maneuver of choice. Huff coughing is a forced expiratory technique (FET) that is performed through sharp exhalation from high to mid lung volumes through an open glottis. The individual takes in a slow, deep breath, followed by a 1- to 3-second breath hold, and then performs short, quick forced exhalation with the glottis open. Toddlers can also be taught blowing games (e.g., pinwheel, bubbles) to encourage prolonged exhalation maneuvers.8

Manually Assisted Cough The manually assisted cough involves thrusts with hands and arms positioned on the patient’s abdomen, coordinated with expiration (Figure 16-5). Compression of the lateral aspect of the chest also can be effective. Often this technique is augmented with manual inflation for patients with a low vital capacity. The manually assisted cough requires a cooperative patient, good coordination between patient and clinician, and a clinician with sufficient physical strength to reliably perform the maneuver. Its efficacy is limited for patients with significant scoliosis and osteoporosis of the rib cage. This technique is used most commonly in patients with neuromuscular disease or quadriplegia; thus, it is sometimes called quad coughing.

FIGURE 16-5 To produce manually assisted (quad) coughing, the clinician applies external abdominal pressure under the diaphragm during exhalation following maximal inspiration, resulting in an increased expiratory flow and airway clearance.

Active Cycle of Breathing The active cycle of breathing technique combines breathing control, thoracic expansion control, and the forced expiration technique (Box 162 and Figure 16-6). Breathing control entails gentle breathing with the lower chest. With the upper chest and shoulders relaxed, the patient breathes at a normal tidal volume and rate. The patient should feel a swelling around the waist on inspiration, which subsides while breathing out. Breathing control is the default maneuver between the more active techniques. Thoracic expansion exercises, by contrast, are large breaths with active inspiration (involving both the diaphragm and rib cage musculature) and relaxed expiration. The expanding lung volume increases flow through the small airways and collateral ventilation channels, thereby increasing the volume of gas available to help mobilize secretions on expiration. Thoracic expansion is limited to three or four deep breaths to avoid fatigue and hyperventilation. The FET consists of one or two forced expirations or huffs, combined with a period of controlled breathing. A normal breath is taken in, and then the air is squeezed out by contraction of the chest wall and abdominal muscles. The mouth and glottis are kept open, and the huff should not be a violent or explosive exhalation.

FIGURE 16-6 (A) Lung volumes during the active cycle of breathing technique. (B) The active cycle of breathing technique. (C) Three active cycle of breathing routines. Reproduced from Fink JB. Forced expiratory technique, directed cough, and autogenic drainage. Respir Care 2007;52(9):1210–1223. Reprinted with permission.

Description

BOX 16-2 Procedure for Active Cycle of Breathing 1. The patient should be in a relaxed, sitting, or reclined position. 2. Have the patient do several minutes of relaxed diaphragmatic breathing (breathing control). 3. Instruct the patient to take three to four active deep inspirations with passive relaxed exhalations (thoracic expansion exercises). 4. Have the patient do relaxed diaphragmatic breathing (breathing control). 5. As the patient feels secretions entering the larger central airway, instruct the patient to do two to three huffs (forced expiratory technique) starting at low volume, followed by two to three huffs at higher volume, followed by relaxed breathing control. 6. Repeat the cycle two to four times, as tolerated.

Autogenic Drainage Autogenic drainage aims to achieve the highest possible airflow in the different generations of bronchi to move secretions without forced expirations (Figure 16-7).8

FIGURE 16-7 The three phases of autogenic drainage. ERV, expiratory reserve volume; RV, reserve volume; FRC, functional residual capacity; IRV, inspiratory reserve volume; VT, tidal volume. Reproduced from Fink JB. Forced expiratory technique, directed cough, and autogenic drainage. Respir Care 2007;52(9):1210–1223. Reprinted with permission.

Mechanical Insufflation–Exsufflation The mechanical insufflator–exsufflator (MIE), also called the Cough Assist, inflates the lungs with positive pressure, followed by application of a negative pressure to simulate a cough.9 Cough assist can be applied using a stand-alone device (Figure 16-8) or a device integrated with ventilation and suction (Ventec VOCSN). Treatment consists of five cycles of mechanical insufflation–exsufflation followed by 20 to 30 seconds of normal breathing, with repetitions continuing until secretions are cleared. For each cycle, the inspiratory pressure is 25 to 35 cm H2O for 1 to 2 seconds, followed by an expiratory pressure of –30 to –40 cm H2O for 1 to 2 seconds. The MIE can be used with an oronasal mask or with a mouthpiece, or it can be attached to an artificial airway.10 Combining manual abdominal thrusts with expiration can help increase expiratory flow expulsion of secretions. This procedure is effective in patients with neuromuscular disease. In patients with bulbar disease, use of the MIE can be limited by upper airway closure that occurs during the active negative pressure expiratory phase.11,12

FIGURE 16-8 Cough Assist mechanical insufflation–exsufflation device. Reproduced with the permission of Koninklijke Philips N.V. All rights reserved.

Stop and Think You are told that a patient is prescribed albuterol for airway clearance. How effective do you think this therapy will be?

Aerosol Therapy Recombinant human deoxyribonuclease (dornase alfa) was the first mucoactive agent to receive Food and Drug Administration (FDA) clearance for the treatment of CF. Its efficacy has not been demonstrated in the treatment of other chronic airway diseases. Acetylcysteine (N-acetyl-L-cysteine sodium; Mucomyst) has been administered by aerosol or direct instillation based on its in vitro ability to break disulfide bonds of mucoprotein. Evidence does not support its in vivo efficacy, however.13 This airway irritant can induce bronchospasm, and it has a nauseating smell and taste. The clinical benefit of Mucomyst has been questioned, and this agent has fallen out of favor in recent years. Hypertonic saline (7%) has been shown to improve outcomes in patients with CF14 but might not be useful for COPD.15 Aerosolized isotonic saline from a small-volume nebulizer is not an effective airway clearance therapy. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests that bronchodilators might potentially have a therapeutic role as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been used to enhance mucociliary clearance in patients with obstructive lung disease, the existing evidence does not consistently support their clinical effectiveness.13 Although short-acting betaadrenergics have mucociliary-enhancing effects in healthy individuals, they have only minimal effects in patients with depressed airway clearance. Historically, clinicians have been concerned that inhaled anticholinergic agents used to treat airway disease could dry respiratory

tract secretions, but this risk is not clinically important for the anticholinergics commonly used to treat airway disease. Atropine or glycopyrrolate injection and scopolamine patch are used to reduce cholinergic symptoms such as sialorrhea, bronchorrhea, and excessive pharyngeal secretions. Aerosolized anticholinergics, however, are only minimally effective in drying respiratory tract secretions.

Conventional Chest Physiotherapy Conventional chest physiotherapy (CPT) consists of a combination of forced exhalation (directed cough or huff), postural drainage, percussion, and/or shaking.16,17 Conventional CPT has become the standard against which all other bronchial hygiene techniques are compared. Patients report less satisfaction with conventional CPT than with other bronchial hygiene techniques.18 Given the risks associated with this treatment, the time required for therapy, and the paucity of evidence to support its use, prudence is necessary regarding use of CPT. Postural drainage (PD) is used in the treatment of excessive sputum production that the patient has difficulty clearing or expectorating. In patients with CF, this therapy results in greater expectoration compared with no treatment. PD consists of positioning so that secretions drain from specific segments and lobes of the lung toward gravity-dependent central airways, where they can be more readily removed with cough or mechanical aspiration. This action is accomplished by positioning the patient so that the affected lung segments are superior to the carina, with each position maintained for 5 to 10 minutes (Figure 16-9). Typically, 11 to 12 positions are identified to drain all areas of the lungs, requiring at least 1 hour for a complete session. Because of this time commitment, therapy is concentrated in those positions that drain the most affected segments. Box 16-3 describes the general procedure for CPT.

FIGURE 16-9 Positions for postural drainage.

Description

BOX 16-3 Procedure for Chest Physiotherapy 1. Assess the patient and determine the need for chest physiotherapy.

2. Gather the appropriate equipment: a bed or table that can assume a range of positions, pillows to support the patient, a light towel to cover the chest percussion area, and tissues or a basin for secretions. 3. Explain the therapy to the patient, and instruct the patient in the proper cough techniques. 4. Assist the patient in assuming each position and maintaining it for 5 to 10 minutes. 5. Assess the patient response in each position; modify the position if necessary. 6. Perform chest percussion and vibration over the affected area if necessary. 7. Encourage the patient to take slow, deep breaths and cough between positions; note the character of cough and secretions. 8. Document the procedure and the patient’s response to therapy in the medical record; communicate adverse effects to the physician.

PD has no benefit in conditions with scant secretions. Instead, use of this therapy is reserved primarily for patients diagnosed with CF or bronchiectasis, and specifically those who produce more than 30 mL of sputum per day and have difficulty clearing these secretions. Sputum production of less than 25 mL/day is insufficient to justify the application of PD therapy. Some patients have productive coughs with sputum production ranging from 15 to 30 mL/day (occasionally as high as 70 or 100 mL/day), yet do not need PD. If PD does not increase sputum production in a patient who produces more than 30 mL/day of sputum without PD, this therapy is not warranted. Placing the patient in a head-down or Trendelenburg position affects both hemodynamics and interaction of physical forces between the thorax and the abdomen. With the head down, blood flow to the head increases. For this reason, the clinician should avoid the Trendelenburg position in patients with head injury, uncontrolled hypertension, or gross hemoptysis. Shifting of abdominal and thoracic contents with gravity in the Trendelenburg position may have adverse effects in patients at risk for aspiration, with distended abdomens, or after recent esophageal surgery. Reverse Trendelenburg position may also be hazardous for patients with hypotension or those receiving vasoactive medication. During PD therapy, identify any hypoxemia, bronchospasm, acute hypotension, increased intracranial pressure, hemoptysis, pain or injury to the tissue, and vomiting with risk of aspiration. To minimize the risk of vomiting and aspiration, perform the therapy either before meals or more than 1 hour after meals. For patients receiving tube feedings, feedings

should cease 1 hour before and during therapy. For patients with a history of bronchospasm, bronchodilators are commonly administered before PD therapy. Percussion therapy is a technique involving rapid clapping, cupping, or striking of the external thorax directly over the lung segment being drained, with either cupped hands or a mechanical device (Figure 1610). Percussion has been advocated to assist secretion mobilization by shaking loose secretions, similar to the shaking of ketchup from a bottle. Vibrating the chest wall over the draining area with a fine tremulous action may also mobilize secretions during PD. To manually perform vibration therapy, press in the direction that the ribs and soft tissue of the chest normally move during exhalation. Alternatively, mechanical devices can be used to perform chest percussion and vibration. These devices may be more convenient for the caregiver, but data are lacking that confirm they improve airway clearance.

FIGURE 16-10 (A) Movement of cupped hand at wrist to percuss chest. (B) Chest vibration. Reproduced from Egan’s Fundamentals of Respiratory Care, 7th ed. Scanlan CL, Wilkins RL, Stoller JK. Copyright Elsevier (Mosby) 1999.

Percussion and vibration appear to be relatively ineffective and do not add to the effectiveness of the combination of coughing, breathing exercises, and PD.19 Little evidence supports the use of percussion alone, without positioning of the patient. A number of potential hazards and complications are associated with these techniques. Percussion or vibration to the thorax may exacerbate conditions such as irregularities of the skin (e.g., burns, open wounds, skin infections, recent skin grafts), subcutaneous emphysema, a recently placed transvenous pacemaker or subcutaneous pacemaker, or a recent epidural spinal infusion of

anesthetic. Moreover, percussion and vibration are difficult for patients to perform without assistance. Potential damage to the thorax from percussion makes osteoporosis and osteomyelitis of the ribs, as well as complaints of chest pain, relative contraindications to this therapy. Lung contusion and coagulopathies may be aggravated by percussion, resulting in increased bruising or bleeding of the chest wall or in the lungs. Conventional CPT has been suggested as the most stimulating and disturbing procedure in mechanically ventilated patients and, therefore, should not be administered to patients with poor cardiopulmonary reserve. In mechanically ventilated patients, CPT may be accompanied with manual hyperinflation. This practice is discouraged, however, because it may result in dangerously high airway pressures and tidal volumes in patients with acute lung injury. In patients with CF, tolerance for CPT may be improved when this therapy is combined with noninvasive pressure support. Respiratory Recap Conventional Chest Physiotherapy ∎ Postural drainage ∎ May be combined with percussion and vibration

Stop and Think When would you recommend chest physiotherapy for a patient?

Positive Expiratory Pressure Positive expiratory pressure (PEP) therapy is performed with the patient seated comfortably and with elbows resting on a table (Box 164).20 Equipment consists of a soft transparent mask or mouthpiece, a T assembly with a one-way valve, a variety of fixed orifice resistors (or an adjustable expiratory resistor), and a manometer (Figure 16-11). The patient is instructed to relax while performing diaphragmatic breathing, inspiring a volume of air larger than normal tidal volume, but not to the

level of total lung capacity, through the one-way valve. Exhalation to functional residual capacity (FRC) is active, but not forced, through the resistor chosen to achieve a peak airway pressure of 10 to 20 cm H2O during exhalation. The patient performs a series of 10 to 20 breaths with the mask or mouthpiece in place. The patient then removes the mask (or mouthpiece), and next performs several coughs to raise secretions. This sequence of 10 to 20 breaths, followed by huff coughing, is repeated four to six times per PEP therapy session. Each session requires 10 to 20 minutes and may be performed one to four times per day as needed. For lung expansion, patients should be encouraged to take 10 to 20 breaths every hour while awake.

FIGURE 16-11 (A) Equipment for positive expiratory pressure (PEP) therapy. (B) Commercially available PEP device. (A) Adapted from Malmeister MJ, Fink JB, Hoffman GL. Positive expiratory pressure mask therapy: theoretical and practical considerations and a review of the literature. Respir Care 1991;36(11):1218–1229; (B) Courtesy of Smiths Medical.

BOX 16-4 Procedure for Positive Expiratory Pressure Therapy 1. The patient should sit comfortably upright while holding the mask firmly over the nose and mouth or the mouthpiece tightly between the lips (a nose clip may be necessary). 2. Adjust the expiratory resistor dial to the prescribed setting. 3. Have the patient breathe from the diaphragm, taking in a larger than normal tidal breath but not to total lung capacity. 4. Have the patient gently exhale, maintaining a prescribed pressure of 5 to 20 cm H2O. 5. Exhalation time should last approximately three times longer than inhalation. 6. Patient should perform 10 to 20 positive expiratory pressure breaths and then perform two to three forced exhalation maneuvers or huffs. 7. Repeat steps 3 to 6 until secretions are cleared or until the predetermined treatment period has elapsed. Reproduced from Myers TR. Positive expiratory pressure and oscillatory positive expiratory pressure therapies. Respir Care 2007;52(10):1308–1327. Reprinted with permission.

Selection of an appropriate resistance is necessary as part of proper technique. The therapeutic goal is to achieve a PEP of 10 to 20 cm H2O, with an inspiration-to-expiration (I:E) ratio of 1:3 to 1:4. When a fixed orifice is used, most adults achieve this pressure range with an orifice of 2.5 to 4.0 mm in diameter. A manometer is placed in-line to measure the expiratory pressure while the appropriate-sized resistor orifice is determined; the manometer is then removed from the system. Selection of a resistor with too large an orifice produces a short exhalation, with failure to achieve the proper expiratory pressure. A too-small orifice prolongs the expiratory phase, elevates the pressure above 20 cm H2O, and increases the work of breathing. Performing a PEP session for more than 20 minutes may lead to patient fatigue. During periods of exacerbation, individuals are encouraged to increase the frequency with which PEP is performed, rather than extending the length of individual sessions. Although no absolute contraindications to the use of PEP therapy

have been reported, common sense dictates that patients with acute sinusitis, ear infection, epistaxis, or recent facial, oral, or skull injury or surgery should be carefully evaluated before initiating PEP mask therapy. Patients experiencing active hemoptysis or those with unresolved pneumothorax should avoid using PEP therapy.

Oscillatory (or Vibratory) Positive Expiratory Pressure Oscillatory, or vibratory, PEP combines the benefits of PEP with airway vibrations or oscillations.20 Oscillations may decrease the viscoelastic properties of mucus, which makes it easier to move mucus up the airways, and may create short bursts of increased expiratory airflow that assist in mobilizing secretions up the airways. Secretion removal improves when the patient forces exhalation through the device or with subsequent coughing and/or huffing techniques. Several commercially available devices can be used to administer this therapy (Figure 16-12).

FIGURE 16-12 (A) Position of the Flutter valve in a patient’s mouth. (B) During exhalation, the position of the Flutter steel ball changes owing to an equilibrium between the pressure of the

exhaled gas, the force of gravity on the ball, and the angle of the cone where the contact with the ball occurs. As the steel ball rolls and bounces up and down, it creates oscillations in the airway. (C) Acapella device. (D) Quake device. (E) RC-Cornet device. (F) Aerobika Oscillating PEP device. (G) vPEP. (C) Courtesy of Smiths Medical; (D) Courtesy of Thayer Medical Corporation; (E) Courtesy of Curaplex; (F) Courtesy of Monaghan Medical; (G) vPEP® © 2019 Vyaire Medical, Inc.; Used with permission.

The Flutter device is a pipe-shaped device with a steel ball in a bowl loosely covered by a perforated cap. The weight of the ball serves as a PEP device (approximately 10 cm H2O), whereas the internal shape of the bowl allows the ball to flutter, generating oscillations of approximately 15 Hz (2 to 32 Hz), varying with the position of the device. Use of the Flutter device depends on gravity, whereas other devices work independently of gravity. The Acapella uses a counterweighted plug and magnet to create airflow oscillations during expiratory flow. The Quake PEP device has a manually operated rotating handle that creates the oscillations; the speed with which the handle is rotated controls the oscillation frequency. Rotating the handle slowly creates a low-frequency oscillation and a higher pulsatile expiratory pressure. Rotating the handle quickly provides faster oscillations while decreasing the pulsatile expiratory pressure. With the RC-Cornet device, therapy is fine tuned by twisting the mouthpiece from the starting position to tailor changes to pressure and flow characteristics. It can be used as combined PEP, which is characterized as continuous positive pressure above baseline with applied pressure changes, or as dynamic PEP, which is characterized by a pressure increase from zero to maximum with a drop back to zero. The Aerobika device has five resistance settings. Selection of the proper resistance setting will produce the desired I:E flow ratio of 1:3 or 1:4 for 10 to 20 minutes without creating excess fatigue in the patient.

High-Frequency Chest Wall Compression High-frequency chest wall compression (HFCWC) generates negative changes in transpulmonary pressure difference by compressing the chest externally (i.e., body surface pressure goes positive relative to the pressure at the airway opening, which remains at atmospheric pressure)

to cause short, rapid expiratory flow pulses; it relies on chest wall elastic recoil to return the lungs to functional residual capacity. HFCWC is accomplished by encasing the chest in an inflatable vest.21,22 A highoutput compressor rapidly inflates and deflates the vest. On inflation, pressure is exerted on the body surface (range 5 to 20 cm H2O), which forces the chest wall to compress and generates a short burst of expiratory flow. Pressure pulses are superimposed on a small (about 12 cm H2O) positive pressure baseline. On deflation, the chest wall recoils to its resting position, causing inspiratory flow. The Vest Airway Clearance System (Figure 16-13A) operates at 2 to 25 Hz and generates esophageal pressure and airflow oscillations as shown in Figure 16-14. HFCWC can generate volume changes of 17 to 57 mL and flows up to 1.6 L/s. This produces mini-coughs to mobilize secretions. HFCWC causes a decrease in end-expiratory lung volume, although the consequences of that decrease are unclear.23 Other commercially available HFCWC devices include the InCourage system (Figure 16-13B) and the SmartVest (Figure 16-13C). Box 16-5 describes the procedure for use of HFCWC.

FIGURE 16-13 (A) Vest® Airway Clearance System. (B) InCourage device for high-frequency chest wall compression (HFCWC). (C) SmartVest device for HFCWC. (A) © 2014 Hill-Rom Services PTE Ltd. Reprinted with permission. All rights reserved; (B) Courtesy of RespirTech; (C) Courtesy of Electromed, Inc.

FIGURE 16-14 Flow, airway pressure, and esophageal pressure waveforms while breathing with the Vest Airway Clearance System. Reproduced from Fink JB, Mahlmeister MJ. High-frequency oscillation of the airway and chest wall. Respir Care 2002;47(7):797–807. Reprinted with permission.

BOX 16-5 Procedure for High-Frequency Chest Wall Compression Ramping Session Using Hill-Rom Vest Frequency

Pressure

Time

6, 8, 10 Hz

10

5 minutes at each frequency Pause machine and cough three times Resume session

16, 18, 20 Hz

6

5 minutes at each frequency Pause machine and cough three times Resume session

Therapy Session with InCourage 1. Push the Quick Start button to initiate the preprogrammed 30-minute automatic

ramping session. 2. Push the Pause button at any time to allow for coughing. 3. Push the Run button to resume therapy. 4. Pressure can be increased or decreased during a therapy session.

Standard Protocol for SmartVest Frequency

Duration

10 Hz

10 minutes, then huff cough

12 Hz

10 minutes, then huff cough

14 Hz

10 minutes, then huff cough

Reproduced from Lester MK, Flume PA. Airway-clearance therapy guidelines and implementation. Respir Care 2009;54(6):733–753. Reprinted with permission.

Stop and Think You are asked to recommend an airway clearance therapy for a patient with neuromuscular disease. Which therapy do you think would be most beneficial?

Intrapulmonary Percussive Ventilation Intrapulmonary percussive ventilation (IPV) creates positive changes in transrespiratory difference by injecting short, rapid inspiratory flow pulses into the airway opening and relies on chest wall elastic recoil for passive exhalation.24,25 It delivers high-flow mini-bursts of air, along with an aerosolized medication to the lungs, at a rate of 300 to 400 pulses per minute. The Percussionator (Figure 16-15) operates at 1.7 to 5 Hz; treatments with this device last approximately 15 to 20 minutes. It can be used with a mouthpiece or mask. Similar devices include the Breas IMP2, which operates at about 1 to 6 Hz and can also deliver aerosol medication, and the single-patient-use PercussiveNeb. The PercussiveNeb operates at frequencies of 11 to 30 Hz and can also deliver an aerosolized medication; however, it cannot be used with a ventilator. All three devices produce roughly comparable pressure

waveforms (Figure 16-16). Each device delivers flow oscillations with normal spontaneous breathing.

FIGURE 16-15 (A) Percussionaire Percussionator. (B) Patient using Percussionator. (C) Vortran® PercussiveNeb. (A Courtesy of Dr. Pamela Bird, Percussionaire Corporation; (B) Courtesy of Dr. Pamela Bird, Percussionaire Corporation; (C) Courtesy of VORTRAN® Medical Technology 1, Inc., Sacramento, CA.

FIGURE 16-16 Flow, airway pressure, and esophageal pressure waveforms while breathing with an intrapulmonary percussive ventilator. Reproduced from Fink JB, Mahlmeister MJ. High-frequency oscillation of the airway and chest wall. Respir Care 2002;47(7):797–807. Reprinted with permission.

With the MetaNeb device (Figure 16-17), aerosol is delivered with therapies intended to improve lung expansion and airway clearance. In the continuous positive expiratory pressure mode, aerosol delivery is combined with positive airway pressure. In the continuous high-frequency oscillation mode, aerosol is delivered while oscillating the airways with pulses of positive pressure. A typical therapy session consists of 10 minutes of alternating sessions between the two modes.

FIGURE 16-17 MetaNeb device. © 2014 Hill-Rom Services PTE Ltd. Reprinted with permission. All rights reserved.

High-Frequency Chest Wall Oscillation High-frequency chest wall oscillation (HFCWO) uses a chest cuirass to generate biphasic changes in transrespiratory pressure difference. The Hayek oscillator is an electrically powered, microprocessor-controlled,

noninvasive oscillator ventilator that uses an external flexible chest enclosure (cuirass) to apply alternating negative and positive pressure to the chest wall to deliver noninvasive oscillation to the lungs (Figure 1618). The negative pressure generated in the cuirass causes the chest wall to expand for inspiration, whereas positive pressure compresses the chest to produce a forced expiration. Both inspiratory and expiratory phases may be active and not reliant on passive recoil of the chest. Expiratory pressure can be positive, atmospheric, or negative, allowing ventilation to occur above, at, or below the patient’s normal FRC.

FIGURE 16-18 Schematic drawing of the Hayek oscillator. Adapted from materials courtesy of Breasy Medical Equipment, Stamford, CT.

Clinicians’ anecdotal observations of spontaneous expulsion of secretions during high-frequency ventilation have led to the development of several discrete secretion management program recommendations in which the chest is oscillated through two sets of cycles: several minutes at a high frequency of up to 999 per minute (usually 600 to 720 per

minute) at an I:E ratio of 1:1, followed by 60 or 90 cycles per minute at an I:E ratio of 5:1. The setting can be changed according to the patient’s need.

Exercise Exercise causes increased sputum production compared with rest. Exercise augments bronchial hygiene, and patients should be encouraged to be as physically active as tolerated. Generally, however, it should not substitute for other bronchial hygiene regimens. Respiratory Recap Airway Clearance ∎ Coughing ∎ Forced expiratory technique ∎ Manually assisted coughing ∎ Active cycle of breathing ∎ Autogenic drainage ∎ Aerosol therapy ∎ Conventional chest physiotherapy ∎ Mechanical insufflation–exsufflation ∎ Positive expiratory pressure ∎ Oscillatory (or vibratory) positive expiratory pressure ∎ High-frequency chest wall compression ∎ Intrapulmonary percussive ventilation

Selection of Airway Clearance Technique A number of systematic reviews, meta-analyses, and clinical practice guidelines have been published related to airway clearance therapy.19,23,26–39 Relatively few studies have addressed airway clearance therapy, however, and the overall quality of the evidence is low. So far, it does not appear that any particular device is superior to the others. The American Association for Respiratory Care has published clinical practice guidelines on the effectiveness of pharmacologic and

nonpharmacologic airway clearance therapies in hospitalized patients (CPG-1).13,36–38 The Cystic Fibrosis Foundation’s guidelines recommend performing airway clearance therapy on a regular basis in all patients with CF.39 No therapy, however, has demonstrated superiority over the others. For an individual patient, one form of airway clearance therapy may be superior to the others. Airway clearance therapy should be individualized based on factors such as age, patient preference, and adverse events, among other things. Aerobic exercise is recommended for patients with CF as an adjunctive therapy for airway clearance and because of its additional benefits to overall health. One especially important consideration when selecting an airway clearance technique is the patient’s age (Figure 16-19), because some therapies are not appropriate for all age groups.

FIGURE 16-19 Various airway clearance techniques based on the patient’s age and ability to perform the therapy. ACB, active cycle of breathing; AD, autogenic drainage; HFCWC, highfrequency chest wall compression; IPV, intrapulmonary percussive ventilation. Reproduced from Lester MK, Flume PA. Airway-clearance therapy guidelines and implementation. Respir Care 2009;54(6):733–753. Reprinted with permission.

CLINICAL PRACTICE GUIDELINE 16-1 Recommendations Regarding Nonpharmacologic Therapy for Airway Clearance Therapy

▪

For hospitalized adult and pediatric patients without cystic fibrosis:

•

CPT is not recommended for the routine treatment of uncomplicated pneumonia.

• • • ▪

▪

Airway clearance therapy (ACT) is not recommended for routine use in patients with COPD. ACT may be considered in patients with COPD with symptomatic secretion retention, guided by patient preference, toleration, and effectiveness of therapy. ACT is not recommended if the patient is able to mobilize secretions with cough, but instruction in effective cough technique may be useful.

For adult and pediatric patients with neuromuscular disease, respiratory muscle weakness, or impaired cough:

•

Cough assist techniques should be used in patients with neuromuscular disease, particularly when peak cough flow is less than 270 L/min.

•

CPT, positive expiratory pressure, intrapulmonary percussive ventilation, and highfrequency chest wall compression cannot be recommended, due to insufficient evidence.

For postoperative adult and pediatric patients:

•

Incentive spirometry is not recommended for routine, prophylactic use in postoperative patients.

•

Early mobility and ambulation are recommended to reduce postoperative complications and promote airway clearance.

•

ACT is not recommended for routine postoperative care.

Recommendations Regarding Pharmacologic Therapy for Airway Clearance Therapy

▪

Recombinant human dornase alfa should not be used in hospitalized adult and pediatric patients without CF.

▪ ▪

The routine use of bronchodilators to aid in airway clearance is not recommended.

▪

Aerosolized agents to change biophysical properties of mucus or promote airway clearance are not recommended for adult or pediatric patients with neuromuscular disease, respiratory muscle weakness, or impaired cough.

▪

Mucolytics are not recommended to treat atelectasis in postoperative adult or pediatric patients.

▪

The routine administration of bronchodilators to postoperative patients is not recommended.

The routine use of aerosolized N-acetylcysteine to improve airway clearance is not recommended.

Modified from Strickland SL, Rubin BK, Haas CF, Volsko TA, Drescher GS, O’Malley CA. AARC clinical practice guideline: effectiveness of pharmacologic airway clearance therapies in hospitalized patients. Respir Care 2015;60(7):1071–1077; and Strickland SL, Rubin BK, Drescher GS, Haas CF, O’Malley CA, Volsko TA, et al. AARC clinical practice guideline: effectiveness of nonpharmacologic airway clearance therapies in hospitalized patients. Respir Care 2013;58(12):2187–2193.

The following hierarchy of questions should be considered regarding airway clearance therapy for a patient.36,40 1. Is there a pathophysiologic rationale for use of the therapy? Is the patient experiencing difficulty clearing secretions? Are retained secretions affecting lung function in an important way, such as in terms of gas exchange or lung mechanics? Note that the production of large amounts of sputum does not necessarily mean that the patient is experiencing difficulty clearing sputum. 2. What is the potential for adverse effects from the therapy? Which therapy is likely to provide the greatest benefit with the least harm? 3. What is the cost of the equipment for this therapy? The cost of the device may not be covered by third-party insurers, resulting in considerable out-of-pocket expense for the patient or the hospital. 4. What are the patient’s preferences? Given the lack of evidence showing that any technique is superior to another, patient preference is an important consideration. When the decision is made to try an airway clearance technique, a simple clinical trial can be conducted to assess its utility (N-of-1 trial).36,40 Imagine that a decision is made to try PEP therapy for a patient with COPD. The clinician and the patient agree that a clinically useful outcome measure is fewer symptoms related to chest congestion and coughing up phlegm. A randomized controlled trial is designed. PEP is used for 2 weeks, a sham device is used for 2 weeks, and this process is repeated three times. The patient, who is naïve to the therapy, does not know which device is potentially therapeutic. The order of treatments is randomized (the patient flips a coin), and the sequence is repeated four times. Each day, the sputum produced during the therapy session is weighed. The patient also keeps a diary, logging events such as chest infections and other symptoms. At the end of 12 weeks, the results are analyzed (which may include statistical analysis) and then reviewed together by the clinician and patient, and a collaborative decision is made regarding the benefit of the therapy. In this manner, the clinician–patient team can make an objective decision regarding the benefits of this therapy for the individual patient.

Sputum Collection Analysis of a sputum sample can be used as a diagnostic test for pulmonary infection or cancer. A sputum culture is a test to detect and identify bacteria or fungi infecting the lungs. The clinician places the sputum sample into a sterile container and sends it to the microbiology laboratory for Gram stain, culture, and sensitivity. No growth of bacteria or fungi means the culture is negative. If pathogenic organisms grow, the culture is positive and the type of bacteria or fungus is identified. Additional tests are done to determine which antibiotics are most effective in treating the infection—a process called susceptibility or sensitivity testing. Bacteria usually need 2 to 3 days to grow, fungi often take a week or longer to grow, and tuberculosis may take 6 weeks to grow. Any bacteria or fungi that multiply in the culture can be identified under a microscope or by chemical tests. Sensitivity testing to determine the best antibiotic to use against the organism often takes 1 to 2 additional days. The sputum sample is usually collected by coughing, most often first thing in the morning. The patient should not use mouthwash before collecting a sputum sample because it may contain antibacterial agents. Other factors that can affect the results of sputum culture include recent use of antibiotics, contamination of the sputum sample, an inadequate sputum sample, and waiting too long to deliver the sample to the laboratory. Sputum cytology can be done when lung cancer is suspected or to detect certain noncancerous lung conditions. However, it is not used as a screening test for people at risk for developing lung cancer, such as smokers.

Induced Sputum Aerosols of bland solutions, such as hypertonic saline, are used to stimulate cough and sputum production. Such therapy is used for diagnostic sputum induction. For example, hypertonic saline (e.g., 3% sodium chloride) on the mucosa moves water via osmosis from the

airway into the secretions. This action causes bronchorrhea, diluting the secretions and increasing their bulk to ease expectoration. The delivery of hypertonic saline is used to induce sputum for the diagnoses of Pneumocystis jirovecii, tuberculosis (acid-fast bacilli), Legionella species, and Mycobacteria atypical infections. In this procedure, the patient breathes hypertonic saline until they produce approximately 5 mL of sputum. The patient should expectorate sputum from the lower respiratory tract, as expectoration of saliva is not helpful. During sputum induction, the respiratory therapist should observe appropriate infection control procedures. Sputum induction is often repeated over 3 days. Induced sputum contains a higher proportion of viable cells compared to spontaneously produced sputum.

Tracheal Aspirate When the patient cannot effectively expel secretions in the airway by coughing, mechanical aspiration may be required. Tracheal aspiration for sputum collection uses a Lukens trap, a plastic collection unit designed for specimens collected from the lungs during suction (Figure 16-20). Patients with artificial airways almost always require suctioning of airway secretions, but some patients without artificial airways may also need suctioning of bronchial secretions. To remove secretions from the upper airway, the clinician can perform oropharyngeal suction with a Yankauer tip or suction catheter. To remove secretions from the lower respiratory tract, the clinician performs nasotracheal suctioning. Box 16-6 outlines the nasotracheal suctioning procedure; Box 16-7 lists possible complications. Patients who require frequent nasotracheal suctioning may benefit from placement of a nasopharyngeal airway to reduce the trauma of repeated catheter insertion. Many patients respond to nasopharyngeal insertion of the catheter with a cough, which effectively removes secretions.

FIGURE 16-20 Lukens trap for sputum collection during tracheal suctioning. Courtesy of Covidien. Used with permission.

BOX 16-6 Procedure for Nasotracheal Suctioning 1. Assess the patient and preoxygenate. 2. Assemble the equipment, and select an appropriate suction pressure. 3. Determine which nasal passage is most patent.

4. Lubricate the suction catheter. 5. Gently insert the catheter through the patient’s nose to the level of the glottis; if obstruction is encountered, use the other nostril. 6. During inspiration, pass the catheter into the trachea. 7. Assess for signs that the catheter is in the trachea—airflow through the catheter (listening over the thumb port), patient coughing. 8. If the catheter is not in the trachea, withdraw it to the level of the pharynx, assess the patient, and re-advance the catheter. 9. Insert the catheter until resistance is met, then withdraw it by 1 to 2 cm, apply suction for 1 to 2 seconds, release the suction, withdraw the catheter several centimeters, and repeat until the catheter is withdrawn from the airway; do not exceed 15 seconds. 10. Assess the patient and determine the need to repeat the procedure.

BOX 16-7 Complications of Nasotracheal Suctioning Trauma to upper airway and pain Hypoxemia Cardiac dysrhythmia, bradycardia, cardiac arrest Hypertension or hypotension Respiratory arrest Uncontrolled coughing Gagging/vomiting Laryngospasm or bronchospasm Nosocomial infection Misdirection of catheter Increased intracranial pressure

Bronchoscopy Diagnostic bronchoscopy is used in combination with bronchoalveolar lavage (BAL) or a protected specimen brush to obtain respiratory secretions for diagnostic purposes. This procedure can be performed in the setting of suspected ventilator-associated pneumonia (VAP). Therapeutic bronchoscopy is used to remove retained secretions, such as in hospitalized patients with new atelectasis or collapse of a lung segment, when less invasive procedures have failed.

Mini-bronchoalveolar Lavage

Mini-bronchoalveolar lavage (mini-BAL) is a nonbronchoscopic bedside method of performing a small-volume BAL with goal of obtaining quantitative culture results to guide antibiotic therapy for patients with suspected VAP. These catheters have a smaller diameter than a bronchoscope, and the lavage volume is smaller—both of which minimize the risk of complications. Some mini-BAL catheters are directional, meaning that they can be directed into one lung versus the other. Some mini-BAL catheters have a polyethylene-glycol plugged tip that protects the inner sampling catheter from contamination (Figure 16-21). The miniBAL procedure typically uses a small lavage volume of 20 to 60 mL in one to three aliquots. Enthusiasm for this technique has waned in recent years after publication of recommendations to use endotracheal aspirate rather than more invasive means (bronchoscopy and mini-BAL) for diagnosis of VAP.41

FIGURE 16-21 (A) Protected catheter for mini-bronchoalveolar lavage (mini-BAL). (B) Catheter tip. The red plug is removed to allow the inner protected catheter to exit. (C) Respiratory therapist performing mini-BAL procedure. (A) Courtesy of Prodimed; (B and C) Courtesy of KOL Bio-Medical Instruments, Inc.

Transtracheal Aspiration With the transtracheal aspiration, or transtracheal wash, technique, the clinician inserts a needle through the skin overlying the trachea and through the cricothyroid ligament. The clinician then introduces a catheter into the trachea and passes it to the level of the tracheal bifurcation. Saline is then injected and withdrawn, with the sample being sent to the laboratory for histologic and microbiologic examination. Stop and Think You are asked for your suggestions to prevent postoperative pulmonary complications in the surgical ward. Would you recommend incentive spirometry? IPPB? Something else?

Respiratory Recap Collection of Sputum for Diagnosis ∎ Cough ∎ Induced sputum ∎ Tracheal aspiration ∎ Bronchoscopy ∎ Mini-bronchoalveolar lavage ∎ Transtracheal aspiration

Lung Expansion Therapy Continuous Positive Airway Pressure Continuous positive airway pressure (CPAP) is an effective lung expansion therapy that can be used with a mask or mouthpiece. Therapy can be administered at a pressure of 5 to 10 cm H2O for 30 minutes every 3 to 4 hours, more frequently if necessary, and continuously in the setting of postoperative respiratory failure. With more severe cases, noninvasive ventilation can be used. EZPAP is a positive airway pressure device that is used as lung expansion therapy (Figure 16-22). It is connected to a flow meter (air or O2), adjusted to a flow of 5 to 15 L/min. EZPAP amplifies the input of air or oxygen by approximately four times by taking advantage of the Coandă effect. Flow is adjusted until the desired expiratory airway pressure is reached. The patient is instructed to breathe normally through a mouthpiece or mask.

FIGURE 16-22 EZPAP device. EZPAP device, Smiths Medical.

Incentive Spirometry Incentive spirometry (IS) is a technique designed to mimic natural sighing or yawning maneuvers, also referred to as sustained maximal inspiration (CPG 16-2).42 Because postoperative patients often adopt a pattern of rapid, shallow breathing, they should be encouraged to take 5 to 10 deep breaths every hour. IS provides patients with sensory feedback to quantify the depth of the breath. IS should provide patients with an objective comparison to the volumes (of flows) they were generating preoperatively, with the goal of attaining or returning to that preoperative volume in spite of the pain experienced. In addition, the IS device instruction should ideally include recording how long breaths were held, how many times the breaths were attempted, and how many times the patient succeeded in meeting his or her volume goals (Box 16-8). CLINICAL PRACTICE GUIDELINE 16-2 Incentive Spirometry

▪

Incentive spirometry alone is not recommended for routine use in the preoperative and postoperative settings to prevent postoperative pulmonary complications.

▪

It is recommended that incentive spirometry be used with deep breathing techniques, directed coughing, early mobilization, and optimal analgesia to prevent postoperative pulmonary complications.

▪

Deep breathing exercises may provide the same benefit as incentive spirometry in the preoperative and postoperative setting to prevent postoperative pulmonary complications.

▪

Routine use of incentive spirometry to prevent atelectasis in patients after upperabdominal surgery is not recommended.

▪

Routine use of incentive spirometry to prevent atelectasis after coronary artery bypass graft surgery is not recommended.

▪

A volume-oriented device should be selected as an incentive spirometry device.

Modified from Restrepo RD, Wettstein R, Wittnebel L, Tracy M. AARC clinical practice guideline: incentive spirometry. Respir Care 2011;56(10):1600–1604. Reprinted with permission.

BOX 16-8 Procedure for Incentive Spirometry 1. Explain to the patient the importance of deep breathing and coughing. 2. Establish the volume goal for incentive spirometry.

3. Assist the patient to a sitting or semi-Fowler position. 4. Instruct or assist the patient to splint the incision when appropriate. 5. Instruct the patient to do the following: a. Place the spirometer on a flat surface or hold it in an upright position. b. Place the lips firmly around the mouthpiece. c. After a normal exhalation, inhale slowly through the mouthpiece, raising the flow/volume indicator while taking as deep a breath as possible. d. Hold the breath for 3 to 5 seconds. e. Remove the mouthpiece and exhale normally. f. Relax and breathe normally for several breaths. g. Repeat the maneuver for 10 breaths each session. 6. Have the patient repeat the series of breaths once each hour while awake. 7. Visit the patient periodically to reinforce the instruction. 8. Document the procedure and the patient’s response in the medical record.

The objectives of IS are to increase transpulmonary pressure and inspiratory volumes to near-preoperative vital capacity, improve inspiratory muscle performance, and reestablish the normal pattern of periodic deep breathing. It should not be used as the sole treatment for major lung collapse or consolidation, but rather as a part of a more comprehensive program of lung re-expansion. Because IS requires patient cooperation, as well as the ability to understand and demonstrate proper use of the device, it is not a viable therapeutic option for the obtunded, confused, or uncooperative patient. Most IS devices direct the patient’s inspiratory flow through a tube to lift one or more light balls (or disks). The higher the patient’s inspiratory flow, the higher the ball is raised or the greater the number of balls that are raised (Figure 16-23). The longer the flow is maintained, the larger the volume is; thus, the patient is encouraged to take slow, deep breaths. Unfortunately, high flows can be generated (with low volumes) to raise the flow indicator to target levels without the patient meeting therapeutic volume or breath-holding objectives.

FIGURE 16-23 (A) Flow-oriented incentive spirometer. (B and C) Commercially available incentive spirometers. (A) Adapted from Eubanks DH, Bone RC. Comprehensive respiratory care. St. Louis: Mosby; 1985; (B) Robert Byron/Dreamstime.com; (C) Courtesy of Teleflex Incorporated. Unauthorized use prohibited.

Evidence suggests that deep breathing alone, without mechanical aids, may be as beneficial as IS in preventing or reversing pulmonary complications, and controversy exists concerning overuse of IS. Mounting evidence suggests that IS may not have a role in the treatment of postoperative patients and should not be used routinely.43

Intermittent Positive Pressure Breathing Intermittent positive pressure breathing (IPPB) consists of short-term or episodic mechanical ventilation for the primary purpose of assisting ventilation and providing short-duration hyperinflation therapy.44 IPPB is usually administered with pneumatically driven, pressure-triggered, and pressure-cycled ventilators (Figure 16-24 and Box 16-9). First described in 1947, IPPB gained popularity in the 1950s as a method to treat and prevent postoperative atelectasis. In the 1960s, IPPB became a popular therapy for patients with pulmonary disease. In the 1970s, it came under scrutiny both scientifically and by healthcare payers. Although IPPB has been used to administer aerosolized medication, it has no advantage over nebulizers or inhalers. IPPB has short-lived mechanical effects, which last an hour or less after the treatment. Efficacy of IPPB for ventilation and aerosol delivery depends on use of the proper technique (e.g., coordination, breathing pattern, selection of appropriate inspiratory flow, peak pressure, inspiratory hold). In addition, efficacy depends on the design of the device (e.g., flow, volume, pressure capability) and on the aerosol output and particle size.

FIGURE 16-24 (A) Vortran® intermittent positive pressure breathing (IPPB) device. (B) Bird Mark 7 for IPPB therapy. (A) Courtesy of VORTRAN® Medical Technology 1, Inc., Sacramento, CA; (B) Courtesy of Dr. Pamela Bird, Percussionaire Corporation.

BOX 16-9 Procedure for Intermittent Positive Pressure Breathing (IPPB) Therapy 1. Assess the need for IPPB, and determine whether another therapy might be equally efficacious or superior. 2. Assemble the necessary equipment. 3. Explain the therapy to the patient. 4. Determine the appropriate interface: mouthpiece, lip seal, or mask. 5. Instruct the patient to do the following: a. Sit comfortably. b. If using a mask, apply it tightly but comfortably over the nose and mouth; if a mouthpiece is used, place the lips firmly around it, and breathe through the mouth. c. Begin breathing to trigger the IPPB machine. d. Allow the machine to passively inflate the lungs to a larger than normal volume. 6. Make appropriate adjustments on the IPPB machine: a. Flow for I:E ratio of approximately 1:3 b. Pressure to deliver an appropriate volume 7. Monitor the inspiratory time, and observe the patient to prevent hyperventilation. 8. Encourage the patient to rest and cough as needed; do not exceed 20 minutes of treatment. 9. Rinse the mouthpiece or mask, nebulizer, and manifold assembly with sterile water. 10. Document the settings used, volume achieved, and patient response.

Assessment of the need for IPPB should include evidence of atelectasis, reduced pulmonary function precluding an effective cough, neuromuscular disorders, or kyphoscoliosis with decreased lung volumes. IPPB may be applicable in situations of fatigue or muscle weakness with impending respiratory failure, in the presence of acute severe bronchospasm, and in COPD exacerbation that fails to respond to other therapy. This therapy should focus on volume, with the clinician adjusting the tidal volume during IPPB to deliver breaths that are at least 25% larger than the patient’s tidal volume. The effects of IPPB can be assessed by improved airway clearance, breath sounds, chest x-ray film,

and dyspnea. IPPB does not appear to have any benefit greater than other lung expansion techniques in spontaneously breathing patients. Its use for lung expansion should be considered only after other alternatives have been exhausted. Respiratory Recap Inflation Therapy ∎ Incentive spirometry ∎ Intermittent positive pressure breathing

Key Points Mucociliary transport normally clears secretions from the lower respiratory tract. Coughing clears secretions in patients with acute and chronic respiratory diseases. Conventional chest physiotherapy comprises postural drainage, percussion, and vibration. Active cycle of breathing technique consists of breathing control, thoracic expansion control, and forced expiratory technique. Autogenic drainage aims to achieve the highest possible airflow in different generations of bronchi to move secretions. Positive expiratory pressure, oscillating positive expiratory pressure, intrapulmonary percussive ventilation, and external chest wall compression are techniques that can be used for airway clearance. Techniques for sputum collection include cough, induced sputum, tracheal aspiration, bronchoscopy, mini-bronchoalveolar lavage, and transtracheal aspiration. Airway suctioning, nasotracheal suctioning, and bronchoscopy are used to mechanically clear secretions from the lower respiratory tract. Incentive spirometry can facilitate deep breathing in postoperative patients. Intermittent positive pressure breathing is used for short-term hyperinflation therapy. Evidence supporting incentive spirometry and intermittent positive airway pressure is weak.

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CHAPTER

17 Airway Management John D. Davies Dean R. Hess

© Andriy Rabchun/Shutterstock

OUTLINE Oropharyngeal Airways Nasopharyngeal Airways Airway Management Training Anatomy of the Upper Airway and Airway Assessment Indications for Endotracheal Intubation Initial Approach to Airway Management Procedure of Endotracheal Intubation The Difficult Airway: Assessment and Strategy Extubation Tracheostomy Airway Cuff Concerns Airway Clearance

OBJECTIVES 1. 2. 3. 4.

Demonstrate use of manual airway maneuvers. Compare oropharyngeal and nasopharyngeal airways. Demonstrate the techniques for inserting oropharyngeal and nasopharyngeal airways. Describe the construction of an endotracheal tube.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Identify key roles and responsibilities for the airway management team. Describe the technique for orotracheal and nasotracheal intubation. Demonstrate the technique used to secure an endotracheal tube. Demonstrate the technique used to measure cuff pressure. Discuss the approach to evaluation and management of the difficult airway. Compare conventional and percutaneous tracheostomy. Compare various designs of tracheostomy tubes. Compare conventional and closed suction catheters. Describe techniques used to prevent complications from suctioning. Discuss the important points of extubation and decannulation.

KEY TERMS airway cuff bite block cricothyrotomy decannulation endotracheal intubation endotracheal tube extraglottic airway extubation gum elastic bougie laryngeal mask airway (LMA) laryngoscope nasopharyngeal airway nasotracheal intubation oropharyngeal airway orotracheal intubation speaking valve suction catheter team resource management tracheostomy tube tube exchanger video laryngoscope

Introduction Airway management is an important aspect of respiratory care. Manual airway maneuvers, intubation, and airway maintenance can be high-risk and unpredictable procedures, underlining the importance of a thoughtful, interdisciplinary approach to maximize patient outcomes and safety. This chapter provides a systematic overview of the planning, preparation, teamwork, and technical skills required to effectively care for patients with airway issues.

Oropharyngeal Airways The oropharyngeal airway is useful to promote airway patency in patients without a gag reflex. This device is inserted into the patient’s mouth between the lips and teeth and extends from the lips to the pharynx, following the natural curvature of the tongue and palate, without entering the larynx or esophagus (Figure 17-1). Oropharyngeal airways are usually made of hard plastic and are relatively rigid. They generally consist of a flange, a bite portion (body), and an air channel. The flange at the mouth opening prevents the airway from falling back and obstructing the airway. It also provides a means to stabilize the patient’s jaw against the lips or teeth. The bite portion, which fits between the upper and lower teeth or gums, is straight and firm enough to prevent the patient from obstructing airflow by biting down. A flange at the proximal end helps stabilize the oropharyngeal airway and prevent it from slipping too far into the airway. The air channel, or curved portion, extends upward and backward along the curve of the tongue, pulling it and the epiglottis away from the posterior pharyngeal wall to improve airway patency.

FIGURE 17-1 Oropharyngeal airway in place.

Oropharyngeal airways are designed to open and stabilize the airway by preventing the tongue from falling into the hypopharynx, thereby partly or completely obstructing the upper airway. Use of an oropharyngeal airway may be indicated during mask or mouth-to-tube ventilation. Oropharyngeal airways allow ready access to the mouth and pharynx for suctioning and may be inserted instead of a bite block to prevent a patient from biting an oral endotracheal tube. These airways also may help optimize mask ventilation by improving airway patency. It is important to note that because of its placement location, an oropharyngeal airway may gag a semicomatose or an alert patient, which could induce vomiting and increase the risk of aspiration. Respiratory Recap Oropharyngeal Airways

∎ Prevent upper airway obstruction ∎ May be used as a bite block ∎ May make mask ventilation more effective ∎ Should not be used in semicomatose or alert patients

Types The Berman airway (Figure 17-2) has a flange at the oral end, a rigid support beam through the center, and open sides. The open sides allow for suctioning and serve as air channels. The center may have openings for suctioning if the airway becomes lodged sideways in the patient’s mouth. Advantages of the Berman airway include the ease of cleaning the device and the dual side air channels, which are less likely to be obstructed by mucus or foreign bodies. Because the Berman airway is uniformly rigid throughout, it is less susceptible to airway occlusion by a patient’s bite than is the Guedel airway.

FIGURE 17-2 Berman airway. © deepspacedave/Shutterstock.

The Guedel airway (Figure 17-3) has a large flange at the oral end and a supportive bite section. The curved portion of this device that follows the curve of the tongue is made of a semirigid material. The

Guedel airway differs from the Berman airway in that it is reinforced only in the bite region. This may pose a problem if a patient bites down on the Guedel airway before it is completely inserted, which both prevents complete insertion and may lead to occlusion of the airway by the unreinforced portion. The Guedel airway also differs from the Berman airway in that it has an enclosed tubular channel to facilitate air exchange and suctioning.

FIGURE 17-3 Guedel airway. Courtesy of Smiths Medical.

Insertion Assess the patient for proper sizing before inserting an oropharyngeal airway. When the device is placed on the patient’s cheek with the flange parallel to his or her front teeth, the tip of the oropharyngeal airway should reach no farther than the pinna of the ear (Figure 17-4). If the oropharyngeal airway selected is too large, its tip may press the epiglottis against the posterior pharyngeal wall or the larynx, obstructing both the device and the patient’s airway. If the airway is inserted improperly or is too small, the tongue may be pushed against the posterior pharynx, causing airway obstruction. Oropharyngeal airways come in a variety of different sizes to accommodate adults, children, and infants (Figure 17-

5).

FIGURE 17-4 Sizing the oropharyngeal airway.

FIGURE 17-5 Different sizes of Guedel airways. Courtesy of BV Medical, http://bvmedical.com/.

To insert an oropharyngeal airway, stand at the patient’s head, hyperextend the head and neck, and use the cross-finger technique to open the mouth (Figure 17-6). Turn the airway 180 degrees from its resting position as it passes over the tongue to avoid pushing the tongue back into the pharynx. When the tip of the airway reaches the uvula, rotate the airway 180 degrees so that the tip is positioned behind the tongue and facing the larynx (Figure 17-7A). An alternative insertion method is to insert the airway from the lateral aspect of the mouth, followed by a 90-degree rotation to the position in which it will rest (Figure 17-7B). Once it is in place, assess the airway for proper size and position by determining whether it facilitates unobstructed breathing.

FIGURE 17-6 Cross-finger technique to open the mouth. © Jones & Bartlett Learning. Courtesy of MIEMSS.

FIGURE 17-7 (A) Anti-anatomic insertion of an oral airway. (B) Insertion of an oral airway from the side of the mouth. (A) © Jones & Bartlett Learning. Courtesy of MIEMSS; (B) adapted from Cairo JM, Pilbeam SP. Mosby’s respiratory care equipment. 7th ed. St. Louis: Mosby; 2004.

Complications The major risks associated with oropharyngeal airway placement are regurgitation and aspiration. Oropharyngeal airways can also cause coughing and laryngospasm in the awake patient. Coughing and laryngospasm are likely to occur when the device is too long and comes into contact with the epiglottis or vocal cords. Teeth can also be broken or torn forcibly from the mouth if the patient bites down on the oral airway. Oropharyngeal airways should be used judiciously if the patient has dental disease, decay, caps, crowns, and other dental appliances. In such cases, a nasopharyngeal airway or bite block may be indicated instead. When the oropharyngeal airway is in place, the patient’s lip may also be damaged if the airway becomes pinched between the teeth and the airway. In the comatose patient, continuous chewing motions may

damage the tongue. Pressure necrosis of the tongue may potentially occur if the airway is left in place for a prolonged period. Frequent assessment of the oropharyngeal airway and patient will minimize the chances of these types of complications.

Nasopharyngeal Airways The nasopharyngeal airway (Figure 17-8) is an alternative to the oropharyngeal airway. This type of airway is inserted into the nose and directed along the floor of the nose parallel to the hard palate. Its curved structure follows the anatomy of the nasopharynx so that the tip rests behind the tongue, just above the epiglottis. Nasopharyngeal airways are made of plastic or rubber and resemble a shortened endotracheal tube. All types have some degree of flange at the nasal end to facilitate insertion and prevent accidental aspiration of the tube. To determine the proper length of airway, the clinician measures the distance from the tip of the patient’s nose to the meatus of the ear or from the tip of the nose to the tragus of the ear plus 2 cm (Figure 17-9).

FIGURE 17-8 Nasopharyngeal airway. Courtesy of Smiths Medical.

FIGURE 17-9 Sizing the nasopharyngeal airway.

The nasopharyngeal airway can be an alternative to the oropharyngeal airway to help maintain airway patency. In some situations, the patient’s mouth cannot be opened, an active gag reflex limits the use of an oral airway (and actually can lead to vomiting and aspiration), or an oral airway fails to relieve the obstruction. A nasopharyngeal airway is better tolerated and more comfortable than an oropharyngeal airway in a semi-awake patient, and it eliminates the risk of tongue and tooth trauma. Nasopharyngeal airways can provide easy access to the trachea for nasotracheal suctioning and protect the nasopharyngeal mucosa from the traumatic effects of repeated nasotracheal suctioning. Such an airway may also serve as a conduit for oxygenation during bronchoscopy if an upper airway obstruction arises during the procedure. Respiratory Recap Nasopharyngeal Airways ∎ May be used to bypass an upper airway obstruction ∎ Reduce trauma caused by repeated nasotracheal suctioning

Insertion Nasopharyngeal airways, like oropharyngeal airways, come in a variety of sizes. After ensuring proper measurement lubricate the nasopharyngeal airway with a water-soluble gel. The airway is introduced into the naris, with the end pointed parallel to the hard palate. It is advanced gently, so as to prevent trauma and bleeding (Figure 17-10). If resistance is met, redirect the airway. In case of excessive resistance, the attempt should be aborted, and repeat attempts should be made either through the other nostril or using a smaller airway.

FIGURE 17-10 Insertion of a nasopharyngeal airway. © Jones & Bartlett Learning. Courtesy of MIEMSS.

Complications Incorrect sizing of a nasopharyngeal airway carries risks. Laryngospasm and coughing can be induced by insertion of a too-long nasopharyngeal airway that comes in contact with the epiglottis or vocal cords. Epistaxis can occur from insertion of a nasopharyngeal airway, particularly if it is too large, and excessive force can also result in lacerations to the superior aspect of the soft palate. These airways should be used with caution in patients with low platelet counts or undergoing anticoagulation therapy because excessive bleeding can occur. Improper insertion of nasopharyngeal airways may damage the turbinate, and insertion of a nasopharyngeal airway into a patient who is draining blood or cerebrospinal fluid may cause infection. Prolonged use of this airway may result in sinus infection. In patients with severe facial or head trauma,

insertion of a nasopharyngeal airway may result, in rare cases, in cranial vault intubation—this risk is greatest in patients with basilar skull fractures. As when oropharyngeal airways are used, assess both the patient and the nasopharyngeal airway on a regular basis. Stop and Think A patient needs an artificial airway and intubation equipment is not readily available. The patient does not arouse but does cough. Which airway would you use?

Airway Management Training Understanding the concepts of airway management and becoming proficient in the techniques used to establish and maintain a patent airway are paramount in the practice of respiratory care. The airway should never be taken for granted. At times, a simple manual maneuver to reestablish a patent airway may prove to be lifesaving. The major objectives of airway training are to (1) recognize the need for airway management; (2) properly identify airway anatomy and identify high-risk patients; (3) develop skills in mask ventilation, laryngoscopy, and intubation; (4) develop strategies for the difficult airway; and (5) maintain ongoing proficiency in airway management. The literature offers little guidance on who should manage the airway; as a result, regional practices vary considerably. In surgical areas, anesthesiologists and certified registered nurse anesthetists usually manage the airway. In the nonhospital setting, most regions are comfortable with paramedics performing endotracheal intubation. Airway management of hospitalized patients outside of the operating room is generally considered high risk, with an approximately 10% incidence of difficult airways and higher complication rates even in the hands of experienced airway managers.1,2 In support of current guidelines, a growing body of literature demonstrates that an interdisciplinary team approach to airway management that emphasizes airway assessment, preoxygenation, and a preplanned airway management strategy can maximize intubation success and significantly reduce both patient complications and the need for surgical airways.3–5 Respiratory therapists are essential members of the airway management teams and frequently serve as the primary airway manager in the absence of more highly trained personnel. The National Board for Respiratory Care (NBRC) includes endotracheal intubation in its examination outline for registered respiratory therapists, and most respiratory therapy training programs instruct their students in the technique of endotracheal intubation. Opportunities to practice intubations tend to be limited in the clinical setting, prompting many programs to provide learners with initial training, which is then followed by a controlled experience performing 10 to 15

intubations in the operating room closely supervised by an anesthesiologist. After the operating room experience, a set number of supervised intubations are generally required before a trainee is considered competent in airway management. The number of intubations required to reach competence depends greatly on the experience level and psychomotor skills of the learner and the training received. The use of a videolaryngoscope to assist in initial airway instruction may accelerate progression to competence based on other small studies, possibly because this tool provides learners with better visualization and subsequent understanding of anatomic structures involved in the procedure.6,7 Incorporating simulation-based training improves learner satisfaction and confidence with airway management skills but has not been clearly associated with more rapid psychomotor proficiency in these procedures even when human cadavers have been employed.8 Evolving evidence supports the use of a simulated clinical environment to build teamwork skills and gain experience with a systematic approach to patient and equipment preparation using realistic clinical scenarios. A carefully designed iterative performance improvement program in airway management showed that a combined team approach, which included intensive simulation-based airway skills for physicians, team resource management training, use of a mandatory checklist during each intubation, and postevent debriefing, significantly improved the safety of airway management in that facility.5 Skill decay is a concern in hospitals where intubations are not commonplace, and lack of regular participation in procedures may lead to competency erosion. Trained respiratory therapists should perform at least 10 intubations per year to be requalified or should undergo a repeat training course. If the need for intubation outside the operating room arises only infrequently, training may be limited to supervisors or designated members of the airway or code team to ensure their continued competence. Respiratory Recap Healthcare Workers Who Perform Endotracheal Intubation ∎ Anesthesia personnel (anesthesiologists and nurse anesthetists)

∎ Critical care and emergency physicians ∎ Paramedics ∎ Respiratory therapists

Anatomy of the Upper Airway and Airway Assessment A thorough understanding of basic upper airway anatomy is essential to airway management, regardless of the technique used. The airway consists of five regions: the nose and nasopharynx, oral cavity and oropharynx, hypopharynx, larynx, and tracheobronchial tree (Figure 1711).

FIGURE 17-11 Anatomy of the upper airway.

The nose and nasopharynx region consists of the nasal cavity, turbinates, nasal septum, and adenoids. These nasopharyngeal structures primarily function to warm, humidify, and filter inspired air; the region’s large mucosal surface area and rich blood supply make them well suited to these tasks. The ethmoid artery and the maxillary artery

provide the vascular supply to the nasopharyngeal area. Sensory innervation is supplied by the trigeminal nerve through the pterygopalatine branches of the maxillary division. The nasal cavity includes openings to the paranasal sinuses, so drainage of these sinuses may be interrupted if they are occluded by an endotracheal tube or nasogastric tube, resulting in sinusitis. Endotracheal intubation also interferes with the sense of olfaction. The oral cavity and oropharynx consist of the teeth, tongue, buccal mucosa, faucial pillars, hard palate, soft palate, uvula, tonsils, and posterior pharyngeal wall. Functionally these structures are important for mastication, taste, phonation, humidification, and warming of inspired gas. As swallowing occurs, the soft palate closes the inferior aspect of the nasopharynx. The oropharynx has a rich mucosal blood supply, and innervation is complex, involving mandibular branches of the trigeminal, facial, and glossopharyngeal nerves. The mandible houses the tongue, and the temporomandibular joint (TMJ) determines the ability to mobilize these structures. Reduced TMJ mobility may make direct laryngoscopy difficult or impossible. Prominent upper incisors may also impede glottis visualization using direct laryngoscopy. Remove any dental appliances prior to intubation attempts to prevent damage and possible migration of these devices into the trachea. The hypopharynx (laryngopharynx) is located below the oropharynx and above the larynx; it is an extension of the oropharynx. This area contains the epiglottis and the opening to the esophagus. A laryngeal mask airway seats in this area. The larynx is a complex structure composed of nine cartilages, seven muscles, and the vocal ligaments (Figure 17-12). The space between the vocal cords is the glottis; in adults this is the narrowest part of the upper airway, whereas in children the narrowest point is the cricoid ring. The vocal cords protect the lower airway from aspiration of foreign objects and allow phonation. The cartilaginous structures and complex muscle groups of the larynx are responsible for the intricate vocal abilities of human beings. Nerve or muscle damage can result in a damaged or paralyzed vocal cord, which can increase the risk of aspiration and present additional challenges to avoid damage during intubation.

FIGURE 17-12 Anatomy of the larynx.

Age-Specific Angle In adults, the glottis is the narrowest point of the upper airway. In children, the cricoid ring is the narrowest point.

The trachea is located inferior to the larynx, starting just below the cricoid ring. C-shaped cartilaginous rings connected by fibromuscular tissue extend approximately 10 to 12 cm to where the trachea bifurcates

into the left and right main stem bronchi at the carina. The carina usually is located at the level of the fourth thoracic vertebra. Posteriorly the tracheal cartilage rings are incomplete and are bridged by a membranous wall formed by a longitudinal fibromuscular band. This allows for inward expansion of the trachea when food traverses down the esophagus.

Indications for Endotracheal Intubation Conditions requiring airway management include respiratory failure due to inadequate oxygenation and/or ventilation, the need for airway protection due to obstruction, and inability to maintain a patent airway due to other patient factors (e.g., depressed level of consciousness and the subsequent risk of aspiration). In addition to providing an intact airway conduit, artificial airways can facilitate airway secretion clearance and hyperventilation in the setting of increased intracranial pressure and herniation. Box 17-1 lists specific conditions that require emergency endotracheal intubation. BOX 17-1 Indications for Emergency Intubation Persistent apnea Traumatic upper airway obstruction Accidental extubation of a patient unable to maintain adequate spontaneous ventilation Obstructive angioedema Massive uncontrolled upper airway bleeding Coma with potential for increased intracranial pressure Infection-related upper airway obstruction (e.g., epiglottitis, acute uvular edema, tonsillopharyngitis or retropharyngeal abscess, supportive parotitis) Laryngeal and upper airway edema Absence of airway protective reflexes Cardiopulmonary arrest Massive hemoptysis Neonatal or pediatric disorders (e.g., perinatal asphyxia, severe tonsillar hypertrophy, severe laryngomalacia, bacterial tracheitis, neonatal epignathus, obstruction from abnormal laryngeal closure caused by arytenoid masses, mediastinal tumors, congenital diaphragmatic hernia, thick and/or particulate meconium in the amniotic fluid) Reproduced from Hess DR. Indications for translaryngeal intubation. Respir Care 1999;44(6):604–609. Reprinted with permission.

Maintaining a patent airway is a vital and most basic intervention, without which meaningful survival is impossible. Endotracheal intubation remains the gold standard for establishing a definitive artificial airway. However, both extraglottic devices and surgical airways can serve as effective temporizing bridges in an emergency situation when patient oxygenation and ventilation are compromised.

Noninvasive ventilation (NIV) and continuous positive airway pressure (CPAP) can be used to effectively manage patients with self-limited conditions, such as exacerbations of chronic obstructive pulmonary disease (COPD) or congestive heart failure, without the use of an endotracheal tube.9–11 Endotracheal intubation, however, remains the preferred initial management in these patients in the setting of significant alterations of consciousness, hemodynamic instability, severe derangements of oxygenation or ventilation, or a failure to improve with noninvasive therapy. When high oxygen concentrations are required to correct hypoxemia, placement of an endotracheal tube may be necessary. Most oxygen delivery devices fall short of providing a 100% oxygen concentration because of air entrainment caused by poorly fitting devices or inadequate flow delivery. Tight-fitting masks work well for high oxygen delivery if the inspiratory flows are high enough, but patients find these devices uncomfortable and often remove them, causing the FIO2 to drop to potentially dangerous levels. When high oxygen concentrations are needed, administration is usually required for several hours; in this case, positive pressure through an endotracheal tube can reduce the levels of inspired oxygen. Aspiration is a major mechanism for pneumonia and respiratory failure and can result in significant morbidity and mortality. Although not completely effective, placement of an endotracheal tube in the trachea minimizes the risk of large-volume aspiration in the setting of a patient with a decreased level of consciousness (Glasgow Coma Scale score 95% or PaO2 > 100 mm Hg) might contribute to higher mortality in critically ill patients. Although the underlying mechanism remains to be elucidated, this relationship suggests that clinicians should avoid hyperoxemia in critically ill mechanically ventilated patients.19

Ventilator-Associated Pneumonia An endotracheal tube compromises the natural laryngeal mechanism that protects the lower respiratory tract from aspiration. This permits oropharyngeal debris to leak into the airways, even in the presence of a cuff seal. The endotracheal tube also impairs the cough reflex and serves as a potential portal for pathogens to enter the lungs. The underlying disease process also makes the lungs prone to infection. In addition, heavy antibiotic use in the ICU and the presence of very sick patients in close proximity are risk factors for antibiotic-resistant infection. In the past, ventilator-associated pneumonia (VAP) prevention strategies were considered important. However, mortality attributable to VAP is low, and VAP is only one factor affecting adverse outcomes during mechanical ventilation. Traditional VAP prevention strategies include hand washing, elevating the head of the bed, oral care, and carefully choosing antibiotic regimens. However, the supporting evidence for these practices is weak and sometimes contradictory. Endotracheal tubes that provide continuous drainage of subglottic secretions, specialized cuff designs, and tubes made with antimicrobial materials can reduce lung contamination with oropharyngeal material. Their effects on important outcomes remain controversial, however, and their costs can be high.20 More recently, surveillance of ventilator-associated events (VAE) has been recommended, related to a sustained increased in FIO2 and/or PEEP. Patients with VAE spend more time on the ventilator and are approximately twice as likely to die in the hospital. Thus, avoidance of VAE has important implications for patient outcomes. Potential strategies

to prevent VAE focus on decreasing the duration of mechanical ventilation such as by minimizing sedations, pairing spontaneous awakening and spontaneous breathing trial, ensuring low tidal volume ventilation, providing conservative fluid management, and supporting early mobilization.21 Respiratory Recap Types of Ventilator-Induced Lung Injuries ∎ Volutrauma ∎ Atelectrauma ∎ Biotrauma ∎ Oxygen toxicity

Auto-PEEP Auto-PEEP (also known as intrinsic PEEP or air trapping) is the result of the lungs not returning to the baseline proximal airway pressure at endexhalation.22 The determinants of auto-PEEP are high minute volume, a long inspiratory-to-expiratory time relationship, and a long expiratory time constant (i.e., obstructed airways and high-compliance alveolar units). Because it results in dynamic hyperinflation, auto-PEEP increases intrathoracic pressure, which can affect gas delivery, hemodynamics, end-inspiratory distention (and thus VILI), and patient breath triggering. Although sometimes desired in ventilatory strategies that rely on long inspiratory time, auto-PEEP should generally be avoided because it is difficult to recognize and to predict its effects.

Hemodynamic Effects of Positive Pressure Ventilation Because positive pressure ventilation increases intrathoracic pressure, it can reduce venous return and increase right ventricular afterload, which may result in decreased cardiac output and a drop in arterial blood pressure. Fluid administration and drug therapy (such as with vasopressors and inotropes) may be necessary to maintain cardiac

output, blood pressure, and urine output under these circumstances. Mechanical ventilation can also cause an increase in plasma antidiuretic hormone (ADH) and a decrease in atrial natriuretic peptide (ANP), which may reduce urine output and promote fluid retention. The effects of reduced filling on cardiac output may be partially counteracted by better left ventricular function due to elevated intrathoracic pressures, which reduce left ventricular afterload. In patients with fluid overload and left heart failure, the reduced cardiac filling and reduced left ventricular afterload effects of elevated intrathoracic pressure may actually improve cardiac function, such that intrathoracic pressure removal may produce left ventricular failure. Intrathoracic pressure can also influence distribution of perfusion, as described by the West model of pulmonary perfusion. In the human lung, blood flow is greatest in gravity-dependent zone 3. As intra-alveolar pressure rises, blood flow in zone 2 and zone 1 (dead space) regions increases, creating high ventilation-perfusion ( ) units. Dyspnea, anxiety, and discomfort associated with inadequate ventilatory support can lead to stress-related catecholamine release, with subsequent increases in myocardial oxygen demands and risk of dysrhythmias. In addition, coronary blood flow is compromised by inadequate gas exchange from the lung injury coupled with low mixed venous PO2 due to high oxygen consumption demands by the inspiratory muscles. Respiratory Recap Indications for and Complications of Mechanical Ventilation ∎ Mechanical ventilation supports gas exchange in patients with acute respiratory failure. ∎ A number of complications are possible with mechanical ventilation, and healthcare providers must strive to minimize these complications.

Ventilator Settings Volume Control Versus Pressure Control The ventilator controls either flow or pressure with each breath delivery. Although many breath types exist on modern ventilators, they all derive from ventilator control of either flow (volume) or pressure during the inspiratory phase. With volume control (VC), the ventilator controls the inspiratory flow (Figure 20-5). The flow and inspiratory time settings determine the tidal volume. In practice, however, the flow and tidal volume are set on the ventilator. Because flow and volume delivery are fixed with VC, airway pressure varies with changes in resistance and compliance. Flow and tidal volume represent the independent variables, and pressure is the dependent variable. With VC, the tidal volume is delivered regardless of patient effort, resistance, or compliance, provided that the high-pressure alarm limit is not reached, and the peak airway pressure varies (Box 204). VC should be used whenever a constant tidal volume is important in the maintenance of a desired PaCO2. Because inspiratory flow is fixed, VC can be associated with patient–ventilator asynchrony, particularly if the inspiratory flow is set too low. With VC, the set flow can be constant or a descending ramp. A descending ramp flow pattern produces a longer inspiratory time unless the peak flow is increased.

FIGURE 20-5 (A) Constant-flow (square wave) volume control. (B) Descending ramp flow with volume control.

BOX 20-4 Factors That Affect Peak Inspiratory Pressure (PIP) with Volume Control Peak inspiratory flow setting: A higher flow setting increases the PIP. Inspiratory flow pattern: PIP is lower with descending ramp flow. Positive end-expiratory pressure (PEEP): An increase in PEEP increases the PIP. Auto-PEEP: Auto-PEEP increases the PIP. Tidal volume (VT): An increase in VT results in a higher PIP. Resistance: Greater airways resistance results in a higher PIP. Compliance: Decreased compliance results in a higher PIP.

Respiratory Recap Volume Control Versus Pressure Control ∎ Volume control: Tidal volume remains constant with changes in respiratory mechanics or effort, but airway and plateau pressures can fluctuate. ∎ Pressure control: Tidal volume fluctuates with changes in respiratory mechanics or effort, but pressure is limited to the peak pressure set on the ventilator.

With PC (Figure 20-6), airway pressure is set and remains constant despite changes in effort, resistance, and compliance. The pressure set is the independent variable, and the flow and tidal volume are the dependent variables. Box 20-5 lists factors that affect the tidal volume with PC. PC generally prevents localized alveolar overdistention with changes in resistance and compliance, because the peak alveolar pressure cannot exceed the pressure set on the ventilator. Remember that patient effort during PC can result in additional tidal volume and endinspiratory transpulmonary pressure.

FIGURE 20-6 Pressure control.

BOX 20-5 Factors That Affect Tidal Volume (VT) with Pressure Control Driving pressure: A higher difference between peak inspiratory pressure and PEEP increases VT. Auto-PEEP: An increase in auto-PEEP reduces the VT. Inspiratory time: An increase in inspiratory time increases the VT if inspiratory flow is present; after flow decreases to zero, further increases in the time do not affect the VT. Compliance: Decreased compliance decreases the VT. Resistance: Increased resistance decreases the VT; after flow decreases to zero, resistance no longer affects the delivered VT. Patient effort: Greater inspiratory effort increases the VT.

Because the flow can vary with PC, these breaths might improve patient–ventilator synchrony during patient-triggered breaths in some

patients,23 but this benefit is limited during attempts to constrain the tidal volume during lung-protective ventilation.24 The choice of VC or PC is often determined by clinician or institutional bias, and both modes have advantages and disadvantages (Table 20-1).25,26 Whichever breath type is chosen, the principles of lung-protection ventilation should be observed —namely, volume and pressure limitation with appropriate levels of PEEP. TABLE 20-1 Advantages and Disadvantages of Volume Pressure Control Type

Advantages

Disadvantages

Volume control

Constant tidal volume (VT) with changes in resistance and compliance Type of ventilation familiar to most clinicians

Increased Pplat with decreasing compliance (alveolar overdistention) Fixed inspiratory flow may cause flow mismatch

Pressure control

Reduced risk of overdistention with changes in compliance Variable flow improves flow matching in some patients

Changes in VT with changes in resistance, compliance, and effort Less familiar type of ventilation for some clinicians

Ventilator Modes Options for breath delivery are referred to as modes of ventilation.27 Traditional modes include continuous mandatory ventilation (CMV), also called assist-control (A/C); synchronized intermittent mandatory ventilation (SIMV); and pressure support (PS). The choice of mode often is based on institutional policy or the clinician’s bias. No one mode is clearly superior; each has its advantages and disadvantages (Table 20-2). TABLE 20-2 Advantages and Disadvantages of Common Modes of Mechanical Ventilation

Mode of Ventilation

Advantages

Disadvantages

Continuous mandatory ventilation (CMV) (assist/control)

Guaranteed volume (or pressure) with each breath Low patient workload if sensitivity and inspiratory flow are set correctly

High mean airway pressure Respiratory alkalosis and autoPEEP if the patient triggers breaths at a rapid rate Respiratory muscle atrophy possible

Synchronized intermittent mandatory ventilation (SIMV)

Lower mean airway pressure Prevents respiratory muscle atrophy

Asynchrony if rate is set too low High work of breathing with older ventilators

Pressure support (PS)

Variable flow may improve synchrony in some patients Overcomes tube resistance Prevents respiratory muscle atrophy

Requires spontaneous respiratory effort Fatigue and tachypnea when PS is set too low Activation of expiratory muscles when PS is set too high

Adaptive pressure control

Ventilator maintains tidal volume with changes in respiratory system mechanics Variable flow may improve synchrony in some patients

Does not precisely control tidal volume Support is taken away if the patient’s tidal volume consistently exceeds the target

Adaptive support ventilation (ASV)

Ventilator adapts settings to the patient’s physiology

May not precisely control tidal volume

Airway pressure release ventilation (APRV)

Allows spontaneous breathing at any time during the ventilator cycle May improve ventilation to dependent lung zones May improve oxygenation in patients with ARDS

May be uncomfortable for some patients May result in large tidal volumes, depending on Phigh – Plow difference Large transpulmonary pressure swings may occur during spontaneous breathing

Tube compensation (TC)

Overcomes resistance through artificial airway

Effect is usually small and may not affect patient outcomes

Proportional assist ventilation (PAV)

Pressure applied to the airway is determined by respiratory drive and respiratory mechanics

Not useful with weak drive or weak respiratory muscles Clinician has little control over

tidal volume or respiratory rate Neurally adjusted ventilatory assist (NAVA)

Pressure applied to the airway is determined by diaphragm activity

Requires insertion of a special gastric tube to measure diaphragm EMG Not useful with weak respiratory drive or motor neuron disease

ARDS, acute respiratory distress syndrome; EMG, electromyelogram; Phigh, high airway pressure setting; Plow, pressure release level; PEEP, positive end-expiratory pressure.

CMV (or A/C) delivers VC or PC (could be adaptive pressure control with a volume target) and a set minimum respiratory rate (Figure 20-7). The patient can trigger additional breaths above the minimum rate, but the set volume or pressure and the inspiratory time remain constant. When mechanical ventilation is initiated, it often is best to use CMV (A/C) to produce nearly complete respiratory muscle rest (i.e., full ventilatory support). Regardless of the mode used, the goal is to strike a balance between excessive respiratory muscle rest, which promotes atrophy, and excessive respiratory muscle activity, which promotes fatigue. Put simply, the clinician seeks to avoid the extremes of too much rest or too much exercise.

FIGURE 20-7 Continuous mandatory ventilation illustrating ventilator-triggered and patienttriggered breaths.

Continuous positive airway pressure (CPAP) is a spontaneous breathing mode that maintains a constant positive pressure throughout the breathing cycle (Figure 20-8). CPAP is commonly used as a means of maintaining alveolar recruitment in mild to moderate forms of pulmonary edema and parenchymal lung injury. Clinicians may use this mode to evaluate a patient’s ability to breathe spontaneously before attempting extubation.

FIGURE 20-8 Continuous positive airway pressure.

Pressure support (PS) is a breathing mode in which the patient’s spontaneous effort is augmented by a clinician-determined level of pressure (Figure 20-9).28 Although the clinician sets the level of pressure support, the patient establishes the respiratory rate and inspiratory flow. Inspiratory time is determined by a flow cycle mechanism. The pressure support level, the amount of patient effort, the flow cycle criteria, and the resistance and compliance of the respiratory system determine VT.

FIGURE 20-9 Pressure support.

PS is a frequently used mode of mechanical ventilation. Because it is patient triggered, however, it is not an appropriate mode for patients who do not have an adequate respiratory drive. PS normally relies on flow cycling, combined with secondary cycling mechanisms of pressure and time. Although often considered a simple mode of ventilation, PS can be quite complex (Figure 20-10). First, the ventilator must recognize the patient’s inspiratory effort, which depends on the ventilator’s trigger sensitivity and the amount of auto-PEEP. Second, the ventilator must deliver an appropriate flow at the onset of inspiration. A too-high flow can produce a pressure overshoot, whereas a too-low flow can result in patient flow starvation and asynchrony. Third, the ventilator must appropriately cycle to the expiratory phase without the need for active exhalation.

FIGURE 20-10 Design characteristics of a pressure-supported breath. In this example, baseline pressure (i.e., PEEP) is set at 5 cm H2O, and pressure support is set at 15 cm H2O (PIP 20 cm H2O). The inspiratory pressure is triggered at point A by a patient effort resulting in an airway pressure decrease. Demand valve sensitivity and responsiveness are characterized by the depth and duration of this negative pressure. The rise to pressure (line B) is provided by a fixed high initial flow delivery into the airway. Note that if flows exceed patient demand, initial pressure exceeds the set level (B1), whereas if flows are less than patient demand, a very slow (concave) rise to pressure can occur (B2). The plateau of pressure support (line C) is maintained by servo control of flow. A smooth plateau reflects appropriate responsiveness to patient demand; fluctuations indicate less responsiveness of the servo mechanisms. Termination of pressure support occurs at point D, which should coincide with the end of the spontaneous inspiratory effort. If termination is delayed, the patient actively exhales (bump in pressure above plateau) (D1); if termination is premature, the patient will have continued inspiratory efforts (D2). Reproduced from McIntyre N, Nishimura M, Usada Y, Tokioka H, Takezawa J, Shimada Y. The Nagoya conference on system design and patient–ventilator interactions during pressure support ventilation. Chest 1990;97(6):1463–1466. Used with permission from the American College of Chest Physicians.

The flow at which the ventilator cycles to the expiratory phase during PS can be a fixed absolute flow, a flow based on the peak inspiratory flow, or a flow based on peak inspiratory flow and elapsed inspiratory time. With airflow obstruction, the inspiratory flow decreases slowly during PS, and the flow necessary to cycle may not be reached. This can result in excessive inspiratory time and auto-PEEP or active exhalation to pressure cycle the breath. The problem increases with higher levels of PS and with higher levels of airflow obstruction. On many ventilators, the clinician can adjust the flow cycle criteria to a level appropriate for the patient (Figure 20-11).

FIGURE 20-11 Effect of changing the flow termination criteria (cycle-off flow as a percentage of peak flow) during pressure support. Note the effect on inspiratory time.

Another concern that arises with PS is leaks, such as with a bronchopleural fistula, uncuffed airway, or mask leak with noninvasive ventilation. If the leak exceeds the termination flow at which the ventilator cycles, either active exhalation occurs to terminate inspiration or the ventilator applies a prolonged inspiratory time. With a leak, the clinician should use either PC or a ventilator that allows for adjusting termination flow. Another option is to set a maximum inspiratory time during PS such that the breath can be time cycled at a clinician-determined setting. This secondary cycle typically has been fixed at a time to prevent untoward

effects of long inspiratory times. Note that this is identical to using PC with the set rate set very low, in which case all breaths are patient triggered, pressure limited, and time cycled. Some new ventilators allow the clinician to set both the flow cycle and the time cycle. The flow at the onset of the inspiratory phase may have important implications for PC or PS. Rise time encompasses the time required for the ventilator to reach the set pressure at the onset of inspiration. Flows that are too high or too low at the onset of inspiration can cause asynchrony. For example, with a high inspiratory flow at the onset of inspiration, the inspiratory phase may be prematurely terminated during PS if the ventilator cycles to the expiratory phase at a flow that is a fraction of the peak inspiratory flow. Most ventilators allow adjustment of the pressure rise time during PS and PC (Figure 20-12). Rise time should be adjusted to maintain patient comfort. Ventilator graphics may assist the clinician in selecting this setting, with the target being a smooth square wave of inspiratory pressure.

FIGURE 20-12 Effect of changing rise time during pressure support. Note the effect on peak flow.

Sleep fragmentation may be more likely during PS than during CMV because of the lack of a backup rate.29 Central apnea during PS results in an alarm, which awakens the patient. The pattern of awakening and breathing with sleeping and apnea results in periodic breathing and sleep

disruption. This complication of PS can be addressed by switching to CMV (A/C) or by using a lower level of pressure support. With CMV (A/C), the clinician sets a minimum respiratory rate, while still allowing patient efforts to trigger breaths. With a lower level of pressure support, PaCO2 will likely be greater, and the associated respiratory drive will decrease the risk of apnea. Synchronized intermittent mandatory ventilation (SIMV) provides breaths that are either VC or PC, interspersed with spontaneous breaths (Figure 20-13 and Figure 20-14). The intent is to provide respiratory muscle rest during mandatory breaths and respiratory muscle exercise with the intervening breaths. However, evidence has shown that considerable inspiratory effort occurs with both the mandatory breaths and the intervening spontaneous breaths.30 As the level of SIMV support is reduced, the work of breathing increases for both mandatory and spontaneous breaths (Figure 20-15). This effect can be ameliorated with the addition of pressure support, which results in unloading of spontaneous breaths. The addition of pressure support might result in a reduction in respiratory drive, thereby also unloading the patient-triggered mandatory breaths.

FIGURE 20-13 Synchronized intermittent mandatory ventilation illustrating spontaneous and mandatory breaths.

FIGURE 20-14 Synchronized intermittent mandatory ventilation with pressure support of spontaneous breaths.

FIGURE 20-15 Synchronized intermittent mandatory ventilation. Note that the esophageal (i.e., pleural) pressure change for the mandatory breath is nearly as great as that for the spontaneous breaths.

Newer ventilators have a volume feedback mechanism for PC or PS modes.31,32 The clinician sets the target tidal volume on the ventilator, but the breath type is actually PC or PS. The ventilator then adjusts the inspiratory pressure to deliver the set minimal target tidal volume (Figure 20-16). If tidal volume increases, the machine decreases the inspiratory pressure; conversely, if tidal volume decreases, the machine increases the inspiratory pressure. This mode goes by multiple names: pressureregulated volume control (Getinge), AutoFlow (Dräger), adaptive

pressure ventilation (Hamilton), volume control plus (Puritan Bennett), and volume-targeted pressure control or pressure-controlled volumeguaranteed (General Electric). Volume support is a volume feedback mode in which the breath type is only pressure support.

FIGURE 20-16 (A) Effect of adaptive pressure control with a compliance increase or respiratory effort increase. (B) Effect of adaptive pressure control with a compliance decrease or respiratory effort decrease. Reproduced from Branson RD, Johannigman JA. The role of ventilator graphics when setting dual-control modes. Respir Care 2005;50(2):187–201.

Because breath delivery during these volume feedback modes relies on pressure, tidal volume will vary with changes in respiratory system compliance, airway resistance, and patient effort. If changes in lung mechanics cause the tidal volume to change, the ventilator adjusts the pressure setting in an attempt to restore the tidal volume. Note, however, that providing a volume guarantee negates the pressure-limiting feature of a clinician-set pressure (i.e., worsening respiratory system mechanics will increase the applied pressure). Another potential problem with these approaches is that if the patient’s demand inappropriately increases (e.g., with pain) and produces a larger tidal volume, the pressure level will diminish—a change that may not be appropriate for a patient in respiratory failure.33,34

Airway pressure release ventilation (APRV) is a time-cycled, pressure-controlled mode of ventilatory support.35,36 With this mode, an active exhalation valve allows the patient to breathe spontaneously throughout the ventilator-imposed pressures (with or without PS). Because APRV is often used with a long inspiratory-to-expiratory timing pattern, most of the spontaneous breaths will occur during the long lung inflation period (upside-down SIMV) (Figure 20-17). APRV is available under a variety of proprietary trade names: APRV (Dräger), BiLevel (Puritan Bennett), BiVent (Siemens), BiPhasic (Avea), PC+ (Dräger), and DuoPAP (Hamilton).

FIGURE 20-17 Airway pressure release ventilation.

APRV uses different terminology to describe breath delivery phases. Lung inflation depends on the high airway pressure setting (Phigh). The duration of this inflation is termed Thigh. In consequence, Phigh, Thigh, and FIO2 heavily influence oxygenation. The magnitude and duration of lung deflation are determined by the pressure release level (Plow) and the

release time (Tlow). The ventilator-determined tidal volume (release volume) is therefore dependent on lung compliance, airways resistance, and the duration and timing of this pressure release maneuver. The timing and magnitude of this tidal volume coupled with the patient’s spontaneous breathing determine alveolar ventilation (PaCO2). Thigh is usually much greater than Tlow; thus, in the absence of spontaneous breathing, APRV is functionally the same as pressure-controlled inverse ratio ventilation. To sustain optimal recruitment with APRV, the greater part of the total time cycle (80% to 95%) usually occurs at Phigh; conversely, to minimize derecruitment, the time spent at Plow is brief (0.2 to 0.8 s in adults). Tlow is set according to expiratory flow; Tlow is terminated when expired flow reaches 50% to 75% of the peak expiratory flow. One commercially available ventilator automatically sets the termination flow of Plow (AutoRelease, Dräger V500). Because Tlow is very short, exhalation is often incomplete, leading to intrinsic PEEP. Debates continues regarding how the variables (Phigh, Plow, Thigh, Tlow) are manipulated during APRV.37 Spontaneous breathing during APRV results from diaphragm contraction, which should result in recruitment of dependent alveoli, thereby reducing shunt and improving oxygenation. The spontaneous efforts also may enhance both recruitment and cardiac filling as compared with other controlled forms of support. The long inflation phase recruits more slowly filling alveoli, so it raises mean airway pressure without increasing applied PEEP. Improved gas exchange, often with lower maximal set airway pressures than observed with other modes, can occur with APRV. Nevertheless, the end-inspiratory alveolar distention (transpulmonary pressure) in APRV is not necessarily less than that provided during other forms of support. In fact, it could be substantially higher, because spontaneous tidal volumes can occur while the lung is fully inflated with the APRV set pressure. A low pressure set to zero has been recommended for APRV, which therefore relies on auto-PEEP for alveolar recruitment. This relationship raises concerns about the potential for collapse of low-compliance lung units, which have a high elastic recoil. Thus, at least theoretically, APRV might allow injury of highly compliant alveoli during the high pressure with spontaneous breathing

and injury due to collapse/reopening of low compliance alveoli during the low pressure. The tidal volumes (release volume) with APRV can also be higher than the level generally considered lung protective.38 Evidence supporting improved survival using APRV is inconsistent.39–44 There is also a potential for respiratory muscle injury due to eccentric diaphragm contractions, as the result of diaphragm activation while the muscle is lengthening during the release phase of APRV. Adaptive support ventilation (ASV) automatically selects tidal volume and frequency for mandatory breaths and the tidal volume for spontaneous breaths on the basis of the respiratory system mechanics and target minute ventilation. ASV delivers pressure-controlled breaths using an adaptive scheme that minimizes the work of breathing. The ventilator selects a tidal volume and frequency that the patient’s brain stem would theoretically select based on the minimal work concept. The ventilator calculates the required minute ventilation based on the patient’s ideal body weight and estimated dead space volume (2.2 mL/kg). The clinician then sets the percentage of the target minute ventilation of 0.1 L/min/kg that the ventilator will support (25% to 350%). This target minute ventilation will be more than 100% if the patient has increased ventilatory requirements (e.g., sepsis or increased dead space) or less than 100% during ventilator liberation. The ventilator measures the expiratory time constant and uses this information along with the estimated dead space to determine an optimal breathing frequency in terms of the work of breathing. The target tidal volume is calculated as the minute ventilation divided by the frequency, and the pressure limit is adjusted to achieve an average delivered tidal volume equal to the target. The ventilator also adjusts the inspiration-to-expiration (I:E) ratio to avoid air trapping. Importantly, in the presence of patient triggering, ASV resembles volume support. ASV has been shown to supply reasonable ventilatory support in a variety of patients with respiratory failure,45–49 but tidal volumes might exceed 10 mL/kg ideal body weight in patients with near normal or mildly injured lungs. IntelliVent expands on the concept of ASV by adding closed-loop control of oxygenation to closed-loop control of ventilation.50 Control of ventilation is primarily based on ASV but with the option of additional control based on end-tidal PCO2. End-tidal PCO2 algorithms for normal lungs, ARDS, head injury, and chronic obstructive pulmonary disease

(COPD) are available. Oxygenation is based on the ARDSnet PEEP/FIO2 tables utilizing the SpO2 to adjust PEEP and FIO2. Tube compensation (TC) is designed to overcome the flow-resistive work of breathing imposed by an endotracheal tube or tracheostomy tube.51–54 It measures the resistance of the artificial airway and applies a pressure proportional to that resistance. The clinician can set the fraction of tube resistance for which compensation is desired (e.g., 50% compensation rather than full compensation). Although TC can effectively compensate for resistance through the artificial airway, it has not been shown to improve outcomes. Proportional assist ventilation (PAV) is a positive-feedback control mode that provides ventilatory support in proportion to the neural output of the respiratory center.55,56 The ventilator monitors respiratory drive as the inspiratory flow of the patient, integrates flow and volume, measures elastance and resistance, and then calculates the pressure required from the equation of motion. Using this calculated pressure and the tidal volume, the ventilator calculates the work of breathing (WoB): WoB = ∫P × These calculations occur every 5 ms during breath delivery, so the applied pressure and inspiratory time vary both breath by breath and within the breath (Figure 20-18). The ventilator estimates resistance and elastance (or compliance) by applying end-inspiratory and end-expiratory pause maneuvers of 300 ms every 4 to 10 s. The clinician adjusts the percentage of support (from 5% to 95%), which allows the work to be partitioned between the ventilator and the patient. Typically, the percentage of support is set so that the work of breathing is in the range of 0.5 to 1.0 J/L. If the percentage of support is high, patient work of breathing may be inappropriately low, and excessive volume and pressure may be applied (runaway phenomenon). If the percentage of support is too low, patient work of breathing may be excessive. Unlike conventional interactive modes like PS, PAV does not provide a minimal support level. Thus, alarms and backup modes are important with the use of this mode.

FIGURE 20-18 Proportional assist ventilation. Reproduced from Marantz S, Patrick W, Webster K, Roberts D, Oppenheimer L, Younes M. Response of ventilator-dependent patients to different levels of proportional assist. J Appl Physiol 1996;80(20:397–403.

PAV applies a pressure that varies from breath to breath, depending on changes in the patient’s compliance, resistance, and flow demand. This approach differs from PS or PC, in which the level of applied pressure remains constant regardless of demand, and from VC, in which the level of pressure decreases when demand increases (Figure 20-19). The cycle criterion for PAV is flow, which the clinician can adjust, much as with the PS mode. PAV requires the presence of an intact ventilatory drive and a functional neuromuscular system. This mode is available in the United States for invasive ventilation (PAV+, Puritan Bennett 840 and

980) and noninvasive ventilation (Philips Respironics V60). PAV may be more comfortable compared with other modes, and it may be associated with better patient–ventilator synchrony and sleep. Whether PAV improves clinical outcomes remains to be determined.

FIGURE 20-19 Effect of patient effort on the amount of support provided with various ventilator modes.

Neurally adjusted ventilatory assist (NAVA) is triggered, limited, and cycled by the electrical activity of the diaphragm (diaphragmatic EMG).57,58 The neural drive is transformed into ventilatory output (neuroventilatory coupling). To measure the diaphragmatic EMG, NAVA uses a multiple-array esophageal electrode, which is amplified to determine the support level (NAVA gain). The cycle-off is commonly set at 80% of peak inspiratory activity. The ventilator adjusts the level of assistance in response to changes in the patient’s neural drive, respiratory system mechanics, inspiratory muscle function, and

behavioral influences. Because the trigger relies on diaphragmatic activity rather than pressure or flow, triggering is not adversely affected in patients with flow limitation and auto-PEEP. NAVA is available only on the Servo-i, Servo-u, and Servo-n ventilators. Small clinical studies have demonstrated improved trigger and cycle synchrony with NAVA, but evidence for improved outcomes is lacking. Another concern with NAVA is the expense associated with the esophageal catheter and the invasive nature of its placement. As with PAV, this mode does not provide a minimal support level, so alarms and backup modes are important. High-frequency oscillatory ventilation (HFOV) uses very high breathing frequencies (up to 900 breaths/min in the adult) coupled with very small tidal volumes to provide gas exchange in the lungs. This technology vibrates a bias flow of gas delivered at the proximal end of the endotracheal tube and effects gas transport through complex nonconvective gas transport mechanisms. At the alveolar level, the substantial mean pressure functions as high-level CPAP. The potential advantages to HFOV are twofold. First, the very small alveolar pressure swings minimize overdistention and derecruitment. Second, the high mean airway pressure maintains alveolar patency and prevents derecruitment. Experience with HFOV in neonatal respiratory failure is generally positive. Its routine use in patients with ARDS is not supported by available evidence,59–61 but application of this mode might be considered for refractory hypoxemic respiratory failure in centers experienced with its use.62 Whether its use is associated with better patient outcomes for severe refractory hypoxemic respiratory failure is yet to be determined. Respiratory Recap Ventilator Modes Available on all ventilators: ∎ Continuous mandatory ventilation (CMV) [assist-control (A/C)] ∎ Synchronized intermittent mandatory ventilation (SIMV) ∎ Pressure support (PS) ∎ Continuous positive airway pressure (CPAP) Available on some ventilators: ∎ Adaptive pressure control (APC) ∎ Adaptive support ventilation (ASV)

∎ Airway pressure release ventilation (APRV) ∎ Tube compensation (TC) ∎ Proportional assist ventilation (PAV) ∎ Neurally adjusted ventilatory assist (NAVA) ∎ High-frequency oscillatory ventilation (HFOV)

Breath Triggering Positive pressure breaths can be either time triggered (breaths delivered according to a clinician-set rate or timer) or patient triggered (breaths triggered by either a change in circuit pressure or flow resulting from patient effort or by electrical activity of the diaphragm [NAVA]). The effort required to trigger the ventilator is an imposed load for the patient. Pressure triggering occurs due to a pressure drop in the system (Figure 20-20). The pressure level at which the ventilator is triggered is set so that the trigger effort is minimal but auto-triggering is unlikely to occur (typically this is 1 to 2 cm H2O below the PEEP or CPAP setting).

FIGURE 20-20 (A) Pressure-triggered breath. (B) Flow-triggered breath.

Flow triggering is an alternative to pressure triggering. With flow triggering, the ventilator responds to a change in flow rather than a decrease in pressure at the airway. With some ventilators, a pneumotachometer is placed between the ventilator circuit and the patient to measure inspiratory flow. In other ventilators, the clinician sets

a base flow and flow sensitivity. A decrease in the flow in the expiratory circuit by the amount of the flow sensitivity then triggers the ventilator. For example, if the base flow is set at 10 L/min and the flow sensitivity is set at 3 L/min, the ventilator triggers when the flow in the expiratory circuit drops to 7 L/min (the assumption is that the patient has inhaled at 3 L/min). Neither pressure triggering nor flow triggering may be effective if significant auto-PEEP is present. Regardless of whether the system uses pressure triggering or flow triggering, the current generation of ventilators is more responsive to patient effort, and differences between pressure and flow triggering are minor. Respiratory Recap Conventional Ventilator Triggering ∎ The ventilator self-triggers when a set time is reached. ∎ The patient triggers the ventilator through changes in pressure or flow.

Tidal Volume Tidal volume is selected to provide an adequate PaCO2 but avoid alveolar overdistention, decreased cardiac output, and auto-PEEP.63 Tidal volume is directly set in VC but is determined by the driving pressure and inspiratory time in PC and PS. Large tidal volumes increase mortality in patients with ARDS and increase the risk of new development of ARDS in patients with previously normal lungs.64–69 The tidal volume chosen should maintain Pplat < 30 cm H2O (assuming a near-normal chest wall compliance) or perhaps higher Pplat if chest wall compliance is severely reduced (e.g., morbid obesity, anasarca, ascites, abdominal compartment syndrome). The clinician should select the tidal volume based on PBW, which is determined by height and sex: Male: PBW = 50 + 2.3 × [Height (inches) – 60] Female: PBW = 45.5 + 2.3 × [Height (inches) – 60] A reasonable starting point for most patients with respiratory failure is 6

mL/kg PBW, even in patients with relatively normal lungs. Because lung injury often reduces functional lung volume (baby lungs), tidal volume should be scaled based on actual lung volume rather than ideal lung volume. The underlying notion is that delivered tidal volume stretches only the functional regions of the lung. If this functional lung volume is markedly less than the ideal lung volume, a tidal volume based on normal lung volume can result in overdistention. Functional lung size can be determined visually (computed tomography, electrical impedance tomography) or with other techniques (inert gas washout, plethysmography). At the bedside, the clinician can use the respiratory system compliance as a surrogate for functional lung size. With this approach, scaling tidal volume to compliance is reflected in driving pressure (Pplat-PEEP). Driving pressure should be less than 15 cm H2O.70 Stop and Think You select a lower tidal volume for a patient who is intubated following a drug overdose. A colleague challenges you, suggesting that large tidal volumes are acceptable if the patient has normal lungs. How would you defend your selection of a tidal volume of 6 mL/kg?

Respiratory Rate Respiratory rate is chosen to provide an acceptable minute ventilation: E = VT × fb where fb is the respiratory rate (breathing frequency), E is the minute ventilation, and VT is the tidal volume. A rate of 15 to 25 breaths/min is often used when mechanical ventilation is initiated. If a smaller tidal volume is selected to prevent alveolar overdistention, a higher respiratory rate may be required (25 to 35 breaths/min). The respiratory rate is limited by the development of auto-PEEP. The minute ventilation that produces a normal PaCO2 without risk for lung injury or auto-PEEP may not be possible, so the PaCO2 is allowed to increase (permissive hypercapnia). Because higher PaCO2 may lead to poorer outcomes for

critically ill mechanically ventilated patients, permissive hypercapnia should be reserved for cases where normalization of PaCO2 could result in lung injury.71

Inspiratory Time For patient-triggered breaths, the inspiratory time should be short (1.5 s or less). A shorter inspiratory time requires a higher inspiratory flow, which increases the peak inspiratory pressure (PIP) but does not greatly affect Pplat. Increasing inspiratory time increases mean airway pressure ( aw), which may improve oxygenation in some patients with ARDS. When long inspiratory times are used (more than 1.5 s) and spontaneous breaths are not permitted, the patient may require paralysis or sedation (or both). Long inspiratory times also can cause auto-PEEP and may result in hemodynamic instability. Although inverse ratio ventilation has been advocated to improve oxygenation, unless it is coupled with the ability to breathe spontaneously, this extreme (and potentially hazardous) form of ventilation is seldom necessary to achieve adequate oxygenation. The I:E ratio is the relationship between inspiratory time and expiratory time. For example, an inspiratory time of 2 s with an expiratory time of 4 s produces an I:E ratio of 1:2 and a respiratory rate of 10 breaths/min. With VC, the peak inspiratory flow, flow pattern, tidal volume, and pause time are the principal determinants of inspiratory time and the I:E ratio. With PC, the clinician sets the inspiratory time, I:E ratio, or percentage inspiratory time. In both VC and PC, the principal determinant of expiratory time is the respiratory rate. Respiratory Recap Settings for Tidal Volume, Respiratory Rate, and Inspiratory Time ∎ Tidal volume: Set to avoid overdistention. ∎ Respiratory rate: Set for desired (PaCO2). ∎ Inspiratory time: Set to avoid auto-PEEP and hemodynamic compromise.

Inspiratory Flow Pattern For VC, the inspiratory flow pattern can be constant or descending ramp. For the same inspiratory time, PIP is greater with constant flow than with descending ramp flow, and aw is greater with ramp flow than with constant flow. A descending ramp flow pattern may improve gas distribution but has only a small effect on gas exchange. Some clinicians believe that patient–ventilator synchrony is better in some patients with a descending ramp flow pattern, but evidence to support this belief is lacking. The clinician can set an end-inspiratory pause to improve distribution of ventilation, but this prolongs inspiration and may have a deleterious effect on hemodynamics and auto-PEEP. Experimental evidence suggests greater potential of lung injury with a descending ramp flow pattern, although this relationship has not been confirmed in humans. Clinicians sometimes prefer the lower peak pressure with a descending ramp flow pattern, but the alveolar pressure is the same whether they set a constant flow or a descending ramp of flow. Inspiratory flow decreases exponentially with PC and PS. The peak flow and rate of flow decrease depend on the driving pressure, airways resistance, respiratory system compliance, and patient effort. With high resistance, flow decreases slowly. With low respiratory system compliance, flow decreases more rapidly, and a period of zero flow may be present at end-inhalation (Figure 20-21).

FIGURE 20-21 Flow waveforms during pressure control: low resistance and low compliance (A) and high resistance and high compliance (B).

Positive End-Expiratory Pressure Because critical care patients are often immobile and supine, with compromised cough ability, low-level PEEP (3 to 5 cm H2O) is often used with all mechanically ventilated patients in an effort to prevent atelectasis. In patients with ARDS, more substantial levels of PEEP may be required to maintain alveolar recruitment. An appropriate level of PEEP to maintain alveolar recruitment is also part of a lung-protective ventilation strategy. PEEP should be used cautiously in patients with unilateral disease because it may overdistend the more compliant lung, causing shunting of blood to the less compliant lung. PEEP might also be useful to improve triggering by patients experiencing auto-PEEP.72 Auto-PEEP functions as a threshold pressure that must be overcome before the pressure (or flow) decreases at the airway to trigger the ventilator. Increasing the set PEEP to a level near the auto-PEEP may improve the patient’s ability to trigger the ventilator (Figure 20-22). Whenever PEEP is used to overcome the effect of autoPEEP on triggering, the clinician must monitor PIP and Pplat to ensure that increasing the set PEEP does not exacerbate hyperinflation. Other

uses of PEEP include preload and afterload reduction in the setting of left heart failure, reducing microaspiration around the cuff of the artificial airway, pneumatic splinting in the setting of airway malacia, and facilitation of leak speech with cuff deflation in patients with a tracheostomy.

FIGURE 20-22 Trigger effort is increased when auto-PEEP is present. To trigger the ventilator, the patient’s effort must first overcome the level of auto-PEEP that is present. Increasing the set PEEP level may raise the trigger level closer to the total PEEP, thereby improving the patient’s ability to trigger the ventilator. This method should not be used, however, if raising the set PEEP level results in an increase in the total PEEP.

Respiratory Recap Uses of Positive End-Expiratory Pressure ∎ Maintain alveolar recruitment. ∎ Counterbalance auto-PEEP. ∎ Reduce cardiac preload and afterload. ∎ Reduce microaspiration around the cuff of the artificial airway. ∎ Pneumatic splinting of the airway. ∎ Facilitation of leak speech.

Mean Airway Pressure Across all modes, oxygenation and cardiac effects of mechanical ventilation often correlate best with the mean airway pressure ( aw). aw is a key component of the oxygenation index (OI), which is often used as a reflection of gas transport impairment: OI = 100 × ( aw × FIO2)/PaO2 Factors that affect aw during mechanical ventilation are the PIP, PEEP, I:E ratio, respiratory rate, and inspiratory flow pattern. Most patients can be managed with a mean aw of 10 to 20 cm H2O.

Recruitment Maneuvers A recruitment maneuver is an intentional transient increase in transpulmonary pressure to promote reopening of unstable collapsed alveoli, thereby improving gas exchange.73 High-level evidence demonstrating an outcome benefit from the use of recruitment maneuvers is lacking, however, and one study reported worse outcomes associated with an aggressive approach to lung recruitment.74 Recruitment maneuvers are probably best reserved for the setting of refractory hypoxemia in patients with ARDS.75 Hypotension and hypoxemia might occur during application of the recruitment maneuver.76 A variety of techniques have been described as recruitment maneuvers, but it is uncertain whether any one approach is superior to the others (Table 20-3). After performing a recruitment maneuver, it is important to set PEEP to a level that retains recruitment—that is, to use a decremental PEEP titration after the recruitment maneuver.77 If the patient’s lungs are already maximally recruited as the result of PEEP, a recruitment maneuver will likely offer only minimal benefits. TABLE 20-3 Lung Recruitment Maneuvers Recruitment Maneuver

Method

Sustained high-pressure inflation

Sustained inflation delivered by increasing PEEP to 30–50 cm H2O for 20–40 s

Intermittent sigh

Sighs with a tidal volume reaching Pplat of 45 cm H2O

Extended sigh

Stepwise increase in PEEP by 5 cm H2O, with a simultaneous stepwise decrease in tidal volume over 2 min, leading to a CPAP level of 30 cm H2O for 30 s

Intermittent PEEP increase

Intermittent increase in PEEP from baseline to higher level

Pressure control with PEEP

Pressure control of 10–15 cm H2O with PEEP increase to 25–30 cm H2O, to reach a peak inspiratory pressure of 40–45 cm H2O; this can be done in a rapid stepwise approach with a PEEP increase of 2–5 cm H2O every 30–34 s (total time 1–3 min)

Inspired Oxygen Concentration An FIO2 of 1.0 is commonly used when mechanical ventilation is initiated. Pulse oximetry (SpO2) is useful to guide titration of the FIO2 (and PEEP), provided the clinician obtains periodic blood gas measurements to confirm the pulse oximetry results. A target SpO2 of 88% to 95% usually provides a partial pressure of arterial oxygen (PaO2) of 55 to 80 mm Hg. Clinicians should avoid excessive FIO2, as this leads to poorer outcomes in critically ill patients.19 Although it is common practice to wait 20 to 30 minutes after changing the FIO2 to obtain arterial blood gas measurements, 10 minutes is adequate unless the patient has obstructive lung disease, which requires a longer equilibration time. Respiratory Recap Setting the FIO2 ∎ Initiate mechanical ventilation with 100% oxygen. ∎ Titrate the FIO2 to an appropriate SpO2.

Sigh Some ventilators are capable of providing periodic sigh volumes. The rationale for use of sighs is that the periodic hyperinflation reduces the risk of atelectasis. A sigh is a very brief recruitment maneuver. Although the use of sighs during mechanical ventilation was traditionally not considered important, this practice appears to improve alveolar recruitment in patients with ARDS.78

Alarms Alarms must be set correctly on the ventilator. The most important alarm is the patient-disconnect alarm, which can be a low-pressure alarm or a low exhaled volume alarm (or both). Exhaled CO2 can also be used as a disconnect alarm. A sensitive alarm should detect not only disconnection but also leaks in the system. The ability to detect a leak depends on the site where the volume is measured (Figure 20-23). Other alarms set on the ventilator include those for high pressure, I:E ratio, FIO2, and loss of PEEP. To detect changes in resistance and compliance, the peak airway pressure alarm is important with VC and the low exhaled volume alarm with PC or PS.

FIGURE 20-23 The ability to detect a leak depends on the site where volume is measured. If the volume on the inspiratory limb is greater than the volume on the expiratory limb, the system has a leak (circuit or patient). If the inspired volume at the patient is greater than the expired volume at the patient, the patient is the source of the leak (e.g., around the cuff of the endotracheal tube or a bronchopleural fistula).

Circuit Because of the gas compression in the ventilator circuit and the compliance of the ventilator circuit tubing, as much as 3 to 5 mL/cm H2O can be compressed in the ventilator circuit. In other words, at an airway pressure of 25 cm H2O above PEEP, approximately 100 mL of the gas delivered from the ventilator is not delivered to the patient. Most modern ventilators adjust for the effects of compressible volume such that the volume chosen by the clinician is the actual delivered VT after correction for the effect of compressible volume. The effects of compressible volume on the delivered VT, auto-PEEP, Pplat, and mixed exhaled partial pressure of carbon dioxide (PE-CO2) can be assessed by applying Equation 20-1.

EQUATION 20-1 Effects of Compressible Volume The effect of compressible volume on the delivered tidal volume (VT) can be expressed as follows:

where: VTpt = Tidal volume delivered to the patient Cpc = Compliance of the ventilator circuit Crs = Compliance of the respiratory system VTvent = Tidal volume from the ventilator circuit The effect of compressible volume on auto-PEEP can be expressed as follows:

where auto-PEEP is the patient’s actual auto-PEEP. The effect of compressible volume on Pplat can be expressed as follows:

where Pplat is the patient’s actual plateau pressure. The effect of compressible volume on PĒCO2 can be expressed as follows:

where: PĒCO2 = Patient’s actual PĒCO2 PĒCO2vent = PĒCO2 from the ventilator circuit VTvent = Tidal volume from the ventilator circuit VTpt = Tidal volume delivered to the patient

Mechanical dead space is that part of the ventilator circuit through which the patient rebreathes; thus, it becomes an extension of the patient’s anatomic dead space. Alveolar ventilation is zero if the sum of the volume loss in the circuit and the mechanical dead space is greater than the VT set on the ventilator. The effect of mechanical dead space is particularly important with lung-protective ventilation, where the small tidal volume coupled with excessive dead space might lead to unnecessary hypercapnia.79

Humidification Because use of endotracheal and tracheostomy tubes bypasses the upper airway, the inspired gas must be filtered, warmed, and humidified before delivery to the patient. All ventilator circuits include a filter in the inspiratory limb and an active or passive humidifier. An active humidifier typically humidifies the inspired gas by passing it over or bubbling it through a heated water bath. When an active humidifier is used, the ventilator circuit may be heated to prevent excessive condensation in the circuit. A passive humidifier uses an artificial nose (heat and moisture exchanger) to collect heat and humidity from the patient’s exhaled gas and returns that to the patient on the next inhalation. Regardless of the humidification technique used, condensation should be seen in the inspiratory ventilator circuit or the proximal endotracheal tube or both, which indicates that the inspired gas is fully saturated with water vapor. Respiratory Recap Methods of Humidification with Mechanical Ventilation ∎ Active humidification: Heated humidifier. ∎ Passive humidification: Artificial nose. ∎ The presence of condensate in the inspiratory circuit near the patient indicates adequate humidification.

Monitoring the Mechanically Ventilated Patient Physical Assessment Asymmetric chest motion may indicate main stem (endobronchial) intubation, pneumothorax, or atelectasis. Paradoxical chest motion may be seen with flail chest or respiratory muscle dysfunction. Retractions may occur with an inappropriate inspiratory flow or sensitivity or with airway obstruction. If the patient is not breathing in synchrony with the ventilator (i.e., bucking the ventilator), the settings on the ventilator may not be appropriate or the patient may need sedation or analgesia (or both). A patient respiratory rate greater than the ventilator rate indicates that auto-PEEP is compromising triggering. In conjunction with inspection, the clinician can palpate the patient’s chest to assess the symmetry of chest movement. Palpation of the tracheal position can help detect pneumothorax. Crepitation indicates subcutaneous emphysema. Percussion can help detect unilateral hyperresonance or tympany with a pneumothorax. Unilateral decreased breath sounds may indicate bronchial intubation, pneumothorax, atelectasis, or pleural effusion. An end-inspiratory squeak over the trachea usually indicates insufficient air in the artificial airway cuff.

Blood Gas Measurements The earliest indicators of hypoxemia often are changes in the patient’s clinical status—for example, restlessness and confusion, changes in level of consciousness, tachycardia or bradycardia, changes in blood pressure, tachypnea, bucking the ventilator, or cyanosis. The most commonly used assessment of oxygenation is PaO2. A low PaO2 indicates hypoxemia and dysfunction in the lungs’ ability to oxygenate arterial blood. In mechanically ventilated patients, a number of factors can affect PaO2, such as FIO2, PEEP, and the patient’s lung function (Figure 20-24). The mixed venous oxygenation (P O2 or S O2) is a better indicator of tissue oxygenation. P O2 less than 35 mm Hg (or S O2 less

than 70%) indicates tissue hypoxia.

FIGURE 20-24 Factors affecting PaO2 during mechanical ventilation.

PaCO2 is determined by carbon dioxide production ( CO2) and the alveolar ventilation ( A). If CO2 is constant, PaCO2 varies inversely with A. Minute ventilation ( E) affects PaCO2 indirectly because of the relationship between E and A. An increase in E decreases PaCO2, and a decrease in E increases PaCO2. This is illustrated by the following relationship: PaCO2 = (

CO2 × 0.863)/( E × [1 – VD/VT])

Note that 0.863 is replaced with barometric pressure (e.g., 760 mm Hg) in this equation if the units and conditions of all measurements are the same. Figure 20-25 shows the factors that determine PaCO2 during mechanical ventilation.

FIGURE 20-25 Factors affecting PaCO2 during mechanical ventilation.

The use of noninvasive monitors may reduce the need for arterial blood gas determinations, because they allow continuous assessment between blood gas measurements. Pulse oximetry can be used to titrate an appropriate FIO2 and PEEP. Continuous pulse oximetry has become the standard of care in mechanically ventilated patients. End-tidal PCO2 is used to monitor carbon dioxide levels noninvasively. In patients with normal lungs, end-tidal PCO2 closely approximates PaCO2. In patients with an elevated VD/VT, however, a large and inconsistent gradient can exist between PaCO2 and the end-tidal PCO2. For this reason, monitoring end-tidal PCO2 is of limited value for the assessment of PaCO2 during mechanical ventilation.

Plateau Pressure and Auto-PEEP Pplat is measured by application of an end-inspiratory pause of 0.5 to 1.5

s, and auto-PEEP is determined by application of an end-expiratory pause of 0.5 to 1.5 s (Figure 20-26).80,81 During PC, the inspiratory flow often decreases to a no-flow period at end-inspiration. In this case, the peak pressure and Pplat are equivalent. Both Pplat and auto-PEEP can be accurately measured only when the patient is not actively breathing.

FIGURE 20-26 Airway pressure waveform during volume control. End-inspiratory and endexpiratory breath holds are applied to measure Pplat and auto-PEEP. The difference between peak inspiratory pressure and Pplat is determined by the flow setting on the ventilator and airways resistance. The difference between Pplat and total PEEP is determined by the tidal volume setting on the ventilator and the total level of PEEP (including auto-PEEP).

To avoid overdistention lung injury, the goal is to maintain Pplat below 30 cm H2O (and lower if possible). Circuit measurements of respiratory system pressures all assume normal chest wall compliance to develop a reasonable estimate of transpulmonary pressures; that is, a normal chest wall compliance will have little effect on the measured airway pressures. In the setting of very low chest wall compliance (e.g., obesity, ascites, abdominal compartment syndrome), chest wall stiffness may profoundly

affect these airway pressure measurements; thus, these effects need to be subtracted from the airway pressure to determine true transpulmonary pressure. This can be done with an esophageal pressure measurement or estimated by an experienced clinician. Driving pressure should be monitored, with the target being less than 15 cm H2O. The presence of auto-PEEP leads to manifestations that can be monitored. For example, the clinician can monitor the patient’s breathing pattern: If exhalation is still occurring when the next breath is delivered, auto-PEEP is present. Inspiratory efforts that do not trigger the ventilator also suggest the presence of auto-PEEP. Furthermore, the flow graphics on the ventilator will show that expiratory flow usually does not return to zero before the subsequent breath is delivered. However, in the presence of very narrow and/or collapsing small airways, lung regions may still have trapped gas and regional auto-PEEP, even though the expiratory flow signal on the ventilator reads zero. Stop and Think A patient has a Pplat of 40 cm H2O. What can you do to lower the Pplat to 200 mm Hg).99 Selecting the appropriate PEEP setting demands careful consideration of the benefits of alveolar recruitment balanced against the risks of overdistention. The results of one study suggests that the use of a table such as that used by ARDSnet might best accomplish this goal.100 Some mechanical approaches to setting PEEP are used in ICUs where the staff has considerable experience managing ARDS (Box 206).101 These include titration to the highest compliance, titration to a pressure greater than the lower inflection point of the pressure-volume curve, the best stress index, and incorporation of esophageal pressure measurements in the settings for patients with abnormal chest wall compliance. One study reported no difference in mortality with PEEP titrated using an approach similar to ARDS Network’s high PEEP strategy and with use of esophageal manometry.102 Clinicians should avoid PEEP that results in Pplat > 30 cm H2O (except in patients with abnormal chest wall mechanics) or a driving pressure greater than 15 cm H2O. Higher levels of PEEP should be reserved for cases with demonstrated lung recruitment. In the setting of refractory hypoxemia, clinicians may use recruitment maneuvers, followed by a level of PEEP to maintain alveolar recruitment. When selecting PEEP settings for patients with ARDS, clinicians should also monitor the hemodynamic effects of the increased intrathoracic pressure. BOX 20-6 Methods for Selecting PEEP Incremental PEEP: This approach uses combinations of PEEP and FIO2 to achieve the desired level of oxygenation or the highest compliance. Decremental PEEP: This approach begins with a high level of PEEP (e.g., 20 cm H2O), after which PEEP is decreased in a stepwise fashion until derecruitment occurs, typically with decreases in PaO2 and compliance. PEEP is then applied at a higher level to maintain lung recruitment. Stress index: The pressure–time curve is observed during constant-flow inhalation for signs of tidal recruitment and overdistention. Esophageal pressure: This method estimates the intrapleural pressure by using an esophageal balloon to measure the esophageal pressure and subsequently determine the optimal level of PEEP required to counterbalance pleural pressure. Pressure–volume curve: PEEP is set slightly greater than the lower inflection point.

Obstructive Lung Disease Respiratory failure from airflow obstruction is due to increases in airway resistance. This increases the pressure required for flow, which may overload inspiratory muscles, producing a ventilatory pump failure with spontaneous minute ventilation inadequate for gas exchange. In addition, the narrowed airways create regions of lung that cannot properly empty, leading to auto-PEEP. These regions of overinflation create dead space and put inspiratory muscles at a substantial mechanical disadvantage, which further worsens muscle function. Overinflated regions may also compress healthier regions of the lung, impairing matching. In addition, regions of air trapping and intrinsic PEEP function as a threshold load to trigger mechanical breaths. Noninvasive ventilation (NIV) is standard first-line therapy in patients with COPD and has been shown to improve outcomes by reducing the need for endotracheal intubation and improving survival in this patient population.103 NIV has also been used in other forms of obstructive lung disease (e.g., asthma, cystic fibrosis), but less evidence supports better outcomes in these patient populations. Invasive ventilatory support is usually reserved for those patients who fail NIV or in those in whom NIV is contraindicated. Tidal volume should be sufficiently low (e.g., 6 mL/kg) to ensure that Pplat values are less than 30 cm H2O. The set rate is used to control pH. The elevated airways resistance and the low elastic recoil pressure with emphysema increase the potential for air trapping, however, which limits the range of breath rates available. Permissive hypercapnia may be an appropriate trade-off to limit overdistention. The inspiratory time in obstructive lung disease is set as low as possible to minimize the development of air trapping. Judicious application of PEEP (up to 75% to 85% of auto-PEEP) can counterbalance auto-PEEP to facilitate triggering.104

Neuromuscular Disease The risk of VILI is generally less in a patient with neuromuscular failure, because lung mechanics are often near normal, which means regional overdistention is less likely to occur. Accumulating evidence supports that

a target tidal volume of 6 mL/kg PBW is appropriate even in patients with normal lungs. One study reported increased risk of developing ARDS when higher tidal volumes are used in patients with spontaneous intracerebral hemorrhage.105 A low level of PEEP is often beneficial for preventing atelectasis. If patients with neuromuscular disease develop ARDS, they should be managed using ventilator strategies incorporating lower tidal volumes and higher levels of PEEP. Lung-protective ventilation is also recommended for brain-dead patients who are potential donors for lung transplantation.106,107

Intraoperative and Postoperative Mechanical Ventilation Progressive atelectasis occurs during anesthesia. In the past, use of high VT was recommended to combat this problem. Although large VT might recruit collapsed alveoli, this strategy might also promote cyclical alveolar collapse and reopening. A smaller VT to avoid overdistention and PEEP to maintain alveolar recruitment can protect the lungs, even in patients with normal lung function such as in the intraoperative and postoperative periods. In nonobese patients without ARDS undergoing open abdominal surgery, it has been suggested that mechanical ventilation should be performed with VT (6 to 8 mL/kg PBW) combined with PEEP 5 cm H2O: The use of higher PEEP combined with recruitment maneuvers does not confer further protection against postoperative pulmonary complications.108 If hypoxemia develops, the clinician should increase the PEEP level and consider recruitment maneuvers. Patients with ARDS who are ventilated in the operating room should be ventilated with the same lung-protective strategies used in the ICU.

Ventilatory Support Trade-Offs To provide adequate support yet minimize VILI, mechanical ventilation goals require trade-offs. For example, the need for potentially injurious ventilating pressures, volumes, and supplemental O2 must be weighed against the benefits of better gas exchange. Accordingly, pH goals as low as 7.15 and PaO2 goals as low as 55 mm Hg are often considered acceptable if necessary to protect the lungs from VILI. Ventilator settings are selected to provide an adequate, but not necessarily normal, level of gas exchange while providing enough PEEP to maintain alveolar recruitment and avoid a PEE tidal volume combination that unnecessarily overdistends alveoli at end-inspiration. This has led to ventilatory strategies such as permissive hypercapnia, permissive hypoxemia, and permissive atelectasis.

Liberation from Mechanical Ventilation An important aspect of the management of patients receiving mechanical ventilation is recognizing when the patient is ready to be liberated from the ventilator and extubating the patient at that point. Evidence-based clinical practice guidelines have been published related to liberation from mechanical ventilation. CPG 20-1109 and CPG 20-2110 list the recommendations from these guidelines. CLINICAL PRACTICE GUIDELINE 20-1 Evidence-Based Guidelines for Discontinuing Ventilatory Support

▪

In patients requiring mechanical ventilation for more than 24 hours, search for all the causes that may be contributing to ventilator dependence. This is particularly true in the patient who has failed attempts at withdrawing the mechanical ventilator. Reversing all possible ventilatory and nonventilatory issues should be an integral part of the ventilator discontinuation process.

▪

Patients receiving mechanical ventilation for respiratory failure should undergo a formal assessment of discontinuation potential if the following criteria are satisfied: (1) evidence for some reversal of the underlying cause for respiratory failure, (2) adequate oxygenation and pH, (3) hemodynamic stability, and (4) the capability to initiate an inspiratory effort.

▪

Formal discontinuation assessments for patients receiving mechanical ventilation for respiratory failure should be performed during spontaneous breathing rather than while the patient is still receiving substantial ventilatory support. An initial brief period of spontaneous breathing can be used to assess the capability of continuing on to a formal spontaneous breathing trial (SBT). The criteria used to assess patient tolerance during SBTs are the respiratory pattern, the adequacy of gas exchange, hemodynamic stability, and subjective comfort. The tolerance of SBTs lasting 30 to 120 minutes should prompt consideration for permanent ventilator discontinuation.

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The removal of the artificial airway from a patient who has successfully been discontinued from ventilatory support should be based on assessments of airway patency and the ability of the patient to protect the airway.

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When patients receiving mechanical ventilation for respiratory failure fail an SBT, the clinician should determine the cause for the failed SBT. Once reversible causes for failure are corrected, subsequent SBTs should be performed every 24 hours.

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Patients receiving mechanical ventilation for respiratory failure who fail an SBT should receive a stable, nonfatiguing, comfortable form of ventilatory support.

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Anesthesia/sedation strategies and ventilator management aimed at early extubation

should be used in postsurgical patients.

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ICUs should develop and implement weaning/discontinuation protocols that are designed for nonphysician healthcare professionals. They should also develop and implement protocols aimed at optimizing sedation.

▪

Tracheostomy should be considered after an initial period of stabilization on the ventilator when it becomes apparent that the patient will require prolonged ventilator assistance. Tracheostomy then should be performed when the patient appears likely to gain one or more of the benefits ascribed to the procedure. Patients who may derive particular benefit from early tracheostomy include those requiring high levels of sedation to tolerate a translaryngeal tube; those with marginal respiratory mechanics (often manifested as tachypnea) in whom a tracheostomy tube having lower resistance might reduce the risk of muscle overload; those who may derive psychological benefit from the ability to eat orally, communicate by articulated speech, and experience enhanced mobility; and those in whom enhanced mobility may assist physical therapy efforts.

▪

Unless the patient shows evidence of clearly irreversible disease (e.g., high spinal cord injury or advanced amyotrophic lateral sclerosis), a patient requiring prolonged mechanical ventilatory support for respiratory failure should not be considered permanently ventilator dependent until 3 months of ventilator liberation attempts have failed.

▪

Critical care practitioners should familiarize themselves with facilities in their communities, or units in hospitals they staff, that specialize in managing patients who require prolonged dependence on mechanical ventilation. Such familiarization should include reviewing published peer-reviewed data from those units, if available. When medically stable for transfer, patients who have failed ventilator discontinuation attempts in the ICU should be transferred to those facilities that have demonstrated success and safety in accomplishing ventilator discontinuation.

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Ventilator liberation strategies in the patient with prolonged mechanical ventilation should proceed at a slow pace and should include gradually lengthening self-breathing trials.

Reproduced from MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE, et al. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine. Chest 2001;120(Suppl 6):375S–396S. Copyright Elsevier 2001.

CLINICAL PRACTICE GUIDELINE 20-2 American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults

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For acutely hospitalized patients ventilated for more than 24 hours, suggest that the initial SBT be conducted with inspiratory pressure augmentation (5 to 8 cm H2O) rather than without it (T piece or CPAP). (Conditional recommendation; moderate certainty in the

evidence.)

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For acutely hospitalized patients ventilated for more than 24 hours, suggest protocols attempting to minimize sedation. (Conditional recommendation; low certainty in the evidence.)

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For patients at high risk for extubation failure who have been receiving mechanical ventilation for more than 24 hours and who have passed a spontaneous breathing trial, recommend extubation to preventive NIV. (Strong recommendation; moderate certainty in the evidence.)

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For acutely hospitalized patients who have been mechanically ventilated for more than 24 hours, suggest protocolized rehabilitation directed toward early mobilization. (Conditional recommendation; low certainty in the evidence.)

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Suggest managing acutely hospitalized patients who have been mechanically ventilated for more than 24 hours with a ventilator liberation protocol. (Conditional recommendation; low certainty in the evidence.)

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Suggest performing cuff leak test in mechanically ventilated adults who meet extubation criteria and are deemed at high risk for post-extubation stridor. (Conditional recommendation; very low certainty in the evidence.)

▪

For adults who have failed a cuff leak test but are otherwise ready for extubation, suggest administering systemic steroids at least 4 hours before extubation. A repeat cuff leak test is not required. (Conditional recommendation; moderate certainty in the evidence.)

From Schmidt GA, Girard TD, Kress JP, Morris PE, Ouellette DR, Alhazzani W, et al. Official executive summary of an American Thoracic Society/American College of Chest Physicians clinical practice guideline: liberation from mechanical ventilation in critically ill adults. Am J Respir Crit Care Med 2017;195(1):115–119.

Respiratory Muscles For successful liberation from the ventilator, the load placed on the respiratory muscles must be balanced by the muscles’ ability to meet that load (Figure 20-31). Respiratory muscle fatigue occurs if the load placed on the muscles is excessive, if the muscles are weak, or if the duty cycle (the inspiratory time relative to total cycle time) is too long. Common causes of a high load are high airways resistance, low lung compliance, and high minute ventilation. In addition, malposition of the diaphragm from dynamic hyperinflation compromises inspiratory muscle function. Diminished respiratory muscle function may also result from systemic disease, disuse, malnutrition, hypoxia, or electrolyte imbalance. The clinical signs of respiratory muscle fatigue are tachypnea, abnormal

respiratory movements (respiratory alternans and abdominal paradox), and an increase in PaCO2.111

FIGURE 20-31 Respiratory muscle performance is determined by the balance between the load that is placed on the respiratory muscles and the ability of the muscles to meet that load.

Description Because the maximum inspiratory pressure (PImax) is a good indicator of overall respiratory muscle strength, a low PImax may predict respiratory muscle fatigue. To measure PImax, the clinician attaches an aneroid manometer to the endotracheal or tracheostomy tube. The patient then forcibly inhales after maximum exhalation. During this process, a unidirectional valve should be used and the airway should be completely obstructed for 20 to 25 s (Figure 20-32). A PImax more negative than –20 cm H2O suggests adequate inspiratory muscle strength. If the patient has high airways resistance or low compliance, however, even a PImax of –20 cm H2O might not be adequate for unassisted breathing.

FIGURE 20-32 The one-way valve system used to measure maximum inspiratory pressure. The patient is connected at A, the manometer (B) is connected at C, and the patient exhales through D. In this way, maximum inspiratory pressure is measured at functional residual capacity. Reproduced from Kacmarek RM, Cycyk-Chapman MC, Young PJ, Romagnoli DM. Determination of maximal inspiratory pressure: a clinical study and literature review. Respir Care 1989;34(12):868–878

If fatigue occurs, the patient should rest the respiratory muscles; a rest period of 24 hours may be required.112 Appropriate respiratory muscle rest usually is provided by ventilatory support high enough to provide patient comfort and still allow some inspiratory efforts. Importantly, total rest (i.e., no inspiratory muscle activity with controlled mechanical ventilation) can also be harmful, because muscle atrophy has been shown to develop in as little as 24 hours under these conditions. If respiratory muscle fatigue results from an excessive load, the clinician should reduce the load before attempting to liberate the patient from the ventilator. This is done with provision of therapies that can increase lung compliance or reduce airways resistance.

Assessing Readiness for Liberation A number of factors should be improved before the healthcare team attempts to liberate the patient from the ventilator (Box 20-7). Weaning parameters,113 which are often used to assess liberation potential, are divided into two categories: parameters affected by lung mechanics and gas exchange parameters. The spontaneous VT (5 mL/kg), respiratory rate (30 breaths/min), minute ventilation (12 L/min), vital capacity (15 mL/kg), and PImax (–20 cm H2O) have been used as predictors of success. To calculate the rapid shallow breathing index (RSBI),114 divide the spontaneous respiratory rate by the VT (in liters). An RSBI less than 105 appears to be predictive of successful ventilator liberation, whereas an RSBI greater than 105 may predict failure. An increase in VD/VT (which should be less than 0.6) and an increase in CO2 and O2 imply an increased ventilatory requirement. BOX 20-7 Criteria Assessed to Determine Readiness for

Ventilator Discontinuation (Liberation) 1. Evidence for some reversal of the underlying cause for respiratory failure 2. Adequate oxygenation (e.g., PaO2/FIO2 > 150 to 200; PEEP = 8 cm H2O; FIO2 ≤ 0.4 to 0.5) and pH (e.g., >7.25) 3. Hemodynamic stability, defined as absence of active myocardial ischemia and absence of clinically significant hypotension (i.e., requiring no vasopressor therapy or therapy with only low-dose vasopressors) 4. The capability to initiate an inspiratory effort

Despite the many weaning parameters that have been reported, no single criterion is better at predicting extubation readiness than a spontaneous breathing trial (SBT) with an integrated assessment focusing on the respiratory pattern, gas exchange, hemodynamics, and comfort. Over-reliance on weaning parameters may result in prolonged stay on the ventilator.115 It also is important to reduce or temporarily discontinue sedation in preparation for ventilator liberation; this strategy has been reported to decrease both days of ventilation and mortality.92,116 Respiratory Recap Liberation from Mechanical Ventilation ∎ Regularly assess for liberation readiness. ∎ Perform a spontaneous breathing trial to assess readiness for extubation. ∎ If a spontaneous breathing trial is not tolerated, assess for causes of failure. ∎ Do not use SIMV as a weaning mode. ∎ Use protocols to improve successful liberation.

Approaches to Liberation Two prospective randomized controlled trials compared intermittent mandatory ventilation (IMV) weaning (i.e., gradual reduction in mandatory breath rate), PS weaning (i.e., gradual reduction in the level of PS), and daily (or twice-daily) SBT.117,118 In these studies, after the patient met screening criteria, the healthcare team performed an SBT. Both studies reported that the majority of patients were successfully extubated after the first SBT. In those who failed the initial SBT, no difference in

duration of ventilation was seen between the T piece and PS methods. Both the SBT and PS methods were superior to IMV in both studies. Although newer-generation ventilators feature modes intended to facilitate weaning (e.g., SmartCare, adaptive support ventilation, volume support), conclusive evidence is lacking that they hasten ventilator liberation compared with use of a daily SBT. The traditional approach to an SBT uses a T piece; the patient is removed from the ventilator, and humidified supplemental oxygen is provided. Humidified gas typically is provided as a heated or cool aerosol of water from a large-volume nebulizer. For patients with reactive airways, this aerosol may induce bronchospasm. In such cases, a humidification system that does not generate an aerosol should be used, such as a heated passover humidifier. Avoid the use of passive humidifiers (e.g., artificial noses, heat and moisture exchangers) because of their dead space and resistive workload. The SBT can be conducted without removing the patient from the ventilator—an approach that has several advantages. No additional equipment is required, and if the patient fails the SBT, the team can quickly reestablish ventilatory support. All the monitoring functions and alarms on the ventilator remain available during the SBT, which may allow prompt recognition that the patient is failing the SBT. The SBT can be performed with no positive pressure applied to the airway, with a low level of CPAP (5 cm H2O), with a low level of PS (5 to 8 cm H2O), or with the use of inspiratory pressure automatically titrated to overcome endotracheal tube resistance (i.e., tube compensation). Proponents of the CPAP approach argue that in a patient with obstructive lung disease, this low level of CPAP maintains airway patency if the patient cannot control exhalation because of the presence of the artificial airway. In patients with marginal left ventricular function, however, a low level of positive intrathoracic pressure may support the failing heart. Such patients may tolerate a CPAP trial but then develop congestive heart failure when extubated. Also, a low level of CPAP may counterbalance auto-PEEP and facilitate breath triggering in patients with COPD, resulting in a successful SBT but respiratory failure soon after extubation. Proponents of the low-level PS (or tube compensation) approach argue that this approach overcomes the resistance to breathing through the artificial airway.110 However, this argument fails to recognize that the

upper airway of an intubated patient typically is swollen and inflamed; thus, the resistance through the upper airway after extubation may be similar to that seen with the endotracheal tube in place.119 In one study, an SBT consisting of 30 minutes of 8 cm H2O PSV, compared with 2 hours of T piece led to significantly higher rates of successful extubation.120 However, that study did not evaluate the outcomes for a 30-minute T piece trial. Similar outcomes have been reported with or without the use of tube compensation during an SBT.54,121 Whether the team uses an on-ventilator or off-ventilator approach, the SBT might best be performed with no additional support.122,123 Similar outcomes are likely with a 2-hour SBT or a 30-minute SBT.124 In the acute care setting, tolerance of an SBT of 30 minutes’ to 2 hours’ duration should prompt consideration for extubation. For chronically ventilator-dependent patients with a tracheostomy, the length of each SBT is increased, with alternating periods of ventilatory support and SBT. In this case, the goal may be daytime liberation with nocturnal ventilation. Stop and Think You are caring for a patient who has been intubated for the past 3 days. How would you know if the patient is ready for liberation from mechanical ventilation?

Recognition of a Failed Spontaneous Breathing Trial A failed SBT is discomforting for the patient and may induce significant cardiopulmonary distress. Commonly listed criteria for discontinuation of an SBT include tachypnea (respiratory rate exceeding 35 breaths/min for 5 minutes or longer); hypoxemia (SpO2 less than 90%); tachycardia (heart rate of more than 140 beats/min or a sustained increase above 20%); bradycardia (sustained decrease in the heart rate of more than 20%); hypertension (systolic blood pressure of more than 180 mm Hg); hypotension (systolic blood pressure of less than 90 mm Hg); and agitation, diaphoresis, or anxiety. In some patients, the last three factors are not caused by SBT failure and can be appropriately treated with verbal reassurance or pharmacologic support. When SBT failure occurs, the team should promptly reestablish ventilatory support.

Causes of a Failed Spontaneous Breathing Trial When a patient fails an SBT, the reason should be identified and corrected before the healthcare team performs another SBT. Patients may fail an SBT for a variety of physiologic and technical reasons. For example, an excessive respiratory muscle load may be the cause. High airways resistance and low compliance contribute to the increased effort necessary to breathe. Auto-PEEP may delay liberation in patients with COPD, because it increases the pleural pressure needed to initiate inhalation. Electrolyte imbalance may cause respiratory muscle weakness. Inadequate levels of potassium, magnesium, phosphate, and calcium impair ventilatory muscle function. Appropriate nutritional support often improves the ventilator discontinuation process, but care should be taken to avoid overfeeding, because excessive caloric ingestion elevates carbon dioxide production. Failure of any major organ system can result in failure to liberate the patient from the ventilator. Fever and infection are of particular concern because they increase both oxygen consumption and carbon dioxide production, resulting in an increased ventilatory requirement. Cardiac dysfunction can delay liberation until the patient’s cardiovascular status has been appropriately managed. Diaphragm dysfunction is increasingly recognized as a potential consequence of mechanical ventilation. Too much support leads to atrophy whereas too little support leads to injury. This has led to the concept of diaphragm protective ventilation,125 where the proper level of support is applied to avoid atrophy and injury. Diaphragm dysfunction can lead to diaphragm fatigue, failed SBT, and prolonged mechanical ventilation. Once the patient has been judged to no longer need mechanical ventilatory support, attention turns to the need for the artificial airway. This requires a different set of assessments that focus on the patient’s ability to protect the natural airway. Key parameters include cough strength and the need for suctioning (i.e., suctioning requirements exceeding every 2 hours should preclude extubation). Although the ability to follow commands is desirable before extubation, it is not essential in patients who are otherwise able to protect the airway. In appropriately selected patients (e.g., those recovering from a COPD exacerbation), extubation to NIV may reduce the duration of

mechanical ventilation.126 Extubation to NIV can also be considered to prevent extubation failure in patients at risk for this outcome, such as those with COPD or cardiac disease. NIV is generally not recommended to rescue a failed extubation, except in patients with hypercapnic respiratory failure. NIV should not be used routinely following extubation.

Ventilator Discontinuation Protocols Ventilator discontinuation protocols based on routine SBTs have become increasingly popular in recent years, and respiratory therapists and nurses typically implement these protocols. Studies have reported improved outcomes when such protocols are used.127,128 Figure 20-33 presents the elements of an effective protocol. From these elements incorporating best evidence, the ICU can develop a specific protocol that matches its local culture. Note that the use of an SBT is central to the protocol.

FIGURE 20-33 An evidence-based approach to ventilator discontinuation and extubation.

Description

Sedation Critically ill mechanically ventilated patients often receive sedatives in the form of benzodiazepines and analgesics in the form of opioids to ensure comfort, minimize distress, and make invasive procedures tolerable. Oversedation may be responsible for prolonged mechanical ventilation and increased ICU length of stay. Strong evidence indicates that protocols aimed at targeting minimal sedation facilitate the performances of SBTs and shorten the discontinuation process. A more aggressive approach to manage sedation is to conduct daily interruptions of sedative infusions, called a

spontaneous awakening trial (SAT). These trials, when coupled with SBTs, have been shown to shorten the duration of mechanical ventilation. Notably, the control groups in most of these studies did not follow sedation minimization protocols—they received only physician-directed sedation.92 Unless contraindicated (e.g., because of active seizures, alcohol withdrawal, escalating sedative doses due to agitation, receiving neuromuscular blockers, evidence of active myocardial ischemia in the previous 24 hours, or evidence of increased intracranial pressure), an SAT can be considered on a daily basis. If the patient does not tolerate the SAT (as demonstrated by anxiety, agitation, pain, a tachypnea, desaturation, acute cardiac dysrhythmia, or respiratory distress), the clinician should restart the sedatives at half of the previous dose. If the patient tolerates the SAT, the healthcare team should conduct an SBT.

ABCDEF Bundle ICU-acquired weakness affects as many as half of all critically ill patients and prolongs mechanical ventilation. Early mobilization, including ambulation, of mechanically ventilated patients is safe and feasible and may result in better functional outcomes. Combining protocols for early mobility and sedation management may have synergistic benefits, as do combined protocols for sedation and SBTs. This has informed the ABCDEF bundle:129 A. Assess, prevent, and manage pain B. Both spontaneous awakening and breathing trials C. Choice of analgesia and sedation D. Delirium—assess, prevent, and manage E. Early mobility and exercise F. Family engagement/empowerment

Key Points The healthcare team should strive to avoid complications during mechanical ventilation. Ventilator-induced lung injury includes alveolar overdistention and repetitive opening and closing. Volume control maintains minute ventilation but allows airway pressure and plateau pressure to fluctuate. Pressure control allows minute ventilation to fluctuate but limits airway pressure to the peak pressure set on the ventilator. Modes on modern ventilators include continuous mandatory ventilation (assist/control), synchronized intermittent mandatory ventilation, pressure support, continuous positive airway pressure, adaptive pressure control, adaptive support ventilation, airway pressure release ventilation, tube compensation, proportional assist ventilation, neurally adjusted ventilatory assist, and high-frequency oscillatory ventilation. Tidal volume should be set to avoid overdistention lung injury: 6 mL/kg PBW is a suggested initial setting. Respiratory rate and I:E ratio are set to control the PaCO2 and to avoid hemodynamic compromise and auto-PEEP. FIO2 initially should be set at 1 and then weaned according to pulse oximetry to maintain an SpO2 in the range of 88% to 95%. PEEP should be set to avoid alveolar derecruitment for patients with ARDS and to counterbalance auto-PEEP in patients with COPD. The following items should be monitored in the mechanically ventilated patient: physical signs and symptoms, blood gas measurements, lung mechanics, hemodynamics, patient–ventilator synchrony, and sedation. The most important aspect of liberation from mechanical ventilation is assessment for readiness. A spontaneous breathing trial identifies most patients who are ready for liberation from mechanical ventilation. The poorest outcomes from the ventilator discontinuation process have been reported with SIMV.

If patients do not tolerate a spontaneous breathing trial, clinicians should reestablish ventilatory support, reassess sedation targets, and identify the cause of the failure. Early mobility of mechanically ventilated patients can lead to improved functional outcomes.

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Care Med 1999;159(2):512–518. 125. Schepens T, Dres M, Heunks L, Goligher EC. Diaphragm-protective mechanical ventilation. Curr Opin Crit Care 2019;25(1):77–85. 126. Hess DR. The role of noninvasive ventilation in the ventilator discontinuation process. Respir Care 2012;57(10):1619–1625. 127. Girard TD, Ely EW. Protocol-driven ventilator weaning: reviewing the evidence. Clin Chest Med 2008;29(2):241–252. 128. Haas CF, Loik PS. Ventilator discontinuation protocols. Respir Care 2012;57(10):1649–1662. 129. Pun BT, Balas MC, Barnes-Daly MA, Thompson JL, Aldrich M, Barr J, et al. Caring for critically ill patients with the ABCDEF bundle: results of the ICU liberation collaborative in over 15,000 adults. Crit Care Med 2019;47(1):3–14.

CHAPTER

21 Noninvasive Respiratory Support Dean R. Hess

© Andriy Rabchun/Shutterstock

OUTLINE High-Flow Nasal Cannula Interfaces for CPAP and NIV Continuous Positive Airway Pressure Noninvasive Positive Pressure Ventilation Sequential Use of NIV and HFNC Negative Pressure Ventilation, Rocking Beds, and Pneumobelts

OBJECTIVES 1. Compare high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and noninvasive ventilation (NIV). 2. List selection criteria for HFNC, CPAP, and NIV. 3. Describe interfaces and ventilators for HFNC, CPAP, and NIV. 4. Compare acute care applications of CPAP and CPAP to treat obstructive sleep apnea. 5. Discuss issues of adherence with CPAP for treatment of obstructive sleep apnea. 6. Describe the operation and use of auto-positive airway pressure devices. 7. Compare noninvasive positive pressure ventilation, negative pressure ventilation, and continuous positive airway pressure. 8. Discuss the role of humidification in the application of HFNC, CPAP, and NIV. 9. Describe the principles of negative pressure ventilation, rocking beds, and pneumobelts.

KEY TERMS auto-positive airway pressure (APAP) continuous positive airway pressure (CPAP) cuirass expiratory positive airway pressure (EPAP) helmet high-flow nasal cannula (HFNC) inspiratory positive airway pressure (IPAP) iron lung nasal mask nasal pillow negative pressure ventilation noninvasive ventilation (NIV) oronasal mask pneumobelt rocking bed total face mask

Introduction Noninvasive respiratory support refers to high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and noninvasive ventilation (NIV) (Figure 21-1). HFNC and CPAP provide respiratory support, and NIV provides ventilatory support without an endotracheal tube or tracheostomy tube. Both positive pressure and negative pressure approaches can be used to provide NIV. This chapter covers the clinical and technical aspects of the application of HFNC, CPAP, and NIV.

FIGURE 21-1 A comparison of the physiologic effects of high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and noninvasive ventilation (NIV).

High-Flow Nasal Cannula The conventional nasal cannula is limited to a flow of 6 to 8 L/min, because higher flows are uncomfortable for patients. With the use of heated humidification, however, higher flows become more comfortable. HFNC delivers flows of up to 60 L/min.1,2 The gas source (air/oxygen blender, ventilator, or turbine flow generator) is connected via an active heated humidifier to a nasal cannula and allows FIO2 adjustment independent from the flow (Figure 21-2).

FIGURE 21-2 High-flow nasal cannula (HFNC). An air/oxygen blender, allowing FIO2 ranging from 0.21 to 1.0, generates flows of up to 60 L/min. The gas is heated and humidified by an active heated humidifier and delivered via a single limb. From Papazian L, Corley A, Hess D, Fraser JF, Frat JP, Guitton C, et al. Use of high-flow nasal cannula oxygenation in ICU adults: a narrative review. Intensive Care Med 2016;42(9):1336– 1349.

Mechanism of Action

HFNC can provide respiratory support by several mechanisms (Figure 21-3).1–5 The high flow minimizes room-air entrainment, making a more precise FIO2 possible, in any concentration from room air to 100% O2. The high flow flushes CO2 from the upper airway during exhalation, which reduces the anatomic dead space. Owing to the high flow presented to the pharynx, the respiratory muscles do not need to overcome the resistance through the upper airway. A common finding in studies evaluating HFNC is a reduction in respiratory rate, which is likely the result of a lower minute ventilation requirement because dead space is decreased. The reduction of anatomic dead space and upper airway resistance reduces the work of breathing. The high flow opposes expiratory flow, which results in a modest CPAP effect with an increase in lung volume (Figure 21-4). With the mouth closed, pharyngeal pressure increases approximately 1 cm H2O for each 10 L/min of flow.6 However, the CPAP effect can be lost if the patient opens their mouth. Because the gas is humidified, HFNC might also help with airway clearance.

FIGURE 21-3 Mechanisms of action for high-flow nasal cannula (HFNC) in acute hypoxemic respiratory failure. HFNC exerts a range of important and interdependent physiologic effects on a variety of factors that may determine clinical outcomes for patients with acute respiratory failure. From Goligher EC, Slutsky AS. Not just oxygen? Mechanisms of benefit from high-flow nasal cannula in hypoxemic respiratory failure. Am J Respir Crit Care Med 2017;195(9):1128-1131.

Description

FIGURE 21-4 Relationship between cumulative change in end-expiratory lung impedance, mean breathing frequency, and mean nasopharyngeal airway pressure. From Parke RL, Bloch A, McGuinness SP. Effect of very-high-flow nasal therapy on airway pressure and end-expiratory lung impedance in healthy volunteers. Respir Care 2015;60(10):1397-1403.

Increasing flow with HFNC leads to a dose–response physiologic effect.7,8 One of the important benefits of HFNC is patient comfort, which seems to be better with HFNC than with other forms of noninvasive support such as CPAP and NIV. A temperature of 31° C has been reported to be more comfortable than a temperature of 37° C. Comfort is similar at a flow of 30 L/min and 60 L/min.9 Respiratory Recap Physiologic Mechanism of HFNC

∎ Precise FIO2 ∎ Flushing of anatomic dead space ∎ Overcomes upper airway resistance ∎ Increased pharyngeal pressure and lung volume ∎ Heated humidity might improve airway clearance

HFNC Prongs Special prongs for HFNC are available in various sizes from several manufacturers (Figure 21-5). They are available in two types: large bore and small bore. The large-bore cannula has a larger diameter to accommodate high flow (up to 60 L/min), whereas the small-bore cannula uses a lower flow (up to 40 L/min). The small-bore cannula produces high-velocity nasal insufflation: The gas velocity exiting such a cannula is greater than that for the larger-bore cannula. The larger-bore cannula should produce partial occlusion of nares, thereby increasing pharyngeal pressure. The high velocity from the small-bore cannula may produce better clearing of dead space. However, this effect has not been well studied, and whether one style results in better outcomes than another is not known.

FIGURE 21-5 Commercially available nasal prongs for high-flow nasal cannula. (A) Flo Easy™, Westmed. Retrieved from https://westmedinc.com/flo-easy/; (B) High Flow Oxygen Therapy, Flexicare Medical Limited. Retrieved from https://www.flexicare.com/categories/high-flow-oxygen-therapy-en-us/?lang=en-us. (C) AcuCareTM high flow nasal cannula (HFNC), © Resmed. All Rights Reserved (D) Comfort Flo® Plus Cannula. Image courtesy of Teleflex Incorporated. © Teleflex Incorporated. All rights reserved.

Clinical Indications The most common indication for HFNC is acute hypoxemic respiratory failure.10 Compared to conventional oxygen therapy, the intubation rate is decreased with HFNC.11 The benefit of HFNC with immune compromise is controversial.12–14 Use of HFNC post-extubation is also controversial, with conflicting results from randomized controlled trials.15–17 Evidence is not sufficiently mature to recommend the use of HFNC for other acute illnesses such as chronic obstructive lung disease (COPD), asthma, or congestive heart failure.18–20 Figure 21-6 provides an algorithm for the application of HFNC.21 It is important to recognize when this therapy is failing and the clinician needs to proceed to a definitive therapy such as endotracheal intubation. The ROX index has been reported as a valid method to determine success or failure of HFNC.22 It is calculated as follows:

FIGURE 21-6 Flow diagram of use of high-flow nasal cannula for hypoxemic acute respiratory failure. Levy SD, Alladina JW, Hibbert KA, Harris RS, Bajwa EK, Hess DR. High-flow oxygen therapy and other inhaled therapies in intensive care units. Lancet 2016; 387(10030):1867–1878.

Description ROX = (SpO2/FIO2)/(respiratory rate) ROX ≥ 4.88 is associated with success of HFNC. With ROX < 3.85, the clinician should consider implementing endotracheal intubation. With ROX = 3.85–4.77, the patient should be monitored closely, such as in an intensive care unit (ICU). Respiratory Recap Indications for HFNC Evidence to support HFNC: ∎ Acute hypoxemic respiratory failure ∎ Risk of post-extubation hypoxemic respiratory failure Evidence not sufficiently robust: ∎ Chronic obstructive lung disease ∎ Asthma ∎ Cardiogenic pulmonary edema

Interfaces for CPAP and NIV Similar interfaces are used for CPAP and NIV.23,24 The interface has a major impact on patient comfort and adherence during NIV, as a poorly fitting interface decreases clinical effectiveness and patient adherence. A number of interfaces are available, each of which has both advantages and disadvantages (Table 21-1). The most commonly used interfaces are oronasal masks and nasal masks. Other options include nasal pillows, mouthpieces, total face masks, hybrid masks, and helmets (Figure 217). In each case, a variety of sizes and designs are commercially available. Desirable features of a mask include low dead space, transparency, light weight, being easy to secure, having an adequate seal with low facial pressure, being disposable or easy to clean, being nonirritating to the skin, and low cost.

FIGURE 21-7 Interfaces for NIV and CPAP. (A) Oronasal mask. (B) Nasal mask. (C) Nasal pillows. (D) Total face mask. (E) Hybrid. (F) Helmet. (A) ResMed 2010. Used with permission; (B) Courtesy of Philips Respironics; (C) ResMed 2014. Used with permission (D) Courtesy of Philips Respironics; (E) ResMed 2010. Used with permission; (F) Courtesy of StarMed SpA.

TABLE 21-1 Advantages and Disadvantages of Various Types of Interfaces for Noninvasive Ventilation Interface

Advantages

Disadvantages

Nasal mask

Less risk for aspiration Easier airway clearance Less claustrophobia Easier speech May be able to eat

Mouth leak Higher resistance through nasal passages Less effective with nasal obstruction Nasal irritation and rhinorrhea

Easy to fit and secure Less dead space

Upper airway dryness with mouth leak

Nasal pillows

Lower profile Less facial skin breakdown Simple headgear Easy to fit

Mouth leak Higher resistance through nasal passages Less effective with nasal obstruction Nasal irritation and rhinorrhea Upper airway dryness with mouth leak

Oronasal mask

Better oral leak control More effective in mouth breathers

Increased dead space Increased aspiration risk Increased difficulty speaking and eating Asphyxiation with ventilator malfunction

Mouthpiece

Less interference with speech Very little dead space May not require headgear

Less effective if the patient cannot maintain a good mouth seal Usually requires a nasal or oronasal interface at night Nasal leak Potential for orthodontic injury

Hybrid

Eliminates mouth leak Lower profile allows wearing eyeglasses Less facial skin breakdown

Increased aspiration risk Increased difficulty speaking and eating Asphyxiation with ventilator malfunction

Total face mask

May be more comfortable for some patients Easier to fit Less facial skin breakdown

Potentially greater dead space Potential for drying of the eyes Cannot deliver aerosolized medications

Helmet

May be more comfortable for some patients Easier to fit (one size fits all) Less facial skin breakdown

Rebreathing Poorer patient–ventilator synchrony Asphyxiation with ventilator malfunction Cannot deliver aerosolized medications

The mask cushion produces the seal between the mask and the patient (Figure 21-8). Although the mask fit should minimize air leakage, small leaks are common and do not necessarily compromise the effectiveness of CPAP or NIV. Nasal or oronasal masks designed for CPAP and NIV often use an open cushion with an inner lip, in which pressure inside the mask pushes the cushion against the face. The mask cushion should be soft and malleable to the facial anatomy. Anesthesia

and resuscitation masks are not desirable for NIV. Some masks have an inflatable cushion, and some are gel filled. A correctly sized mask minimizes leak, improves comfort, and improves effectiveness.

FIGURE 21-8 Styles of cushions on masks for NIV and CPAP. (A) Inner flap. (B) Gel. (C) Air filled. (D) Foam filled. (A), (B), and (C) Courtesy of Philips Respironics; (D) Courtesy of Med Systems.

Masks for use with a bilevel ventilator or CPAP machine may incorporate a leak port and an anti-asphyxia port that opens if flow is lost from the ventilator (Figure 21-9). Masks used with a conventional ventilator have a standard elbow without a leak port. Oronasal masks also have quick-release features so that the mask can be removed quickly. The hybrid interface is a combination of nasal pillows and a mask that fits over the mouth. The total face mask fits over the entire face.

FIGURE 21-9 Masks with anti-asphyxia valve, leak ports, and standard elbow. (A) and (C) Courtesy of Philips Respironics; (B) © ResMed 2014. Used with permission.

The helmet comprises a transparent, latex-free polyvinyl chloride

cylinder linked by a metallic ring to a soft collar that seals the helmet around the neck. It has been proposed as an alternative to conventional face masks for NIV in patients with acute respiratory failure. One concern with the use of the helmet is the risk of rebreathing. The helmet may also be less effective in unloading inspiratory muscles compared with a standard face mask and has been associated with patient–ventilator asynchrony. The nasal mask should fit just above the junction of the nasal bone and cartilage, directly at the sides of the nares, and just below the nose above the upper lip. The oronasal mask should fit just above the junction of the nasal bone and cartilage to just below the lower lip. Sizing gauges are available to properly fit masks. They are mask specific and cannot be interchanged among manufacturers or different mask styles of the same manufacturer. A mask that is too large results in leaks, decreased effectiveness, and patient discomfort. Leaks through the mouth are especially common when using a nasal mask and can lead to unsuccessful NIV. When mouth leak interferes with the effectiveness of ventilation with a nasal mask, healthcare providers might consider trying a chin strap. In addition, use of a nasal mask and mouth leak may produce upper airway dryness, which can be addressed by using an oronasal mask or heated humidification. For many patients with acute respiratory failure, the oronasal mask or total face mask is better tolerated than a nasal interface. Appropriate headgear is needed to maintain the mask in the correct position. Most masks designed specifically for NIV and CPAP use cloth straps and Velcro to secure the mask. A common mistake is to fit the headgear too tightly: The clinician should be able to pass one or two fingers between the headgear and the face. Fitting the headgear too tightly may not improve the fit and decreases patient comfort and adherence. The design of most masks for NIV is such that the top of the mask is secured on the forehead rather than at the bridge of the nose. Forehead spacers and an adjustable bridge on the mask are used to decrease pressure on the bridge of the nose. Respiratory Recap Interfaces

∎ Nasal mask ∎ Oronasal mask ∎ Total face mask ∎ Nasal pillows ∎ Hybrid ∎ Mouthpiece ∎ Helmet

Stop and Think Which do you think is better, a nasal interface or an oronasal interface? Explain why.

Respiratory Recap Choosing an Interface ∎ Use the proper interface for the patient. ∎ Avoid an interface that is too large. ∎ Avoid strapping the mask too tightly.

Pressure sores on the bridge of the nose are a common complaint during NIV, but ulceration and skin breakdown are avoided in most patients. Clinicians should implement measures to reduce pressure injury as soon as signs of soreness occur at the bridge of the nose. They should reassess for correct mask fit and size and reduce the tension of the headgear. They may also try a different mask style, such as a hybrid mask or total face mask. The incidence of facial skin breakdown might be lower with a total face mask compared with an oronasal mask.25 A hydrocolloid dressing can also be applied to prevent pressure sores, such as over the bridge of the nose. Stop and Think A patient receiving noninvasive ventilation is developing facial skin breakdown. What would you do to remedy this problem?

Continuous Positive Airway Pressure CPAP has applications in both the acute and chronic care of patients. In acute care, noninvasive (mask) CPAP is used to administer intermittent lung expansion therapy, to treat acute cardiogenic pulmonary edema, and to treat acute hypoxemic respiratory failure. In chronic care, CPAP is used to treat obstructive sleep apnea (OSA).

Acute Care Applications Mask CPAP is an effortless, painless type of respiratory care to prevent postoperative atelectasis.26 It has been used in patients with acute hypoxemic respiratory failure to improve PaO2.27 Although mask CPAP can produce an initial improvement in PaO2, it may not improve important outcomes such as intubation rate or hospital mortality. The strongest evidence for the use of mask CPAP is for patients with acute cardiogenic pulmonary edema. In these patients, the increase in intrathoracic pressure associated with CPAP decreases preload, decreases afterload, improves lung compliance, decreases intrapulmonary shunt, and increases PaO2. A typical CPAP level of 5 to 10 cm H2O is used in this indication. Mask CPAP, similar to NIV, decreases the intubation rate and improves the survival rate in patients with acute cardiogenic pulmonary edema.28 To provide mask CPAP for acute care applications, a bilevel ventilator is set to the CPAP mode. Otherwise, a stand-alone CPAP circuit can be used. The CPAP circuit (Figure 21-10) consists of a high-flow gas source and an expiratory valve that maintains pressure in the circuit at the desired level (5 to 20 cm H2O). CPAP requires a relatively high gas flow to provide the desired positive airway pressure and to meet patient flow demand. One CPAP device used primarily in the prehospital setting is the Boussignac CPAP system (Figure 21-11). It uses a virtual valve, consisting of a small cylinder with four microchannels. When receiving oxygen flow, turbulence is generated inside the cylinder, resulting in positive pressure. The performance of the Boussignac CPAP system depends on the delivered oxygen flow. The operator cannot set the FIO2

and CPAP, because both result from the oxygen flow setting and the amount of air entrained by the patient’s spontaneous breathing efforts.29

FIGURE 21-10 (A) CPAP circuit for acute respiratory failure. (B) Commercially available CPAP/PEEP valves. (C) Commercially available system for CPAP. (A) Adapted from Branson RD. Spontaneous breathing systems: IMV and CPAP. In: Branson RD, Hess DR, Chatburn RL, eds. Respiratory care equipment. 2nd ed. Philadelphia: JB Lippincott; 1999; (B) Courtesy of Ambu, Inc.; (C) Vital Signs, Inc. Used with permission of GE Healthcare. All rights reserved.

FIGURE 21-11 Boussignac CPAP system. CPAP Boussignac Adolescent Respiratory Assistance Kit, Vygon.

CPAP valves are classified as threshold resistors or fixed orifices. Threshold resistors maintain a constant pressure in the circuit, regardless of flow. A pressure exceeding the threshold opens the valve and allows expiration, whereas pressures below threshold allow the valve to close, sealing the circuit and stopping the flow of gas. Commonly used threshold resistor devices use spring tension to produce CPAP (Figure

21-12). With the fixed-orifice device, a restricted opening of a fixed size is found at the end of the expiratory limb of a breathing circuit. The resistance through the fixed orifice produces backpressure, which is CPAP pressure produced in the circuit. For a given flow, a higher pressure is generated with a smaller orifice. Expiratory pressure depends on the flow, so pressure decreases as flow decreases. Although the fixed-orifice resistor has been largely abandoned in adult respiratory care, it remains in use in neonatal care.

FIGURE 21-12 (A) Threshold resistor CPAP valve. (B) Fixed-orifice CPAP valve. Adapted from Banner MJ, Lampotang S. Expiratory pressure valves. In: Branson RD, Hess DR, Chatburn RL, eds. Respiratory care equipment. 2nd ed. Philadelphia: JB Lippincott; 1999.

Respiratory Recap Acute Care Applications of Mask CPAP ∎ Postoperative pulmonary complications ∎ Hypoxemic respiratory failure ∎ Cardiogenic pulmonary edema

CPAP for Obstructive Sleep Apnea When applied at the appropriate pressure, CPAP eliminates the softtissue obstruction of the upper airway associated with obstructive sleep

apnea (OSA). CPAP pressure is prescribed after a sleep study during which the pressure is titrated to the pressure necessary to eliminate apnea and hypopnea.

CPAP Equipment for OSA Selecting the appropriate interface and the correct size for each individual patient is one of the most important factors determining whether a patient will be successful in long-term use of CPAP therapy. Inappropriate selection of the interface and its size, or incorrect selection, fitting, or adjustment of the headgear, results in leaks around the mask (especially around the bridge of the nose at the corners of the eyes) and skin irritation, which can lead to tissue breakdown and ulceration. Numerous brands and models of CPAP machines are commercially available (Figure 21-13).30 The basic models consist of an electrically operated flow generator (fan or turbine) that draws room air through a particulate filter (a gross particulate filter to remove dust, lint, and other large airborne matter) and a secondary filter (to capture smaller particles, such as pollen and spores). The operator enters the prescribed pressure, usually through digital electronics, into the unit’s microprocessor, which causes the flow generator to deliver the flow necessary to maintain the prescribed pressure. CPAP systems are designed to operate with a builtin leak in the circuit. This leak port usually is found in the mask or between the tubing and mask. Because the system is designed to compensate for this leak and maintain the designated pressure, it also accommodates other small to moderate leaks that occur.

FIGURE 21-13 CPAP machines used in the treatment of obstructive sleep apnea. (A) Reproduced with the permission of Koninklijke Philips N.V. All rights reserved; (B) © ResMed 2014. Used with permission.

The pressure settings on most CPAP units range from 3 to 20 cm H2O. Most units also have an adjustable setting referred to as ramp or delay. When the prescribed pressure exceeds 10 cm H2O, some CPAP users may be bothered by the high flow. Because obstructive episodes do not occur until the patient has been asleep for a period of time, the patient, after putting on the interface and adjusting for any leaks, can activate the ramp/delay feature. This causes the pressure to drop to 4 to 6 cm H2O, a more tolerable level, while the patient falls asleep. The ramp feature can be preset to range from 5 to 45 minutes. The unit’s microprocessor divides the set prescribed pressure by the number of ramp minutes and delivers an increasing pressure until the prescribed level is reached.

Improving Patient Adherence with CPAP for OSA Table 21-2 lists common problems, and usual solutions, associated with the use of CPAP for OSA.31 Respiratory therapists commonly encounter patients who use CPAP, and they should be prepared to assist such patients with these problems. Some patients have difficulty adjusting to their interface and/or therapeutic pressure after their CPAP titration in the sleep lab. These patients may benefit from desensitization. That is, CPAP can be applied with a lower than therapeutic pressure to help the patient adjust to the pressure. When the patient has adapted to the lower pressure, the pressure is gradually increased to the prescribed level. The patient can be encouraged to continue acclimation exercises by performing practice-breathing sessions with the interface and pressure for short periods during a distraction such as watching television, listening to music, or reading a book. Patients should use CPAP when they take a nap and are encouraged to use it during the first 4 to 5 hours of sleep, with the goal of using CPAP throughout the night. TABLE 21-2 Problems with the Use of CPAP for Obstructive Sleep Apnea Problem

Cause

Solution

Nasal irritation, congestion,

Dry air

Heated humidification

or rhinorrhea

Chronic rhinitis Nasal allergies

Nasal decongestants Nasal steroids Antihistamines

Dry throat and/or mouth

Dry air Mouth leak

Heated humidification Chin strap Oronasal or total face interface

Painful pressure in ears

High airway pressure Nasal congestion

Verify CPAP level Decrease CPAP level Trial on auto or bilevel mode Nasal decongestants Nasal steroids

Gastric bloating and/or chest discomfort

Air swallowing High airway pressure

Decrease CPAP level Trial on auto or bilevel mode

Claustrophobia

Anxiety Interface

Desensitization Anxiolytics Optimize interface fit

Nasal pressure sores

Poor interface fit

Readjust headgear Change interface size or style Apply skin protection Reassess patient education on interface fit

Eye irritation

Interface air leak

Readjust headgear Change interface size or style Reassess patient education on interface fit

Skin creases

Improperly adjusted headgear

Readjust headgear Change interface size or style Reassess patient education on interface fit

Skin irritation

Sensitivity to interface Improperly adjusted headgear Heat rash

Trial using nasal pillows Readjust headgear Lower temperature on humidifier Trial using nasal pillows or skin protector

Air leaks

Excessive interface/headgear wear Poor interface fit Improperly adjusted

Replace interface and/or headgear Change interface Readjust headgear

headgear Excessive air pressure Facial hair interference

Verify pressure setting Consider pressure change Consider auto or bilevel mode Trial with nasal pillows Shave

CPAP, continuous positive airway pressure. Reproduced from Allen KY, Bollig S, Selecky PA, Smalling T. The clinician’s guide to PAP adherence. Irving, TX: American Association for Respiratory Care; 2009. Reprinted with permission from the American Association for Respiratory Care.

Upper airway discomforts of dryness of the nasal passages and/or the mouth, epistaxis, nasal congestion, and rhinitis are frequent complaints of CPAP users. The flow of air through the nasal passages during CPAP therapy, especially when high pressures are required, leads to drying and inflammation of the mucous membranes. The inflamed nasal mucosa restricts airflow, increasing nasal airway resistance, which is especially problematic in patients who sleep with their mouths open. The use of a chin strap (Figure 21-14) to help keep the mouth closed may lessen this problem in some patients. Heated humidification during CPAP therapy improves comfort and adherence.

FIGURE 21-14 Chin straps used to prevent mouth leak. (A) Courtesy of SP Medical (B) Courtesy of Philips Respironics.

A number of manufacturers have incorporated into their units the capability to record, and hold in memory, data such as the date, time on and off, time at pressure, leak, and use of a ramp. Some units identify and report an apnea hypopnea index (AHI) and periodic breathing. The stored data can be downloaded to a computer and the raw data uploaded to a computer program that displays the data in various graphic and tabular formats. This information can prove valuable to the equipment provider, referring physician, sleep laboratory, and insurer because it provides details of ongoing patient adherence and helps identify problems requiring intervention. Some patients find exhaling against the CPAP difficult, creating a feeling of discomfort and anxiety. Bilevel positive airway pressure systems are an alternative for individuals unable to tolerate CPAP therapy. With a bilevel device, the IPAP and EPAP are adjusted independently. The IPAP level is set at a point that eliminates the sleepdisordered breathing (apneas, hypopneas, snoring). The EPAP is set at a lower pressure to allow the patient to exhale against less resistance yet maintain airway splinting and patency. The use of bilevel therapy leads to a lower mean airway pressure, which may increase comfort and tolerance. The pressure required to prevent airway collapse varies in most patients from night to night, and from hour to hour throughout any night, because of changes in body position, level and stage of sleep, ingestion of alcohol or caffeine, and airway congestion. Some devices, called autopositive airway pressure (APAP), respond to upper airway changes by automatically adjusting the pressure within a range of 4 to 20 cm H2O.32 These auto-titrating devices monitor one or more of the following parameters: pharyngeal wall vibration (snoring), inspiratory flow limitation, hypopnea, and apnea. The APAP algorithms used by different manufacturers are proprietary and may vary greatly in their response to respiratory events. The system responds automatically when it senses an impending respiratory event by slowly increasing the pressure in a stepwise pattern until airway patency is reestablished. After a few minutes, the pressure slowly decreases to the lowest pressure possible

to maintain airway stability. APAP devices are useful for patients who require different pressures in different sleep positions or sleep stages and for patients who have weight loss or return of daytime sleepiness and require assessment of their CPAP settings. Such systems report useful information such as AHI and periodic breathing. Use of APAP devices is controversial, however, particularly if used in lieu of a formal sleep study. Guidelines for the appropriate use of these devices have been published (CPG 21-1).33 CLINICAL PRACTICE GUIDELINE 21-1 Recommendations for the Use of Auto-Positive Airway Pressure (APAP) from the Standards of Practice Committee of the American Academy of Sleep Medicine

▪

Positive airway pressure (PAP) devices are not recommended to diagnose obstructive sleep apnea (OSA).

▪

Patients with congestive heart failure (CHF); patients with significant lung disease, such as chronic obstructive pulmonary disease (COPD); patients expected to have nocturnal oxygen desaturation due to conditions other than OSA (e.g., obesity hypoventilation syndrome); patients who do not snore (either naturally or as a result of palate surgery); and patients who have central sleep apnea syndromes are not candidates for APAP titration or treatment.

▪ ▪

APAP devices are not currently recommended for split-night titration.

▪

Certain APAP devices may be initiated and used in the self-adjusting mode for unattended treatment of patients with moderate to severe OSA without significant comorbidities (CHF, COPD, central sleep apnea syndromes, or hypoventilation syndromes).

▪

Certain APAP devices may be used in an unattended way to determine a fixed CPAP treatment pressure for patients with moderate to severe OSA without significant comorbidities (CHF, COPD, central sleep apnea syndromes, or hypoventilation syndromes).

▪

Patients being treated with fixed CPAP on the basis of APAP titration or being treated with APAP must have close clinical follow-up to determine treatment effectiveness and safety.

▪

A reevaluation and, if necessary, a standard attended CPAP titration should be performed if symptoms do not resolve or the APAP treatment otherwise appears to lack efficacy.

Certain APAP devices may be used during attended titration with polysomnography to identify a single pressure for use with standard continuous positive airway pressure (CPAP) for treatment of moderate to severe OSA.

Adapted from Morgenthaler TI, Aurora RN, Brown T, Zak R, Alessi C, Boehlecke B, et al. Practice parameters for the use of autotitrating continuous positive airway pressure devices for titrating pressures and treating adult patients with obstructive sleep apnea syndrome: an update for 2007: an American Academy of Sleep Medicine report. Sleep 2008;31(1):141–147.

Expiratory pressure relief (C-Flex) has been shown to be associated with similar outcomes to standard CPAP but improves adherence among those patients with low adherence.34 This feature allows for a slight decrease in pressure at the beginning of exhalation. Although it is primarily designed to address the patient’s comfort level and perception that exhalation against a positive pressure is difficult, the actual pressure decrease varies from one manufacturer to another. Respiratory Recap Factors Affecting CPAP Adherence ∎ Poor patient education and understanding ∎ Improper interface size, selection, and fit ∎ Drying of nose and mouth ∎ High inward flow during exhalation

Stop and Think A patient is admitted to the hospital for routine surgery. You are asked to see the patient because he is intolerant of CPAP, which has been prescribed for severe OSA. What strategies might you recommend to improve the patient’s tolerance for this therapy?

Noninvasive Positive Pressure Ventilation Acute Care Applications NIV is commonly used in the treatment of patients with acute respiratory failure (Box 21-1).35,36 In appropriately selected patients, NIV decreases the need for endotracheal intubation, decreases the risk of nosocomial pneumonia, and improves survival. The strongest evidence supporting the use of NIV is seen in patients with COPD exacerbation, acute cardiogenic pulmonary edema, treatment of postoperative acute respiratory failure, and prevention of post-extubation acute respiratory failure (CPG 21-2).36–38 In addition, NIV is being used increasingly to prevent extubation failure.39 Nevertheless, for patients in whom a spontaneous breathing trial fails, early extubation to NIV does not shorten time to liberation from any ventilation.40 CLINICAL PRACTICE GUIDELINE 21-2 Guidelines for Noninvasive Ventilation tor Acute Respiratory Failure NIV Should Be Used For:

▪ ▪ ▪ ▪ ▪

COPD exacerbation Acute cardiogenic pulmonary edema Postoperative respiratory failure. Chest trauma with acute respiratory failure Prevention of post-extubation respiratory failure in high-risk patients

NIV Should NOT Be Used For:

▪ ▪ ▪

Hypercapnia without acidosis for COPD exacerbation Prevention of post-extubation respiratory failure in non-high-risk patients Established post-extubation respiratory failure

No Recommendation:

▪ ▪

Acute respiratory failure due to asthma De novo acute respiratory failure (e.g., ARDS)

From Rochwerg B, Brochard L, Elliott MW, Hess D, Hill NS, Nava S, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J 2017;50:1602426 [https://doi.org/10.1183/13993003.02426-2016].

BOX 21-1 Selection of Appropriate Patients for Noninvasive Ventilation Step 1: Patient Needs Mechanical Ventilation Respiratory distress with dyspnea, use of accessory muscles, or abdominal paradox Respiratory acidosis; pH < 7.35 with PaCO2 > 45 mm Hg Tachypnea; respiratory rate > 25 breaths/min Diagnosis shown to respond well to noninvasive ventilation (e.g., chronic obstructive pulmonary disease, cardiogenic pulmonary edema)

Step 2: No Exclusions for Noninvasive Ventilation Airway protection: respiratory arrest, unstable hemodynamics, high aspiration risk, copious secretions Unable to fit mask: facial surgery, craniofacial trauma or burns, anatomic lesion of upper airway Uncooperative patient; anxiety Patient wishes

It is important to monitor tidal volume during NIV, as a tidal volume greater than 10 mL/kg is predictive of NIV failure. The initial response to NIV may also predict success or failure.41 A more rapid decrease in PaCO2 occurs in patients for whom NIV is successful. Unsuccessful nasal NIV has been associated with greater severity of illness, greater mouth leak, and increased difficulty acclimating to NIV. Greater mouth leak is often seen with patients who are edentulous, have excess secretions, and use pursed-lip breathing. Better success of NIV has been reported for patients with higher baseline pH levels, perhaps because low pH is a marker of more severe illness. Likewise, a good level of consciousness has been associated with successful responses to NIV for patients with COPD and acute hypercapnic respiratory failure. If a patient does not improve on NIV within 1 to 2 hours of initiation, the clinician should consider alternative therapy such as intubation. The patient using NIV might also be transferred to a monitored unit such as an ICU.42 Figure 21-15 presents an algorithm for use of NIV.

FIGURE 21-15 Clinical algorithm for application of NIV in the acute care setting.

Description Aerophagia commonly occurs with NIV but usually remains benign because the airway pressures are less than the esophageal opening pressure. A gastric tube, therefore, is not routinely necessary for mask

ventilation. A gastric tube might interfere with the effectiveness of mask ventilation in several ways. First, it may be more difficult to achieve a mask seal if a gastric tube is present. Second, compression of the gastric tube against the face by the mask may increase the likelihood of facial skin breakdown. Third, a nasogastric tube will increase resistance to nasal gas flow, which may decrease the effectiveness of mask ventilation —particularly nasal ventilation. Respiratory Recap Benefits of NIV for Acute Respiratory Failure ∎ Decreased intubation rate ∎ Improved survival ∎ Decreased pneumonia rates

Chronic Applications NIV is used for chronic respiratory failure resulting from restrictive lung disease, COPD, and nocturnal hypoventilation.43,44 In many patients receiving chronic NIV, this therapy is administered only at night. Goals of this therapy are to improve symptoms (e.g., fatigue, morning headache), to decrease PaCO2, and to decrease the degree of nocturnal hypoxemia. Box 21-2 lists recommended clinical indications for the use of NIV in chronic applications.43,45 Chronic NIV use is most common with neuromuscular respiratory failure, where it serves as an alternative to tracheostomy and can be used for full-time ventilatory support. Some patients with neuromuscular disease can use a mouthpiece or nasal pillows during the daytime and a mask at night. The use of NIV for chronic stable COPD is controversial. BOX 21-2 Clinical Indications for Noninvasive Positive Pressure Ventilation in Chronic Respiratory Failure Restrictive Thoracic Disorders Examples: Sequelae of polio, spinal cord injury, neuropathies, myopathies and dystrophies, amyotrophic lateral sclerosis (ALS), chest wall deformities, kyphoscoliosis Symptoms: Fatigue, dyspnea, morning headache

Physiologic criteria: PaCO2 ≥ 45 mm Hg, nocturnal oximetry demonstrating oxygen saturation ≤ 88% for 5 consecutive minutes, maximal inspiratory pressure > –60 cm H2O or forced vital capacity 1000

48/25

35

>2000

50/30

40

>3000

50/35

45

>4000

65/40

50

Neonate older than

75/50

60

12 hours Normal respiratory rate: 30 to 60 breaths/min; normal heart rate: 120 to 160 beats/min.

All newborns have an irregular respiratory breathing pattern, but the respiratory rate of a term newborn usually averages 40 to 60 breaths/min. It is common for premature infants to exhibit periodic breathing, which consists of intermittent respiratory pauses that last longer than 5 seconds. When breathing stops for longer than 20 seconds, or for shorter periods in combination with bradycardia, cyanosis, or pallor, it is called apnea. Stressed newborns often have a period of rapid breathing followed by a period of gasping or no breathing called primary apnea. For primary apnea, tactile stimulation will cause breathing to resume. If the infant continues in this pattern without interruption, however, an irregular breathing pattern will follow the primary apnea, and the patient will enter into secondary apnea. For secondary apnea, positive pressure ventilation is required to restore spontaneous ventilation. As children mature, their normal respiratory rates decline until they become teenagers. At that point, their respiratory rates mimic those of adults (Table 22-3).2 TABLE 22-3 Normal Respiratory Rates in Awake Children Age

Mean (breaths/min)

Range (breaths/min)

6–12 months

64

58–75

1–2 years

35

30–40

2–4 years

31

23–42

4–6 years

26

19–36

6–8 years

23

15–30

8–10 years

21

15–31

10–12 years

21

15–28

12–14 years

22

18–26

The Silverman scoring system assesses the magnitude of respiratory distress of an infant (Figure 22-2). The higher the Silverman score, the greater the distress. Signs of respiratory distress include expiratory grunting, retractions, nasal flaring, and tachypnea. Expiratory grunting occurs when the glottis closes during expiration in an attempt to maintain lung volume and expand alveoli. It is a common sign of RDS.

FIGURE 22-2 Silverman score for assessing the magnitude of respiratory distress. Data from Silverman WA, Andersen DH. A controlled clinical trial of effects of water mist on obstructive respiratory signs, death rate and necropsy findings among premature infants. Pediatrics 1956;17(1):1–1.

Description Retractions are a visible sinking in of the chest wall on inspiration. They are usually a sign of decreased chest compliance but can also indicate airway obstruction. Retractions are usually observed between the ribs (intercostal), in the area above the clavicle (supraclavicular),

below the xiphoid process (substernal), and below the rib cage (subcostal). Retractions are more commonly observed in neonates than in adults due to the neonate’s soft, pliable chest wall and thoracic cage. Seesaw respirations, also indicative of severe respiratory distress, occur when the chest moves in and the abdomen pushes out on inspiration. Infants may have nasal flaring to decrease the resistance to air entry. Tachypnea is usually one of the first signs of respiratory distress. Infants and children have difficulty increasing their tidal volume and instead will increase their respiratory rate in an effort to increase their minute ventilation. Auscultation of infants and small children can be difficult. Their chests are small, and sounds sometimes transmit from one lung region to another. Infants and children often cry and hold their breath during examination, making assessment difficult. Symmetric assessment from left to right is crucial and will help identify asymmetric disease such as a pneumothorax or a poorly positioned endotracheal tube. Coarse breath sounds come from air moving through fluid in the large airways. Usually, suctioning or coughing will eliminate the secretions and the coarse crackles. Fine crackles, also known as rales, are indicative of fluid in the small airways and alveoli. They are commonly heard on inspiration in infants with RDS, pneumonia, or pulmonary edema and in normal infants soon after birth. Wheezes are high-pitched musical sounds that can be heard on inspiration or expiration and are caused by a narrowing of the airway. Wheezes are most commonly heard in children with asthma. Wheezing over an isolated area can indicate foreign body aspiration. Stridor is a high-pitched squeaking sound heard on inspiration. It indicates a large upper airway obstruction, as can occur in patients with croup, tracheomalacia, and post-extubation laryngeal edema. Stridor can be easily distinguished from other sounds by placing the stethoscope over the neck region and isolating the sound. Neonates with RDS, atelectasis, and pulmonary interstitial edema (PIE) may also have diminished breath sounds. In the neonate, transillumination of the chest wall can be used to identify a suspected pneumothorax. With this technique, the clinician places a fiberoptic light source on the infant’s chest wall in a darkened room. Normally a lighted halo is seen around the point of contact. A large pneumothorax will glow, or seem very pink and illuminated, in

comparison with the other areas of the chest.

Noninvasive and Hemodynamic Monitoring In addition to physical assessment, chest radiography and blood gas measurements are vital in the respiratory assessment of the pediatric patient. Noninvasive monitoring of oxygenation and ventilation is widely used in the care of infants and children. SpO2 and transcutaneous monitoring (PtcO2 and PtcCO2) are used to closely track these patients’ oxygenation and ventilation status and are correlated with blood gas values when appropriate. Poor tissue perfusion interferes with the accuracy of noninvasive monitoring. Patient movement can make the reliable measurement of pulse oximetry challenging in both neonates and pediatric patients. Blood gas samples can be obtained from umbilical artery catheters (UACs) or umbilical venous catheters (UVCs) in neonates and from peripheral arterial lines in older children. Capillary blood gases are a less invasive way to measure the pH and PCO2 of an infant but are not always reliable in determining oxygenation. Poor sampling technique can greatly influence the results of capillary blood gases. Clinicians often draw umbilical cord blood gases after the birth of the child to document whether the infant was in severe distress in utero, although these blood gas values are not used to treat the infant after birth. Clinicians should interpret blood gas results in the context of the infant’s gestational age, disease state, and risk for complications with additional respiratory support. Be aware, however, that the transition to extrauterine life may take a variable amount of time. Table 22-4 provides normal blood gas values. TABLE 22-4 Normal Cord, Neonatal, and Pediatric Blood Gas Values

Description UACs and arterial lines are used for blood pressure monitoring. The UVC or central venous catheter is primarily used to administer fluids and drugs to the central circulation and for central venous pressure (CVP) monitoring. CVP monitoring allows measurement of the right atrial pressure and assessment of the patient’s fluid volume. Normal CVP is 2 to 7 mm Hg. Pulmonary artery catheters are used to assess left ventricular function, fluid status, and pulmonary artery pressure (PAP). Normal mean PAP is 10 to 20 mm Hg. Respiratory Recap Neonatal Assessment ∎ Infants with LS ratio less than 2:1 are at higher risk for RDS. ∎ The Apgar score evaluates heart rate, respiratory effort, muscle tone, reflex irritability, and color. ∎ Apnea is a cessation of breathing for longer than 20 seconds. ∎ Signs of respiratory distress include expiratory grunting, retracting, nasal flaring, and tachypnea. ∎ Capillary blood gas values are minimally invasive measures of pH and PCO2.

Oxygen Therapy Indications Clinicians administer oxygen therapy to correct hypoxemia and to provide oxygen to the tissues with the lowest possible concentration of oxygen. Preterm babies, term babies, and children have different oxygen requirements depending on their gestational age or disease state. Children and term infants with a PaO2 less than 80 mm Hg and an oxygen saturation less than 95% are generally considered to have hypoxemia. In preterm infants, PaO2 and SpO2 goals are lower than those for term babies and are based on corrected gestational age.

Hazards The hazards of oxygen therapy for the preterm infant include retinopathy of prematurity (ROP). ROP is a potentially blinding disease caused by the abnormal development of the retina in premature infants. Generally, babies born weighing less than 1500 grams or at less than 32 weeks’ gestational ages are monitored for ROP. Oxygen therapy directed toward PaO2 goals of 50 to 80 mm Hg is usually considered safe. Other factors that contribute to the severity of ROP include gestational age, low birth weight, blood transfusion, respiratory distress, PDA, and the overall health of the infant. Excessive use of oxygen also can lead to the development of bronchopulmonary dysplasia (BPD), defined as the need for supplemental oxygen at 36 weeks’ postmenstrual age or 28 days of life.3 The delivery of 100% oxygen can lead to absorption atelectasis as oxygen replaces alveolar nitrogen. The delivery of high concentrations of oxygen can also induce cardiovascular effects such as pulmonary vasodilation and the constriction of the ductus arteriosus. In patients with hypoplastic left heart disease, the increase in pulmonary blood flow that occurs with oxygen therapy can flood the lungs with blood and decrease systemic circulation. The closing of the PDA can further decrease the flow of blood to the systemic circulation and create a life-threatening

situation.

Delivery Devices Clinicians can use many different devices to administer supplemental oxygen. The best device to use is the one that most closely suits the needs of the individual patient. The clinician should consider several factors before choosing an oxygen delivery device, including what fraction of inspired oxygen (FIO2) is required, whether a precise FIO2 is required, what gas temperature and humidity are needed, how the equipment will affect the nursing care and handling of the infant or child, and patient comfort. Oxygen therapy should be administered according to the SpO2 goal. If the patient consistently requires more than 50% oxygen, additional respiratory support may be needed. In the neonatal intensive care unit (NICU), low-flow meters with flows that span 25 mL/min to 3 L/min are commonly used. In most cases, the flow meter is connected to a 100% oxygen source and flow titrated to meet oximetry goals. For neonatal patients requiring high flows, such as 2 L/min, the therapy should incorporate an air–oxygen blender and the FIO2 should be adjusted to meet the patient’s SpO2 goal. The most frequently used oxygen delivery devices include the conventional nasal cannula, high-flow nasal cannula, entrainment mask, oxygen hood, and incubator; each of these has both advantages and disadvantages (Table 22-5). TABLE 22-5 Supplemental Oxygen Delivery Devices

Description FIO2, fraction inspired oxygen; PEEP, positive end-expiratory pressure.

Respiratory Recap Oxygen Therapy ∎ Oxygen therapy directed toward PaO2 goals of 50 to 80 mm Hg is considered safe. ∎ Excessive oxygen use could lead to retinopathy of prematurity and bronchopulmonary dysplasia in the premature infant. ∎ FIO2 should be adjusted to meet oximetry goals for the patient based on gestational age.

Mechanical Ventilation Regardless of the patient’s pathologic condition, the goal is to achieve adequate gas exchange while minimizing the risks and complications associated with mechanical ventilation. Many factors influence the respiratory management of neonates and children, and no single approach is ideal for all. To prevent complications, maintain adequate support of ventilation and oxygenation by reassessing the patient and adjusting the ventilator as necessary. Mechanical ventilation is practiced differently throughout the world, and the method chosen depends on the strategies adopted by the institution.

Manual Ventilation Positive pressure ventilation (PPV) usually begins as manual bag-mask ventilation (BMV), often in the delivery room. Immediately after birth, the infant is placed under a warmer and dried, positioned, and provided with tactile stimulation. BMV is indicated if the infant is apneic or gasping or has a heart rate less than 100 beats/min. Appropriate use of positive pressure can make an important difference in the infant’s course. During the initial resuscitation, titrate oxygen to specific preductal SpO2 goals based on the newborn’s minutes of life (Table 22-6). Although pure (100%) oxygen administration was recommended in the past, current evidence suggests that exposure to excess oxygen can harm neonates.1 After initiating pulse oximetry, the clinician should set both the high and low SpO2 alarms to reduce the risks of hyperoxia and hypoxia. TABLE 22-6 Targeted Preductal SpO2 After Birth 1 min

60%–65%

2 min

65%–70%

3 min

70%–75%

4 min

75%–80%

5 min

80%–85%

10 min

85%–95%

Reproduced from 2010 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 15: neonatal resuscitation. 2010;122(18 Suppl 3):S909–S919. © 2010 American Heart Association, Inc., and American Academy of Pediatrics. Reproduced with permission.

Manual resuscitators are classified as either self-inflating or flowinflating (Figure 22-3).1 A self-inflating bag inflates automatically and does not need an external gas source to provide positive pressure.

These bags usually have a reservoir to deliver 100% oxygen with a flow of 5 to 10 L/min. Most self-inflating bags incorporate a pressure-limiting device and a pop-off valve that releases pressure at a preset level. The pop-off valve reduces the risk of excessive pressure being applied, but it can be manually overridden when delivery of high pressures is indicated. Self-inflating bags do not allow maintenance of positive end-expiratory pressure (PEEP) unless an external valve is added.

FIGURE 22-3 (A) Self-inflating neonatal resuscitation bag. (B) Flow-inflating neonatal resuscitation bag. Courtesy of Mercury Medical.

A flow-inflating bag requires a continuous flow from an external gas source. The flow and the pressure release valve determine the pressure applied. Wide ranges of peak inspiratory pressure (PIP) and PEEP are

attainable with flow-inflating bags. Continuous flow at the patient connection makes the device suitable for the delivery of continuous positive airway pressure (CPAP) and a convenient method to deliver oxygen on a short-term basis to a spontaneously breathing infant. Flowinflating bags are well suited to the needs of neonates but require skill and experience to deliver consistent ventilation pressures. T piece resuscitators are devices that function similar to flow-inflating bags but offer the added benefit of delivering a controlled PIP and consistent PEEP. Clinicians responsible for resuscitating neonates should be familiar with self-inflating and flow-inflating bags and resuscitators used in their institution. If the mask is not the correct size, BMV will be ineffective. A variety of masks are available that fit infants of all sizes. The mask fits over the infant’s nose and mouth, with the edge of the infant’s chin resting on the rim of the mask. When applying the mask to the patient’s face, the clinician creates a seal by encircling the mask with the thumb and index finger and applying a gentle pressure (Figure 22-4). The clinician then pulls the infant’s face into the mask to open the airway, using the ring finger to hold the infant’s chin in the mask. Positioning of the infant is critical to achieve effective BMV. Slight extension of the neck, often accomplished by placement of a blanket roll under the shoulders, can align the airway to allow effective ventilation.

FIGURE 22-4 Positioning of the mask for bag-mask ventilation. Courtesy of David J. Burchfield, MD.

Knowledge of the infant’s gestational age and prenatal history may be helpful during initiation of BMV. Premature infants will likely need higher ventilating pressures (more than 35 cm H2O) during the initial breaths to overcome the surface tension in their surfactant-deficient lungs. Depending on lung maturity, successive breaths may require less pressure as lung volume is established. The pressure used to ventilate should cause the infant’s chest to rise. Maintaining PEEP throughout the respiratory cycle aids in the maintenance of lung volume. Observing chest movement while squeezing the bag allows the clinician to determine the correct application of pressure. Common reasons for poor chest movement are an inadequate mask seal, airway obstruction caused by improper head position, secretions in the airway, fingers on the patient’s neck, or inadequate ventilating pressure. Inadequate pressure leads to low lung volume, inability to oxygenate, and

hemodynamic compromise. Conversely, excessive pressure can result in pneumothorax and further respiratory and hemodynamic compromise. An in-line pressure manometer should be used to monitor the applied peak airway pressure and PEEP levels. To verify the presence of exhaled carbon dioxide, place a disposable carbon dioxide detector between the resuscitation bag and mask. Table 22-7 lists factors to consider with BMV. TABLE 22-7 Bag-Mask Ventilation of the Neonate Problem

Solutions

No seal between mask and face

Reposition mask; consider different mask size

No chest movement

Check head position Do not overextend neck or push head forward with mask pressure



Check for secretions in airway



Check for fingers on the neck

Pressure too low (flowinflating bag)

Check flow Adjust flow meter Check manometer connections

Pressure too low (selfinflating bag)

Ensure pop-off valve is active Consider need to override pop-off valve

Pressure too low (T piece resuscitator)

Check for circuit leaks or disconnections Check flow setting Check pressure setting

An apneic or distressed infant typically requires a rate of 40 to 60 breaths/min with an inspiratory time of 0.4 to 0.5 second. Administration of oxygen during the initial resuscitative effort should be titrated to SpO2. Improvement in the skin color, heart rate, and hemodynamics should become apparent after a brief period of oxygen therapy. If the patient

shows no sign of improvement, review the adequacy of the delivery system, including problems with oxygen disconnection or inadequacy of the gas source, mask seal, or head position. Infants with evidence of meconium on the skin or in the airway and who are not vigorous at birth should be brought to the radiant warmer, and clinicians should perform the initial steps of newborn care (dried, warmed, airway opened) and bulb suctioning of the mouth and nose. If the heart rate is less than 100 beats/min or the baby is not breathing, start positive pressure ventilation. A vigorous infant will have a heart rate greater than 100 beats/min, strong respiratory efforts, and good muscle tone. In the past, it was recommended to perform routine intubation to suction the trachea with evidence of meconium, but this is no longer the case. Mask positive pressure ventilation is contraindicated in infants who have or are suspected of having a congenital diaphragmatic hernia. BMV can promote the entry of air into the gastrointestinal tract and further impair gas exchange. These infants should be intubated and ventilated through an endotracheal tube. Respiratory Recap Neonatal Manual Resuscitators ∎ Self-inflating bags inflate automatically. ∎ Flow-inflating bags require a continuous gas flow. ∎ T piece resuscitators function similarly to flow-inflating bags but offer the benefit of controlled pressure delivery.

Airway Management An oral or nasal airway can be used to assist with maintaining an open airway. Oral airways are generally used only in unconscious patients who do not have a gag reflex. The clinician must select an oral airway large enough to keep the tongue from obstructing the pharynx, but not so large that the tube itself becomes an airway obstruction. Nasal airways are generally better tolerated and can be used in awake patients, but they can become occluded with secretions or cause nasal trauma with insertion or removal.

Endotracheal Intubation After initiating manual ventilation, the clinician reassesses the infant’s condition to determine whether intubation is necessary. In some cases, brief periods of manual ventilation can stabilize the infant’s condition, making intubation unnecessary. Improved SpO2, spontaneous respiratory efforts, and a stable heart rate are indications for withdrawal of manual ventilation. As the bag and mask are withdrawn, the clinician can place free-flowing oxygen near the infant’s face as needed to obtain the desired SpO2 and reassess the infant. Infants who do not respond to brief periods of manual ventilation or who require prolonged ventilatory support require intubation. Oral endotracheal tubes are most commonly used to intubate neonates and children. Nasal intubation is generally more hazardous and, therefore, is less frequently used. The clinician can estimate the appropriate tube size (Table 22-8) and the distance of insertion based on the infant’s weight. If the infant’s weight is not immediately available, gestational age can also serve as a reliable predictor for tube size (Table 22-9). The Broselow Tape, also called the Broselow Pediatric Emergency Tape, is a color-coded patient length-based tape used throughout the world to recommend the appropriate emergency equipment for the individual pediatric patient, including artificial airways.

TABLE 22-8 Suggested Neonatal Endotracheal Tube Size Based on Body Weight Weight (g)

Tube Size*

Less than 1000

2.5

1000 to 2000

3.0

2000 to 3000

3.5

More than 3000

3.5 to 4

* Tube size is given as the inside diameter in millimeters.

TABLE 22-9 Suggested Endotracheal Tube Size Based on Gestational Age Gestational Age (Weeks)

Tube Size*

Less than 30

2.5

30 to 35

3.0

More than 35

3.5

* Tube size is given as the inside diameter in millimeters.

Unlike in adults and large children, the narrowest point of an infant’s airway is at the cricoid cartilage; this characteristic allows the use of uncuffed airways in infants. Although this approach does not always produce a complete seal, the cricoid cartilage provides a functional cuff. Despite some leakage, adequate ventilation can be achieved with an appropriate-sized uncuffed endotracheal tube. Also, use of an uncuffed tube prevents cuff-related tracheal injury in these patients. For these

reasons, cuffed tubes are rarely used in neonates. The correct endotracheal tube (ETT) size for children 1 to 10 years old can be estimated by using the child’s age: Endotracheal tube size (mm internal diameter) = (Age in years/4) + 4 The clinician should have an ETT one-half size larger and an ETT smaller than the estimated size available if needed. ETT size can also be estimated by using a child’s length. Length-based tapes are available and are generally considered useful for children weighing 35 kg or less. Cuffed ETTs are as safe as uncuffed tubes for infants and children in the hospital setting.4 A cuffed ETT does have some applications in these patients, such as when lung compliance is low and high airway pressures are needed. When cuffed ETT tubes are used, cuff inflation pressures should be kept at less than 20 cm H2O.5 To estimate the approximate distance to insert the ETT, measured from the lips, add 6 cm to the infant’s weight in kilograms. In children, adding 10 to the child’s age estimates this distance. These formulas can be used to estimate initial tube placement, but bilateral auscultation of the chest is essential to ensure correct positioning. Placing a disposable CO2 detector between the resuscitation device and the endotracheal tube allows the clinician to quickly and easily confirm that the ETT is in the trachea. Because this device sometimes leads to false positives and negatives, when bilateral breath sounds are noted, secure the tube and confirm its position by chest radiograph. Cut the tube to minimize additional dead space and reduce the risk of inadvertent extubation. In addition, a gastric tube should be inserted and suction applied to decompress the stomach of air inadvertently delivered during mask ventilation. Respiratory Recap Endotracheal Intubation ∎ Oral tubes are most commonly used in neonates and children. ∎ Neonatal tubes are uncuffed. ∎ Pediatric tubes are sometimes cuffed.

Suctioning Suctioning should be performed secondary to clinical assessment, rather than as a routine procedure. Suctioning can cause hypoxia, atelectasis, infection, tissue damage, and changes in the heart rate, blood pressure, and intracranial pressure. The need for suctioning is generally related to the underlying pathologic condition. Infants intubated because of RDS, persistent pulmonary hypertension, or apnea require less suctioning than infants with meconium aspiration, sepsis, or pulmonary hemorrhage. Indications for suctioning include evidence of secretions in the endotracheal tube, diminished breath sounds, decreased tidal volume (during pressure ventilation), or increased peak inspiratory pressure (during volume ventilation). An obstructed airway or endotracheal tube should always be considered when acute desaturation occurs, particularly in infants with meconium aspiration, pulmonary hemorrhage, or pneumonia. Increases in carbon dioxide may also be a sign of airway obstruction, in which case the clinician should attempt suctioning. Providing adequate humidity can reduce the risk of tube obstruction, but plugging of artificial airways in infants with thick or abundant secretions is always a concern given the small internal diameter of the tube. Oral or nasopharyngeal suctioning of infants is most often accomplished with a bulb syringe or other noninvasive technique so as to minimize airway trauma and edema. For the intubated patient, an inline suction catheter (Figure 22-5) offers several advantages over single-use catheters, and its use has become a routine practice in intensive care units (ICUs). With the inline catheter, the clinician can suction the child without disconnecting the ventilator. Maintaining a closed system can reduce the risk of lung volume loss during suctioning. An inline catheter that connects directly to the ETT with minimum dead space is ideal.

FIGURE 22-5 Neonatal inline suction catheter. Courtesy of Melissa Brown, BS, RRT-NPS.

Selection of suction catheter size is based on the ETT size. A common rule of thumb is to select a catheter with a French size two times the size of the inner diameter (in millimeters) of the ETT. The clinician should determine the distance that the catheter will be inserted before beginning the procedure to avoid airway trauma.6 With the ETT in proper position, the distance is measured from the patient’s lips to the tip of the inline catheter when fully withdrawn. The clinician then inserts the catheter 0.5 cm farther than this distance. The recommended suction level is no greater than 75 to 100 mm Hg for infants (some recommend 60 to 80 mm Hg) and no greater than 100 to 125 mm Hg for children (some recommend 80 to 100 mm Hg). Limit the suction pressure to the lowest level that effectively removes secretions, and apply it intermittently during the catheter’s withdrawal. In neonates, an increase in FIO2 of 0.1 for 30 to 60 seconds prior to and during the suction procedure is

generally needed to maintain arterial oxygen saturation. For larger pediatric patients, 100% oxygen may be used to preoxygenate the patient.7 Limit the duration of each suctioning event to 15 seconds, and continue to assess the patient throughout the procedure. A decreased heart rate or significant arterial oxygen desaturation during suctioning is an indication to remove the catheter and support the child as needed. If further suctioning is indicated, the clinician may need to provide additional oxygen before continuing the procedure. After the procedure is completed, reassess the patient’s heart rate, oxygen saturation, color, chest expansion, and breath sounds. It may be necessary to adjust the ventilator settings and change the oxygen concentration to keep the oxygen saturation within the desired range. Stop and Think You are caring for a 28 weeks’ gestational age, 1-kg premature infant who requires intubation. What size endotracheal tube would you select? At what centimeter marking should you initially secure the tube? What size suction catheter would be appropriate for the tube selected?

Respiratory Recap Suctioning ∎ The recommended suction level is as low as will effectively remove secretions. ∎ Select a catheter with a French size 2 times the size of the inner diameter (in millimeters) of the endotracheal tube.

Nasal Continuous Positive Airway Pressure Infants who show adequate spontaneous efforts but whose clinical presentation indicates the potential for low lung volumes and associated hypoxemia may benefit from nasal continuous positive airway pressure (NCPAP). The purpose of NCPAP is to improve oxygenation and lung recruitment, thereby supporting oxygenation at a lower FIO2. The infant who is grunting with reduced lung volumes may benefit from a trial of NCPAP. NCPAP can be applied via a variety of nasal prongs and masks and with different pressure-generating devices (Figure 22-6). This approach may also minimize the risk of airway collapse in patients with tracheomalacia.

FIGURE 22-6 Setup for neonatal nasal continuous positive airway pressure (NCPAP) therapy. © KidStock/Photodisc/Getty Images.

The CPAP level is usually started at 5 to 6 cm H2O, although higher

pressures of 7 to 8 cm H2O are common. Reevaluate the child with pulse oximetry, transcutaneous monitoring, and arterial, venous, or capillary blood gas measurements. Breath sounds should confirm airflow into the lungs. Appropriately sized nasal prongs are needed to achieve the desired benefit. Prongs that are too large can cause skin breakdown at the nares, and prongs that are too small allow the infant to breathe around the device, making continuous airway pressure difficult to maintain. Nasal masks are also available and can be used with some CPAP devices. These masks can be a good alternative to nasal prongs when skin breakdown is an issue and for larger children. The CPAP flow must be adequate to meet the patient’s inspiratory demand but not so large as to create significant work of breathing. Insert an orogastric tube to minimize air accumulation in the gastrointestinal tract. The circuit used to deliver NCPAP must be heated and humidified, because it becomes the major portion of the child’s inspired air. Inadequately humidified gas can increase the risk of airway obstruction, and inadequately heated gas may result in difficulty in maintaining the infant’s neutral thermal environment. Nasal cannulas, variable-flow nasal CPAP generators, bubble CPAP setups, and nasal prongs and masks in conjunction with a conventional mechanical ventilator are used to provide NCPAP in neonatal and pediatric ICUs. All of these devices have their own advantages, disadvantages, and attendant difficulties. Problems of delivering nasal CPAP, regardless of device used, include difficulty in obtaining a seal and maintaining pressure, tubes becoming blocked and preventing pressure from being delivered to the lungs, and nasal trauma and breakdown. Some of the devices also have issues regarding inaccurate or absent pressure monitoring and increased work of breathing due to the device’s design. Nasal cannulas are primarily used to deliver supplemental oxygen. Many hospitals use a high-flow nasal cannula (HFNC) as a substitute for NCPAP. Flows of 2 to 8 L/min are frequently described as HFNC in the neonatal environment.8 An air–oxygen blender is used in combination with the cannula to titrate the FIO2 delivered to the patient. The cannula as a nasal CPAP device offers some advantages: It is low cost, easy to set up, readily available, and usually well tolerated by neonates. Unlike conventional nasal CPAP devices, however, the nasal cannula lacks a

mechanism to monitor or regulate positive airway pressure. The variability in cannula sizes, patient sizes, and disease processes makes it difficult to predict what, if any, airway pressure is actually being delivered. There are also doubts about whether infants treated using HFNC have comparable outcomes to those infants treated using other delivery devices.9 Variable-flow nasal CPAP devices, sometimes called flow drivers, generate CPAP at the airway, unlike continuous-flow CPAP devices such as bubble CPAP. One example of this type of device (Figure 22-7) uses the Bernoulli effect and dual injector jets directed toward each nasal passage to maintain a constant pressure. If the infant needs more flow, the Venturi action of the jets entrains additional flow. The infant can exhale without added work because the expiratory flow is shunted out the expiratory outlet, which opens to ambient air. Residual gas pressure maintains a continuous positive pressure throughout the respiratory cycle. The nasal prongs used can be larger diameter than traditional prongs. They consist of a thin, soft material that flares out during inspiration, increasing the internal diameter and decreasing the leaking around them. No mechanical valves are used, and clinicians can continuously monitor the intranasal pressure. The variable-flow capability of the flow driver assists with spontaneous breathing and creates more stable pressure delivery, which leads to improved functional residual capacity (FRC). Notably, NCPAP creates less work of breathing, and the infant using NCPAP has less thoracoabdominal asynchrony.10

FIGURE 22-7 Vyaire Infant Flow SiPAP System. Infant Flow SiPAP system, Vyaire, https://www.vyaire.com/us/our-products/respiratorycare/mechanical-ventilation/neonatal-ventilation-solutions/infant-flow-sipap-system.

Homemade bubble CPAP systems are popular in the United States (Figure 22-8). These systems comprise a heater/humidifier, a fresh gas source at a flow of up to 10 L/min, separate inspiratory and expiratory tubing, a nasal prong interface, a pressure manometer, and a water seal column of sterile H2O plus 0.25% acetic acid. Most of this equipment can be readily found in any respiratory therapy department. To set the CPAP level, submerge the end of the expiratory tubing under the surface of the liquid to a depth in centimeters that is marked on the side of the column.11 Because the amount of pressure delivered is also influenced by the flow through the system, place a pressure manometer as close to the nasal interface as possible.12,13 An absence of bubbling in the water column suggests a leak. In this event, the clinician needs to assess the circuit and nasal interface for leaks or possibly utilize a chin strap to close the patient’s mouth to maintain airway pressure. Some sources suggest that the oscillations that come from bubble CPAP may improve gas exchange, whereas others dispute this claim.12

FIGURE 22-8 Schematic of bubble NCPAP delivery system. Prongs. Manometer. Oxygen blender with flow meter. Heated humidifier. Inspiratory tubing. Expiratory tubing. Underwater bubble chamber.

Stop and Think You are caring for an infant who is on bubble NCPAP. The infant has acutely developed central cyanosis and oxygen desaturation. Upon inspection of the circuit, you visualize adequate bubbling of the water column. What are the potential patient sources of the infant’s oxygenation problem?

Noninvasive Positive Pressure Ventilation Mechanical ventilation provided without an artificial airway is called noninvasive ventilation (NIV). One of the main advantages of NIV is the ability to provide mechanical support for patients without exposing them to the risks involved with intubation. In addition, support can be provided for a short period of time, intermittently as needed, or for longer periods of time if necessary. The patient interface consists of a nasal mask, an oronasal mask, or nasal prongs for infants. This interface can be connected to either a noninvasive ventilator or a standard mechanical ventilator. Although CPAP can be delivered, more frequently this type of ventilation is used in a bilevel mode that combines positive pressure breaths with PEEP. The goals of NIV include mechanical stenting of the airway with tracheomalacia and treatment of acute respiratory failure. This type of ventilation is frequently used for obstructive sleep apnea, RDS, and post-extubation respiratory failure.12,14,15 It is also used in acute asthma and with respiratory failure associated with cystic fibrosis. With NIV, monitor the patient for facial skin breakdown due to excessive pressure from the mask or prongs.

Conventional Infant and Pediatric Ventilation Indications Mechanical ventilation is required for a variety of clinical presentations in neonates and children. Full-term infants who require mechanical ventilation can have complex presenting symptoms that often include intrapulmonary and intracardiac shunting. Infants with congenital heart disease have particularly complex circulatory alterations. Some of these patients depend on the fetal blood flow that normally occurs only in utero, so maintaining patency of a ductus arteriosus or septal defect may save their lives. During mechanical ventilation, abrupt changes in hemodynamics, normoxia, and hyperoxia can be fatal to these infants. Blood flow through such shunts is sometimes the primary means to maintain blood flow to the systemic circulation. Until the healthcare team can perform corrective procedures, maintaining oxygen concentrations at or below room air can alter intracardiac shunts and ensure the patient’s survival. Thus, an understanding of various cardiac anomalies is essential for appropriate ventilator management. Providing adequate oxygenation and ventilation in neonatal conditions such as pneumonia, meconium aspiration, and congenital diaphragmatic hernia often is difficult. Nonhomogeneous lung disease increases the risk of barotrauma because the most compliant alveoli become overdistended. These underlying conditions often cause difficulty in the maintenance of adequate oxygenation and ventilation and may lead to pulmonary vasoconstriction and significant pulmonary hypertension. As a result, shunting occurs through a patent ductus arteriosus or patent foramen ovale, making oxygenation more difficult. Persistent pulmonary hypertension of the neonate (PPHN) can appear as a primary condition and be extremely difficult to manage. In infants with PPHN, the pulmonary vasculature has increased tone and abnormal responsiveness to vasodilators or the pulmonary arteries are muscularized, with a decreased cross-sectional area. In either condition, blood flow is restricted, pulmonary artery pressure increases, and intracardiac shunting occurs. Because limited blood flow reaches the pulmonary vasculature to participate in gas exchange, adjusting the

ventilator settings will have little effect in this population. Deoxygenated blood is shunted through a patent foramen ovale or a patent ductus arteriosus, making it difficult to achieve adequate arterial oxygen saturation. The pulmonary vasculature responds to hypoxia with further vasoconstriction, creating the possibility of greater amounts of blood being shunted and worsening oxygenation. Definitive diagnosis of PPHN generally is made by cardiac ultrasound. Clinically, right-to-left shunting is detected when oxygen saturation is monitored by SpO2 at a site receiving preductal blood (generally the right arm) and compared with a simultaneously monitored postductal site (left arm or right or left lower extremity). A difference in the oxygen saturation values from these two sites (a preductal value higher than the postductal value) indicates rightto-left shunting, often as a result of pulmonary hypertension. Respiratory Recap Preductal and Postductal SpO2 Monitoring ∎ Used to detect right-to-left shunting ∎ Preductal site: usually the right arm ∎ Postductal site: left arm or either lower extremity

Infant Ventilators Infant ventilators are classified into two major categories: conventional ventilators and high-frequency ventilators. A conventional ventilator offers a variety of modes, alarms, and other options. Selection of the appropriate mode and other ventilator options is based on the infant’s underlying condition and the desired effect of ventilatory support during both spontaneous and ventilator-initiated breaths. Historically, a neonatal ventilator provided a continuous flow, which is time cycled and pressure limited. This is very similar to pressure control, with the rapid rise of gas flow and pressurization of the circuit leading to very early tidal volume delivery and a descending ramp of flow.16 The first ventilators of this type did not allow for patient triggering. Current infantonly ventilators offer volume-limited and pressure-limited options, as well as patient-triggered and non-patient-triggered modes. Most modern

ventilators have the ability to ventilate all patient types: premature infants, pediatric patients, and adults—hence their description as cradle-to-grave ventilators. Most ICU ventilators can be set for neonates or children such that the trigger sensitivity and delivered pressures and volumes respond appropriately to these patient populations. ICU ventilators are capable of responding to neonatal inspiratory efforts and providing initial gas as effectively as traditional infant ventilators.17 When initiating ventilation, the clinician must select a pressure and/or tidal volume, respiratory rate, ventilator mode, inspiratory time or inspiration-to-expiration (I:E) ratio, PEEP, in some cases flow, and FIO2. Table 22-10 shows the initial ventilator settings. TABLE 22-10 Initial Ventilator Settings for Conventional Ventilation Setting

Instructions for Use

Peak inspiratory pressure (PIP)

As needed to provide a tidal volume of 4 to 6 mL/kg

PEEP

5 to 6 cm H2O

Respiratory rate

20 to 40 breaths/min

Inspiratory time

0.3 to 0.5 s

FIO2

As needed to maintain SpO2 based on gestational age

Flow

6 to 12 L/min

Pressure Limit and Tidal Volume In neonatal time-cycled, pressure-limited ventilation, the clinician selects a pressure limit and inspiratory time that results in delivery of the desired tidal volume. Tidal volume varies depending on the PIP, inspiratory time, and lung compliance. For example, if the patient’s lungs are less compliant, as in RDS, a higher PIP is needed to obtain a desired tidal volume. Conversely, if the lungs are more compliant, a lower PIP is

needed. Note that, unlike with most adult ventilators, the pressure setting on a neonatal ventilator is the PIP—not the pressure above PEEP. Thus, the tidal volume is determined by the difference between the PIP and PEEP. For this reason, an increase in PEEP may reduce tidal volume unless the pressure limit is increased by an equivalent amount. With volume control, the delivered tidal volume is preset and the PIP varies. The clinician presets the maximum pressure allowed. Volume ventilation reduces ventilator days, decreases the risk of pneumothorax and grades 3 and 4 intraventricular hemorrhage (IVH), and may reduce the incidence of BPD.18 Monitoring tidal volume at the airway opening is essential to assess the effect of leaks (Figure 22-9). Use of an uncuffed endotracheal tube can pose a concern with volume ventilation in neonates because leaks of greater than 60% can limit the effectiveness of ventilation. To ensure successful volume-targeted ventilation for neonates, always select an appropriate-sized endotracheal tube.

FIGURE 22-9 Flow sensor at airway to measure delivered tidal volume.

With adaptive pressure control (APC), the clinician sets a target tidal volume. The ventilator uses either pressure control or pressure support but increases or decreases the pressure as necessary to achieve the target tidal volume. Pressure-limited ventilation with a target tidal volume is a common approach to neonatal and pediatric ventilation. Whether volume-limited or pressure-limited ventilation is selected, the target for neonates is usually a tidal volume of 4 to 6 mL/kg. For children, 6 to 8 mL/kg is acceptable.19 As changes in tidal volume occur, clinical assessment is necessary to determine the best intervention (Table 2211). TABLE 22-11 Changes in Tidal Volume During Pressure Ventilation Tidal Volume Change

Possible Causes

Solutions

Increase

Increased compliance, decreased resistance, decreased PEEP, increased inspiratory time, decreased leak

Reduce peak inspiratory pressure.

Decrease

Decreased compliance, increased resistance, decreased peak inspiratory pressure, increased PEEP, decreased inspiratory time, increased leak

Suction airway. Reposition infant. Administer surfactant. Increase inspiratory pressure. Perform transillumination to check for pneumothorax. Auscultate to detect pneumothorax or main stem intubation. Obtain chest radiograph. Check tube position.

A practical issue with the ventilation of neonates is the effect of circuit compliance and compressible volume. These can substantially reduce the tidal volume available, particularly with volume ventilation. For this reason, a noncompliant, low-volume circuit typically is used. Because of the high resistance through this smaller-bore tubing, the clinician must monitor airway pressure and flow directly at the Y piece of the ventilator

circuit.18

Respiratory Rate After a tidal volume is established, the respiratory rate becomes the primary adjustment for the achievement of desired minute ventilation. Spontaneously breathing neonates normally take 40 to 60 breaths/min to maintain a normal partial pressure of arterial carbon dioxide (PaCO2). The ventilator rate should target a desired PaCO2. The required respiratory rate depends on the target PaCO2, the degree of lung disease (i.e., the amount of dead space), carbon dioxide production, the ventilator mode, and the amount of spontaneous breathing.

Mode In continuous mandatory ventilation (CMV or assist/control) mode, the clinician sets a minimum respiratory rate. Each spontaneous respiratory effort then triggers a ventilator-assisted breath, with the preset pressure or volume being delivered. The inspiratory time is preset, and the patient determines the total respiratory rate above the set rate. In synchronized intermittent mandatory ventilation (SIMV) mode, the clinician sets a minimum respiratory rate. Between the mandatory breaths, the patient can breathe spontaneously. The patient’s inspiratory efforts trigger the mandatory breaths, which may be pressure or volume limited. If the patient becomes apneic, the ventilator delivers the SIMV rate. Intermittent mandatory ventilation (IMV) mode is similar to SIMV except that the mandatory breaths are not synchronized to patient effort. This mode is rarely used today because of the large number of complications that can result from patient–ventilator asynchrony. With pressure support (PS), all breaths are triggered by the patient. The clinician sets a pressure limit to achieve a target tidal volume. The patient then determines the total rate, inspiratory time, expiratory time, and tidal volume. Because inspiration normally is flow cycled with PS, leaks around the endotracheal tube can prolong inspiratory time unless the ventilator has a mechanism to terminate flow in leak situations. Most ventilators offer mechanisms to adjust the flow cycle, preventing

prolonged inspiratory times with a leak. Pressure support may improve patient–ventilator synchrony in some patients by allowing flows and inspiratory times that are more consistent with the infant’s needs. Improved patient–ventilator synchrony can lead to greater patient comfort, reduce the need for sedation, and potentially reduce the time the infant stays on mechanical ventilation.20,21 Apnea and periodic breathing are contraindications to use of this mode.

Inspiratory Trigger and Expiratory Cycle Depending on the ventilator, patient-initiated breaths may be flow triggered, pressure triggered, or volume triggered. The signal for neonatal flow triggering typically occurs from a pneumotachometer positioned close to the infant’s airway. A change in flow through the pneumotachometer triggers the ventilator. The clinician sets the flow change required to trigger the ventilator—called the flow-trigger sensitivity—at a level that allows the least trigger effort without autotriggering. Pressure triggering occurs with a change in the baseline pressure. The pressure change required to trigger the ventilator is the trigger sensitivity. At a sensitivity of 1 cm H2O, patient effort that reduces the baseline system pressure by 1 cm H2O below PEEP will trigger a breath. The specifics of the trigger mechanism vary from ventilator to ventilator, and some ventilators flow trigger in one mode and pressure trigger in others. Volume triggering uses the integral of the flow signal for triggering. Because this is an averaging of the flow signal over time, it reduces signal noise. This gives volume triggering a theoretical advantage over flow triggering. An adjustable expiratory flow cycle is incorporated into some patienttriggered, pressure-limited modes. The expiratory flow cycle is based on a percentage of the peak flow. This cycle produces a variable inspiratory time, much like pressure support, which may reduce ventilator asynchrony.

Inspiratory Time The inspiratory time is set in conjunction with the respiratory rate, and together these factors determine the I:E ratio. For example, if the respiratory rate is 30 breaths/min, each breath cycle is 2 seconds. If the inspiratory time is 0.5 second, the I:E ratio is 1:3. Clinicians can use the ventilator graphics to determine the best inspiratory time for each patient’s current clinical condition.20 An inspiratory time that is too short can compromise both oxygenation and ventilation. In particular, the mean airway pressure is affected by the inspiratory time. A lower mean airway pressure may result in a loss of lung volume or inability to establish lung volume, causing a decrease in PaO2. Decreased ventilation, resulting in a higher PaCO2, occurs if a shortened inspiratory time reduces the delivered tidal volume. An inspiratory time that is too long may shorten the expiratory time and result in auto-PEEP, which may cause alveolar overdistention, increasing the risk of pneumothorax. Alveolar overdistention may also interfere with pulmonary blood flow, increase dead space ventilation, and reduce carbon dioxide elimination. In addition, too-long inspiratory times can cause a patient to perform a forced exhalation maneuver, potentially causing excessive pressure, poor tidal volume delivery, and ventilator asynchrony (Figure 22-10).

FIGURE 22-10 Excessive inspiratory time scalars. The pressure and flow scalars show an excessive inspiratory time, which can cause active exhalation. The inspiratory time is too long, and this causes a spiked appearance at the completion of each breath. This patient is forcibly exhaling. Reproduced from Waugh JB, Deshpande VM, Brown MK, Harwood R. Rapid interpretation of ventilator waveforms, 2nd ed. Upper Saddle River, NY: Pearson Education. © 2006. Reprinted by permission of Pearson Education, Inc., Upper Saddle River, New Jersey.

A typical inspiratory time with conventional positive pressure ventilation of the neonate is 0.3 to 0.5 second. Pediatric patients will have longer inspiratory times, frequently as long as 1 second. Monitoring the expiratory flow with graphics (Figure 22-11) or expiratory flow monitors and adjustment of the respiratory rate and inspiratory time can help prevent complications related to the I:E ratio such as air trapping and auto-PEEP.

FIGURE 22-11 A ventilator rate set too high can cause breath stacking, resulting in air trapping or auto-PEEP. Point A shows how the flow does not reach baseline before the next breath is delivered. Notice on the volume scalar how tidal volumes are decreasing due to air trapping. Reproduced from Waugh JB, Deshpande VM, Brown MK, Harwood R. Rapid interpretation of ventilator waveforms, 2nd ed. Upper Saddle River, NY: Pearson Education. © 2006. Reprinted by permission of Pearson Education, Inc., Upper Saddle River, New Jersey.

Positive End-Expiratory Pressure PEEP is routinely set in all ventilator modes to prevent alveolar collapse during expiration. PEEP usually is started at 5 to 6 cm H2O. In the neonate, lung volumes are assessed by chest radiograph, with the ideal lung volume expansion being to eight or nine ribs bilaterally. The clinician should adjust PEEP and PIP if the lungs appear underinflated or overinflated. Patients with a persistently low lung volume may need higher PEEP levels. In contrast, those with evidence of pulmonary interstitial emphysema or persistent air leakage after barotraumas may need lower PEEP. Assess the delivered tidal volumes whenever PEEP

levels are adjusted. In pressure-limited ventilation, the change in the PEEP setting may result in a change in the delivered tidal volume. The clinician may need to adjust the pressure limit to maintain the volume target.

Humidification Adequate humidification of the inspired gas is critical to maintain airway patency. A decrease in humidity can lead to dried secretions and atelectasis and may result in partial or complete airway obstruction. Neonates are particularly vulnerable to this risk because of their small airways. An appropriately humidified circuit shows moisture throughout both the inspiratory and the expiratory limbs; routinely inspect the ventilation circuit for evidence of such condensation. Adequate humidification is also important to maintain the neutral thermal environment of the newborn, particularly the premature newborn. Breathing a cool, dry gas may stress the metabolic demands on the newborn, resulting in increased oxygen consumption. One issue with the neonatal ventilator circuit is the position of the temperature sensor.21 Critically ill neonates are usually placed in an incubator or under a radiant heater. If the temperature sensor in the circuit is also placed in the incubator or under the radiant heater, it may be affected by a temperature other than the temperature of the gas in the ventilator circuit, which could result in malfunction of the humidification system. Thus, the clinician should place the temperature sensor in the circuit outside the incubator or radiant heater, or otherwise shield it from the effects of the ambient temperature in these devices. Respiratory Recap Neonatal and Pediatric Ventilator Settings ∎ Ventilator mode ∎ Pressure or tidal volume (or both) ∎ Respiratory rate ∎ Inspiratory time I:E ∎ PEEP ∎ Flow

∎ FIO2

Hazards and Complications Complications from mechanical ventilation in the neonatal and pediatric population can be substantial. They include ventilator-associated pneumonia as well as long-term problems owing to tracheal damage from endotracheal tubes. In addition, a neuropathologic consequence of reduced cerebral blood flow, known as periventricular leukomalacia (PVL), has been associated with ventilator-induced hypocarbia in preterm infants. Some neonates who survive their newborn challenges are left with varying degrees of chronic lung disease, a condition called bronchopulmonary dysplasia. The contribution of mechanical ventilators and oxygen therapy to this condition is not entirely known, but indiscriminate use of high pressure and exposure to high oxygen concentrations over time are thought to be factors. Neonates with BPD have a chronic oxygen requirement, chronic carbon dioxide retention, and pulmonary hypertension, as well as an increased susceptibility to pulmonary infections.3,15

Liberation Consideration of liberation from ventilatory support should begin as soon as the patient’s condition has stabilized from the disorder that required support. To do so, assess the patient’s hemodynamic, pulmonary, neurologic, and nutritional status. Ventilator liberation must not be confused with readiness for extubation, however. Rather, an ongoing process should support adjustment to a level that maintains adequate gas exchange without requiring significantly increased work of breathing. No single approach to liberation can be applied to all patients. Instead, the goal is to provide appropriate support by continuously assessing the patient’s total needs and recognizing when weaning is indicated. In infants and children, liberation generally relies on SIMV, PS, or a combination of the two. With SIMV, the clinician lowers the set respiratory rate to assess the patient’s ability to breathe spontaneously and maintain

adequate minute ventilation. Pressure-support levels can also be reduced gradually, as the patient becomes able to support an adequate tidal volume on his or her own. The presence of an endotracheal tube reduces the airway size and leaves the patient at risk for increased work of breathing. For this reason, infants generally are not expected to demonstrate the ability to breathe without any assistance before extubation. Adjust the pressure or volume limit to keep the tidal volume in the range of 4 to 6 mL/kg. Premature infants weighing less than 500 grams may need tidal volumes closer to 6 mL/kg to overcome the dead space of the ventilator flow sensor at the airway and maintain adequate gas exchange.22 The PEEP level usually is maintained at a minimum of 5 to 6 cm H2O to prevent loss of lung volume. Continually assess the patient’s breathing effort and the ventilatory pattern during the liberation process. Premature infants often experience periods of apnea. In infants whose condition otherwise is stable, respiratory stimulants such as caffeine may be beneficial in reducing the incidence of apnea during weaning. Pulse oximetry, transcutaneous monitoring, apnea, respiratory rate, and minute ventilation monitoring can help alert the clinician to changes in the patient’s respiratory status. Infants with persistent tachypnea, retractions, and an increased oxygen requirement during the weaning process use calories for these processes that are otherwise needed for normal growth and development. In such a case, liberation may achieve adequate gas exchange, but the caloric expense to the patient can far exceed the benefit. Continuous assessment of the patient’s tolerance for weaning from a multisystem perspective is essential throughout the weaning process. Extubation is considered when no contraindications exist related to the neurologic or other nonrespiratory systems, when the patient shows the ability to maintain a stable respiratory and heart rate, and when oxygen saturation is acceptable, with an FIO2 of 0.3 or lower. The ability to feed and the infant’s growth pattern also play roles in the decision to extubate. Because of the effects of the endotracheal tube on lung volume and work of breathing, extubation of the neonate often occurs with ventilator settings of 10 to 20 breaths/min, a PIP of 10 to 18 cm H2O, and a PEEP of 5 to 6 cm H2O. Ventilator settings prior to extubation of the pediatric patient are similar to those of the neonate, except that a higher PIP is acceptable and expected and that lower rates may be tolerated.

Readiness for extubation should be assessed daily in all ventilated patients.

High-Frequency Ventilation High-frequency ventilation (HFV) is an accepted mode of mechanical ventilation in neonatal and pediatric critical care. HFV is defined as positive pressure ventilation at a respiratory rate more than 150 breaths/min and tidal volumes approximating anatomic dead space.23 The advantage of this technique over conventional mechanical ventilation is its ability to deliver an adequate minute ventilation with a lower airway pressure; it is often used when conventional mechanical ventilation has failed. Patients often tolerate treatment with a high mean airway pressure better with HFV than with conventional mechanical ventilation. With conventional mechanical ventilation, the alveolar volume represents the difference between the tidal volume and the dead space volume. Tidal volumes near the dead space volume produce little alveolar ventilation. That gas exchange occurs with HFV, at times more efficiently than with CMV, is intriguing. The mechanism by which it accomplishes adequate gas exchange is not completely understood.

Classification The four general types of HFV are high-frequency positive pressure ventilation, high-frequency jet ventilation, high-frequency flow interrupter ventilation, and high-frequency oscillatory ventilation. High-frequency positive pressure ventilation (HFPPV) is conventional positive pressure ventilation at a high respiratory rate (more than 150 breaths/min) and small tidal volumes.24 The inspiratory time is short to facilitate the increased respiratory rate, and exhalation occurs passively. With HFPPV, the clinician must use the airway graphics to closely monitor changes in mean airway pressure. Although HFPPV laid the foundation for modern high-frequency ventilation, its use has declined with the availability of high-frequency ventilators. High-frequency jet ventilation (HFJV) delivers short pulses of gas directly into the trachea through a narrow-bore cannula or jet injector. Jet ventilators can maintain oxygenation and ventilation over a wide range of patient sizes. These systems have negligible compressible gas volume

and operate effectively at rates of 150 to 600 breaths/min. Exhalation occurs passively. Tidal volume often is equal to or slightly less than dead space volume. The high-flow jet pulse produces a jet mixing effect that creates an area of negative pressure and entrains additional gas into the airway. Unfortunately, the high gas velocities and gas mixing effects make pressure monitoring difficult. Jet ventilators are used with a conventional ventilator that provides PEEP, entrained gas, and intermittent sighs. High-frequency flow interrupter ventilation (HFFIV) delivers an inspiratory flow to the patient in short bursts by means of a rotating ball valve or microprocessor-controlled solenoid valve. These ventilators produce breath rates of 2 to 22 Hz, where 1 hertz (Hz) equals 60 breaths/min. HFFIV is similar to high-frequency oscillatory ventilation in that both inspiration and exhalation are active. Active exhalation is defined as a drop in airway pressure during exhalation to accelerate exhaled gas flow.22 Background mandatory breaths may or may not be used to maintain lung volume. High-frequency oscillatory ventilation (HFOV) essentially uses airway vibrators, usually with piston pumps or vibrating diaphragms that operate at frequencies ranging from 400 to 2400 breaths/min.25 During HFOV, both inspiration and expiration are active. The oscillators produce little, if any, bulk gas delivery. Instead, a continuous flow of fresh gas (bias flow) provides inspired gas and clears carbon dioxide from the system. Pressure oscillations in the airway produce tiny tidal volumes around a constant mean airway pressure. The tidal volume is determined by the amplitude of airway pressure oscillations, determined by the stroke of the device producing the oscillations. Respiratory Recap Categories of High-Frequency Ventilation ∎ High-frequency positive pressure ventilation (HFPPV) ∎ High-frequency jet ventilation (HFJV) ∎ High-frequency flow interrupter ventilation (HFFIV) ∎ High-frequency oscillatory ventilation (HFOV)

Gas Transport Theories Several theories have been proposed to explain gas transport at high respiratory frequencies. The mechanisms of gas exchange during HFV are not completely understood, and several effects appear to interact during HFV.26 In spike formation (Figure 22-12), a high-energy wave impulse of gas penetrates the center of the airway, enhancing bulk flow of gas in the upper airway and providing a more expansive area of gas mixing in the more distal lung. In the more compliant airway of the premature infant, spike formation is less effective. Turbulence may potentially increase with a more compliant airway, limiting spike effectiveness.

FIGURE 22-12 Spike formation in the airway during high-frequency ventilation.

Helical diffusion (Figure 22-13), a variant of the spike theory, also may play a role in HFV. Fresh gas enters the lung through a spike generated in the center of the airway, while gas exits the lung circumferentially along the periphery of the airway (coaxial flow).27 This theory assumes that carbon dioxide removal occurs in a spiral fashion, producing a whirlpool effect, whereby fresh gas moves through the center of the airway while gas simultaneously exits the lungs.

FIGURE 22-13 Helical diffusion during high-frequency ventilation. Adapted from Karp TB, Solon JF, Olson DL, Reppucci PA, Nichols NS. High frequency jet ventilation: a neonatal nursing perspective. Neonatal Netw 1986;4(5):42–50.

Taylor dispersion (Figure 22-14) is the augmented diffusion of gas in

a setting of parabolic gas flow, which results in high energy spikes.28 This augmented diffusion can occur wherever two gas streams meet, such as in coaxial flow in larger airways and with convective streaming more distal in the lung. The increased surface area between two gas streams during HFV facilitates this diffusion process. The high-energy jet spikes probably result in the delivery of more total fresh gas to distal respiratory units before significant contamination of the inflow gas occurs. This preserves the diffusion gradient needed to remove carbon dioxide from the blood.

FIGURE 22-14 Taylor dispersion during high-frequency ventilation.

Pendelluft ventilation (Figure 22-15) results from gas mixing between lung regions that have different time constants; it is also called out-ofphase ventilation. When parallel lung units have different time constants, resistance tends to dominate the rate of filling and emptying at rapid respiratory rates.29 At the end of a rapid inspiration, gas flows from the fast unit, which is beginning to empty, to the slow unit, which is still filling. This motion of gas between two neighboring units during phasic ventilation is called pendelluft.29

FIGURE 22-15 Pendelluft during high-frequency ventilation.

Molecular diffusion is a transport mechanism derived from random thermal oscillation of a molecule. As long as the molecules have a constant temperature, molecular diffusion always occurs. Molecular diffusion is responsible for gas exchange at the level of the alveolocapillary membrane.26 Molecular diffusion is altered during HFV, though the details of the rapid kinetic motion of oxygen and carbon dioxide molecules during HFV and the process of gas exchange at the alveolar level remain speculative at this time.

Patient Selection Specific strategies for the use of HFV depend on the institution. The question of when to use HFV in neonatal and pediatric patients, therefore, is not easily answered. Should HFV be implemented early in the treatment of respiratory failure, or should conventional ventilation be used first and HFV applied only if this approach fails? Some centers are very aggressive and institute HFV without trying conventional ventilation, seeking to protect the patient from pulmonary barotrauma at the onset of ventilation. Others try conventional ventilation before HFV. Use of rescue HFV is considered in the following situations: Preterm infants with severe hyaline membrane disease requiring a PIP of more than 30 cm H2O and children with acute respiratory

distress syndrome (ARDS) requiring a PIP of more than 40 cm H2O Infants with severe meconium aspiration syndrome and persistent pulmonary hypertension that does not respond to maximum ventilatory support with a PIP of more than 35 cm H2O Infants and children with air leak syndrome, including progressive pulmonary interstitial emphysema, recurring pneumothorax, and pneumopericardium Infants with congenital diaphragmatic hernia or pulmonary hypoplasia who have failed conventional ventilation Infants and children with severe parenchymal lung disease, such as group B streptococcal pneumonia, who require high levels of ventilatory support Any of the preceding disease states that may preclude the use of conventional ventilation and that indicate the need to institute HFV as an initial point of care A patient in need of inhaled nitric oxide (iNO), who might benefit from the improved gas distribution properties of HFV

High-Frequency Ventilators The Bunnell Life Pulse jet ventilator (Figure 22-16) is a microprocessorcontrolled system capable of delivering and monitoring 240 to 660 breaths/min. It is used in conjunction with a conventional ventilator that provides a source of continuous gas flow, PEEP, and low-rate IMV. The Life Pulse ventilator is approved for clinical use in neonates and infants. It appears to be most effective in disorders in which hypercarbia is the major problem. With HFJV, carbon dioxide removal is achieved at lower airway pressures than with other types of high-frequency ventilators. When managed properly, HFJV can acutely improve oxygenation and the oxygen index in infants with PPHN and other associated pulmonary conditions.

FIGURE 22-16 Bunnell Life Pulse ventilator. Courtesy of Bunnell Incorporated.

The patient box is an integral component of the Life Pulse ventilator. It contains the pressure transducer and inhalation pinch valve necessary for operation. The patient box, which regulates gas flow, is placed close to the patient’s head to provide accurate monitoring and delivery of gas to the patient. The Life Pulse controls the PIP, respiratory rate, jet valve ontime (inspiratory time), and on/off ratio (I:E ratio). The jet ventilator delivers short pulses of pressurized gas directly into the airway through a narrow-bore cannula or jet injector. The system has negligible compressible volume, and exhalation is always passive. Although tidal

volume is difficult to measure, it is equal to or slightly greater than the dead space volume. With each jet pulse, gas surrounding the injector is entrained into the airway. Airway pressure must be measured far enough downstream from the jet injector to minimize errors caused by air entrainment effects. A special triple-lumen endotracheal tube (Hi-Lo Jet) can be used for HFJV. In addition to the standard endotracheal tube lumen, this tube has a pressure monitoring port at its distal tip and a jet injector port in the tube wall approximately 7 cm upstream from the pressure monitoring port. A triple-lumen endotracheal tube adapter (Figure 22-17) allows jet ventilation without the use of a special tube, which eliminates the need to reintubate the infant solely for use of HFJV. This adapter houses the jet injector port and the pressure monitoring port.

FIGURE 22-17 Triple-lumen endotracheal tube adapter for use with the Bunnell Life Pulse jet ventilator. The 15-mm endotracheal tube adapter (A) is replaced with the Life Pulse adapter (B). The cap on the jet port (C) is removed and the Luer fitting of the Life Pulse circuit (D) is attached to the jet port. The pressure monitoring connector from the jet patient box is attached to the pressure monitoring line (E). The conventional ventilator circuit is attached to the 15-mm port of the Life Pulse adapter.

The Life Pulse ventilator delivers its jet pulse into the endotracheal tube through the injector port. It then servo-controls the driving pressure to the jet to maintain a constant predetermined pressure at the endotracheal tube tip. One notable feature of the Life Pulse ventilator is its ability to monitor and display jet servo pressure, which allows automatic detection of changes in the infant’s lung compliance and airway resistance. Servo pressure is proportional to the lung volume being ventilated. For example, as lung compliance or airway resistance (or both) improves, servo pressure increases. This trend is typically interpreted as an indicator to begin weaning the patient from highfrequency ventilation. Conversely, a decrease in servo pressure indicates that lung compliance or airway resistance has worsened, the endotracheal tube has become obstructed, a tension pneumothorax has developed, or the patient requires suctioning. Respiratory therapists and other clinicians find servo pressure helpful for assessing the patient’s pulmonary status. The SensorMedics 3100A (Vyaire, Yorba Linda, CA) is an electronically controlled oscillatory ventilator (Figure 22-18). Its 365-mL oscillatory driver is a diaphragmatically sealed piston with adjustable displacement, frequency, and I:E ratio. It produces 3- to 15-Hz pressure waves superimposed on an adjustable level of mean airway pressure. The SensorMedics 3100A is distinguished from other types of highfrequency ventilators by its active expiratory phase. It is used for ventilatory support of respiratory failure and barotrauma in neonates and small pediatric patients.

FIGURE 22-18 SensorMedics 3100A. Reproduced with permission from Vyaire.

With the SensorMedics 3100A ventilator, the primary therapeutic effects are determined by just two controls: the oscillatory pressure

amplitude (ΔP) and the mean airway pressure. In some cases, changing the frequency (hertz) or the percent inspiratory time, or both, may provide additional benefits to those patients who do not respond to initial standard settings. End-expiratory lung volume is determined by the mean airway pressure and remains relatively constant during the respiratory cycle. The SensorMedics 3100A does not require use of a special endotracheal tube adapter. It has fewer settings than other high-frequency ventilators, and once the patient’s condition has been stabilized, the settings are changed infrequently. The mean airway pressure on the SensorMedics 3100A is adjusted in a range from 3 to 45 cm H2O. The mean airway pressure limit can operate in two modes. In the safety limit mode, the mean airway pressure limit to a level higher than the range of normal mean airway pressures to protect the patient from accidental overpressure. In the controlled mode, the mean airway pressure limit to a level below that which would otherwise exist through the adjustment of the mean pressure control. In this mode, the mean airway pressure remains constant regardless of changes in bias flow, the percent inspiratory time, or frequency settings. With HFOV, the mean airway pressure is the most important determinant of oxygenation. It dictates whether the patient can be weaned from the potentially harmful effects of an elevated FIO2. Maximize the mean airway pressure initially, paying close attention to hyperinflation and monitoring the chest radiograph to maintain lung volume at the level of T8 to T9. Bias flow is necessary to maintain oxygenation, the mean airway pressure, and an oscillatory waveform. To operate efficiently, the system must be charged with flow. Standardized bias flow settings range from 10 to 20 L/min. A common rule of thumb is that the smaller the child, the lower the bias flows. Manipulations of the PaCO2 level are made primarily with the amplitude or power control (ΔP). Increasing the amplitude increases displacement of the bellows, which increases tidal volume delivery. This is measured as increased pressure amplitude at the airway opening and results in a lower PaCO2. Frequent arterial blood gas measurements or monitoring of transcutaneous PCO2 is necessary to titrate the PaCO2. The rate on the SensorMedics 3100A is measured in hertz. The

concept of active inspiration and active expiration allows for delivery of very rapid rates without air trapping. The rate can be set from 3 to 15 Hz. The higher the rate, the smaller the tidal volume, partly because of the short cycle time at the higher rate. Conversely, the lower the rate, the larger the tidal volume, because of the longer cycle and the ability to move more volume through the circuit. The respiratory therapist must recognize that the delivered tidal volumes are very small and are equal to or less than the dead space volume. As a rule of thumb, larger babies (more than 2 kg) fall into the lower rate category (8 to 10 Hz), whereas smaller infants (less than 2 kg) fall into the smaller tidal volume requirement category and hence require a higher rate (10 to 15 Hz). The selection of rate among hospitals varies, however, and often the clinician adjusts the rate based on the resonance frequency of the particular patient (e.g., how well the chest shakes on the particular hertz setting). The inspiratory time on the SensorMedics 3100A is nearly always set at 33%, the standard inspiratory time setting for this ventilator. Only in extreme cases (e.g., with a large patient with a severely elevated physiologic dead space) should the clinician increase the percent inspiratory time to improve carbon dioxide elimination. Like slowing of the respiratory rate, an increase in the percent inspiratory time allows a longer inspiratory phase, thereby increasing the delivered tidal volume. The inspiratory time can be adjusted from 33% to 50% in 1% increments. Respiratory Recap High-Frequency Ventilators ∎ Bunnell Life Pulse jet ventilator ∎ SensorMedics 3100A

Management Strategies Management strategies are divided into two categories: high lung volume and low lung volume. Most patients fall into the high lung volume management category, which means that the ventilator parameters are maximized at the clinician’s discretion. The only disease that would preclude this approach is air leak syndrome. Establishing lung volume

and restoring it to an acceptable level is a critical component of HFV. Because the delivered tidal volumes are small, the mean lung volume does not change dramatically during inspiration. PEEP is the primary contributor to mean airway pressure and end-expiratory lung volume during HFV. The Bunnell Life Pulse HFV is used with a conventional ventilator. Table 22-12 shows general management strategies for high-frequency jet ventilation. The conventional ventilator is responsible for controlling the PEEP level. Hence, the conventional ventilator controls the mean airway pressure, and the HFJV controls the PIP, respiratory rate, inspiratory time, and I:E ratio. Once the infant’s condition has stabilized, the healthcare team attempts to reduce the mean airway pressure. For example, they may gradually reduce the PIP and drop the respiratory rate to 250 to 300 breaths/min. They also decrease the PEEP if the PaO2 is acceptable and the patient tolerates the change. TABLE 22-12 Patient Management Guidelines for Life Pulse High-Frequency Ventilation

Description Special air leak considerations: (1) Minimize IMV by using HFV + adequate CPAP, and (2) if oxygenation is compromised, increase PEEP even if the lungs appear to be overdistended on chest radiograph. CPAP, continuous positive airway pressure; FIO2, fraction inspired oxygen; FRC, functional residual capacity; HFJV, high-frequency jet ventilation; HFV, high-frequency ventilation; IMV, intermittent mandatory ventilation; aw, mean airway pressure; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure. Modified with permission from materials courtesy of Bunnell, Inc., Salt Lake City, UT.

Table 22-13 shows general management strategies for HFOV. HFOV decouples (separates) ventilation and oxygenation. Mean airway pressure and FIO2 control oxygenation, whereas amplitude, the percent inspiratory time, and respiratory rate determine ventilation. This simplistic

approach to HFOV benefits both clinician and patient. Initially, the clinician maximizes the mean airway pressure and FIO2. Ventilation may be more difficult to control with HFOV, however, because the patient’s size and disease determine what settings are chosen. The smaller the patient, the higher the rate setting; the percent inspiratory time is set at 33%. Amplitude (ΔP) is a more discretional setting, and the respiratory therapist must be judicious in determining it. Amplitude is what ventilates or moves the chest with HFOV. Although the setting of ΔP is arbitrary, what happens to the patient is not. The higher the amplitude setting, the more vigorously the patient’s chest wall will move or wiggle; this is called the chest wiggle factor. The clinician determines the degree of chest wiggle acceptable for the patient. The patient’s compliance determines how aggressive the clinician is with ΔP. TABLE 22-13 General Guidelines for Use of High-Frequency Oscillatory Ventilation Therapeutic Intervention

Treatment Rationale

FIO2 below 0.70 High PaCO2 with: PaO2 satisfactory PaO2 low PaO2 high





FIO2 below 0.70 Normal PaCO2 with: PaO2 satisfactory PaO2 low PaO2 high



FIO2 below 0.70 Low PaCO2 with: PaO2 satisfactory PaO2 low



Clinical Indicators

Increase ΔP Increase aw, ΔP, FIO2 Increase ΔP; decrease FIO2

Increase ΔP to achieve optimal PaCO2 Adjust aw and FIO2 to improve O2 delivery Decrease FIO2 to minimize O2 exposure

Take no action Increase aw, FIO2 Decrease FIO2

Take no action Adjust aw and FIO2 to improve O2 delivery Decrease FIO2 to minimize O2 exposure

Decrease ΔP Increase aw, FIO2; decrease ΔP

Decrease ΔP to achieve optimal PaCO2 Adjust aw and FIO2 to

PaO2 high

Decrease FIO2, ΔP

FIO2 above 0.70 High PaCO2 with: PaO2 satisfactory PaO2 low PaO2 high



FIO2 above 0.70 Normal PaCO2 with: PaO2 satisfactory PaO2 low PaO2 high



FIO2 above 0.70 Low PaCO2 with: PaO2 satisfactory PaO2 low PaO2 high



improve O2 delivery Decrease FIO2 to minimize O2 exposure

Increase ΔP Increase FIO2, ΔP Increase ΔP; decrease aw

Increase ΔP to achieve optimal PaCO2 Increase FIO2 to improve PaO2 Decrease aw to reduce PaO2

Take no action Increase FIO2 Decrease aw, FIO2

Take no action Increase FIO2 to improve PaO2 Decrease aw and FIO2 to reduce PaO2

Decrease ΔP Increase FIO2; decrease ΔP Decrease aw, ΔP

Decrease ΔP to achieve optimal PaCO2 Increase FIO2 to improve PaO2 Decrease aw and FIO2 to minimize O2 exposure

FIO2, fraction of inspired oxygen; ΔP, pressure amplitude; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; aw, mean airway pressure. Reproduced with permission from CareFusion.

One difference between HFOV and HFJV is that higher—rather than lower—mean airway pressures are required to maintain oxygenation with HFOV. Higher mean airway pressure settings are used early in the ventilatory course, with weaning occurring as tolerated when the PaO2 level is acceptable. With HFOV, the clinician increases the mean airway pressure in increments of 1 to 2 cm H2O, provided there is no air leak, until the SpO2 rises to more than 95%, which indicates adequate lung recruitment. A chest radiograph will confirm that inflation is adequate, to the level of the eighth to the ninth rib. Hyperinflation can adversely affect hemodynamics, and the mean

airway pressure should be reduced if it occurs.24 Hyperinflation also poses an increased risk of air leakage. As the patient on HFOV improves, the FIO2 should be weaned to 0.6 before the clinician reduces the mean airway pressure, unless hyperinflation is noted by chest radiograph. When the mean airway pressure has been reduced 10 to 12 cm H2O, the clinician should consider transferring the patient back to CMV or continue weaning to extubation on HFOV.

Complications Complications associated with HFV include tracheal injury, atelectasis, pulmonary overdistention, acute respiratory alkalosis, hypotension, decreased cardiac output, and a displaced or disconnected endotracheal tube.30 In early applications of HFV, tracheal injury was reported in some cases, but improved humidification has eliminated this complication. Atelectasis may occur as a result of mucus plugging or low airway pressures leading to alveolar collapse, which can be prevented by maintaining an adequate mean airway pressure. Pulmonary overdistention and cardiac compromise can result from failure to wean patients from excessive mean airway pressures. Overdistention can cause acute lung injury, pneumothorax, and increased physiologic shunt. After initiation of HFV, clinicians must closely monitor patients for signs of decreased systemic perfusion. A high mean airway pressure may not be tolerated. If myocardial dysfunction occurs, the patient may require inotropic therapy. Minimizing the adverse effects of an increased intrathoracic environment is an essential component of the care of the child on HFV. One unique issue related to HFV is the noise of the ventilator, which contributes to the noise level in the neonatal and pediatric ICU.31 Newer models have been designed to operate more quietly, so this should be less of an issue as hospitals acquire new equipment. Stop and Think You are caring for a pediatric patient on HFOV. You realize that the patient is hypocarbic and is not within the ordered parameters. The patient’s oxygenation status is satisfactory. What ventilator change would you recommend?

Adjuncts to Neonatal and Pediatric Mechanical Ventilation Preterm infants (those less than 34 weeks of gestational age) have varying degrees of lung maturity, and their respiratory needs may differ significantly from those of a full-term infant with mature lungs. Infants born at less than 35 weeks’ gestation often have a surfactant deficiency. Surfactant production begins at approximately week 23 of gestation, and the fetal lungs reach maturity at week 35. Between weeks 23 and 35, lung maturity may be enhanced in utero by administration of corticosteroids. Thus, mothers at risk for premature delivery are often prescribed these medications. Infants who receive corticosteroids in utero are likely to have greater lung maturity than infants of similar gestational age who were not treated with steroids in utero. Many infants are born prematurely with either partial treatment or no treatment with steroids and have a surfactant deficiency, however.

Surfactant Administration Surfactant is a combination of lipoproteins found in mature alveoli that reduces surface tension at the alveolar air–fluid interface.32 Alveoli with low surface tension require less pressure to stabilize lung volume and avoid alveolar collapse. Infants with a surfactant deficiency often show signs of respiratory distress syndrome. Clinical findings associated with RDS include tachypnea, intercostal and sternal retractions, nasal flaring, expiratory grunting, decreased compliance, and an oxygen requirement. The chest radiograph of an infant with RDS typically shows a groundglass appearance and low lung volumes. Administration of exogenous surfactant has been shown to prevent and treat RDS (Table 22-14). Surfactant can be given as a rescue therapy after clinical signs of RDS have developed, or prophylactic surfactant can be given in the delivery room in an attempt to prevent the development of RDS or minimize its effects (CPG 22-1).26 The available evidence suggests that NCPAP initiated in the delivery room, followed by mechanical ventilation only when necessary, is a reasonable alternative

to prophylactic surfactant treatment for preterm infants.33 TABLE 22-14 Commercial Surfactant Preparations

CLINICAL PRACTICE GUIDELINE 22-1 Surfactant Replacement Therapy

▪

Administration of surfactant replacement therapy is strongly recommended in a clinical setting where properly trained personnel and equipment for intubation and resuscitation are readily available.

▪

Prophylactic surfactant administration is recommended for neonatal respiratory distress syndrome in which surfactant deficiency is suspected.

▪

Rescue or therapeutic administration of surfactant after the initiation of mechanical ventilation in infants with clinically confirmed respiratory distress syndrome is strongly recommended.

▪ ▪

A multiple-surfactant-dose strategy is recommended over a single-dose strategy.

▪

Aerosolized delivery of surfactant should not be utilized.

Natural exogenous surfactant preparations are recommended over laboratory-derived synthetic suspensions.

Modified from AARC clinical practice guideline: surfactant replacement therapy. Respir Care 1994:39(8):824–829. Reprinted with permission.

Surfactant is administered endotracheally (Box 22-2). In infants with clinical signs of RDS and impending respiratory failure, intubation and early administration of surfactant are recommended. Before administering surfactant, the infant’s lung compliance is significantly reduced. It may be necessary to use high pressures to ventilate a surfactant-deficient infant. Reassessment of the infant’s ventilatory needs after administration of surfactant is vital. Adjust the ventilator settings as compliance increases and oxygenation improves. Maintenance of a delivered tidal volume of 4 to 6 mL/kg is achieved by a reduction in the PIP or volume setting. Adjust the FIO2 to keep the arterial oxygen saturation in the desired range. Attention to these details is essential to reduce the risk of ventilator-induced complications. BOX 22-2 Administration of Surfactant Determine the surfactant preparation to be used and the dose. Allow the drug to reach room temperature. Confirm the position of the endotracheal tube. Instill the drug directly into the endotracheal tube. Continuously monitor the patient’s heart rate and SpO2 during administration. Monitor for endotracheal tube obstruction. Monitor tidal volume and SpO2 immediately after dose is given. Adjust ventilator support as compliance changes.

Inhaled Nitric Oxide Administration of inhaled nitric oxide (iNO) has been shown to improve oxygenation in neonates with hypoxemia and pulmonary hypertension.34 The primary mechanism is thought to be lowering of pulmonary vascular resistance by vasodilation of the pulmonary vasculature, resulting in decreased right-to-left shunting of blood. Inhaled NO is selective to the pulmonary vasculature; thus, it has not been associated with a lowering of systemic blood pressure. Inhaled NO can be administered with either a conventional or high-frequency ventilator. Although the optimal dose of iNO is not entirely clear, 20 ppm or less usually is sufficient. Because administration of iNO can cause methemoglobinemia, monitor for this

complication during therapy. Nitric oxide and oxygen combine to produce nitrogen dioxide (NO2). Although the clinician should monitor the patient’s NO and NO2 levels during therapy, use of proper delivery equipment can usually prevent the development of a high NO2. Reduce the NO concentration once oxygenation is stable, albeit while maintaining continuous monitoring with pulse oximetry. Before discontinuing NO, the increase FIO2 by 10% to 20% to prevent a rebound effect. During the administration of NO, the manual resuscitation bag at the bedside should be adapted to provide NO if manual ventilation is required so as to avoid abrupt withdrawal of NO and rebound. NO should not flow into the reservoir of the resuscitation bag until needed to avoid production of NO2. Stop and Think You are caring for a 24 weeks’ gestational age, 0.5-kg premature neonate. The physician would like you to administer a dose of Curosurf surfactant after intubation. How much medication should you prepare to administer, and how would you proceed with the administration procedure?

Key Points Awareness and understanding of maternal risk factors are crucial to identify newborns at risk for life-threatening complications. The American Academy of Pediatrics’ Neonatal Resuscitation Program (NRP) outlines a specific sequence of events for neonatal resuscitation. Excessive use of oxygen could lead to retinopathy of prematurity and bronchopulmonary dysplasia in the premature infant. Positive pressure ventilation of infants and children usually begins with bag-mask ventilation. Nasal CPAP and NIV are used to aid lung recruitment and to minimize airway collapse. Uncuffed oral endotracheal tubes are most commonly used in neonates. Infant ventilators are either conventional or high-frequency ventilators. Traditional conventional neonatal ventilators utilize continuous flow and are time cycled and pressure limited. High-frequency ventilators are classified as high-frequency positive pressure ventilation, high-frequency jet ventilation, high-frequency flow interrupter ventilation, and high-frequency oscillatory ventilation. High lung volume and low lung volume management styles are used for high-frequency ventilation. Adjuncts to neonatal mechanical ventilation include surfactant administration and inhaled nitric oxide.

References 1. Part 13: Neonatal resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132 (Suppl 2):S543–S560. 2. Iliff A, Le VA. Pulse rate, respiratory rate, and body temperature of children between two months and eighteen years of age. Child Dev 1952;23(4):237. 3. Deakins KM. Bronchopulmonary dysplasia. Respir Care 2009;54(9):1252–1262. 4. Part 12: Pediatric advanced life support. 2015 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132(Suppl 2):S526–S542. 5. Bhardwaj N. Pediatric cuffed endotracheal tubes. J Anaesthesiol Clin Pharmacol 2013;29(1):13–18. 6. Hess DR. Managing the artificial airway. Respir Care 1999;44(7):759–772. 7. American Association of Respiratory Care. Endotracheal suctioning of mechanically ventilated patients with artificial airways 2010. Respir Care 2010;55(6):758–764. 8. Walsh BK, Brooks TM, Grenier BM. Oxygen therapy in the neonatal care environment. Respir Care 2009;54(9):1193–1202. 9. Finer NN, Mannino FL. High-flow nasal cannula: a kinder, gentler CPAP? J Pediatr 2009;154(2):160–162. 10. Gupta S, Sinha SK, Tin W, Donn SM. A randomized controlled trial of post-extubation bubble continuous positive airway pressure versus infant flow driver continuous positive airway pressure in preterm infants with respiratory distress syndrome. J Pediatr 2009;154(5):645– 650. 11. Diblasi RM. Nasal continuous airway pressure (CPAP) for the respiratory care of the newborn infant. Respir Care 2009;54(9):1209–1235. 12. Courtney SE, Barrington KJ. Continuous positive airway pressure and noninvasive ventilation. Clin Perinatol 2007;34(1):73–92. 13. Kahn DJ, Habib RH, Courtney SE. Effects of flow amplitudes on intraprong pressures during bubble versus ventilator generated nasal continuous positive airway pressure in premature infants. Pediatrics 2008;122(5):1009–1013. 14. Loh LE, Chan YH, Chan I. Noninvasive ventilation in children: a review. J Pediatr (Rio J) 2007;83(Suppl 2):S91–S99. 15. Ramanathan R. Optimal ventilatory strategies and surfactant to protect the preterm lungs. Neonatology 2008;93(4):302–308. 16. Donn SM, Boon W. Mechanical ventilation of the neonate: should we target volume or pressure? Respir Care 2009;54(9):1236–1243. 17. Marchese AD, Chipman D, de la Oliva P, Kacmarek RM. Adult ICU ventilators to provide neonatal ventilation: a lung simulator study. Intensive Care Med 2009;35(4):631–638. 18. Brown MK, Diblasi RM. Mechanical ventilation of the premature neonate. Respir Care 2011;56(9):1298–1311. 19. Kneyber MCJ, de Luca D, Calderini E, Jarreau PH, Javouhey E, Lopez-Herce J, et al. Recommendations for mechanical ventilation of critically ill children from the pediatric mechanical ventilation consensus conference. Intensive Care Med 2017;43(12):1764–1780. 20. Waugh JB, Deshpande VM, Brown MK, Harwood RJ. Rapid interpretation of ventilator waveforms. 2nd ed. Upper Saddle River, NJ: Pearson/Prentice Hall; 2007. 21. Chatburn RL. Physiologic and methodologic issues regarding humidity therapy. J Pediatr

1989;114(3):416–420. 22. Hess D, Mason S, Branson R. High-frequency ventilation design and equipment issues. Respir Care Clin North Am 2001;7(4):577–598. 23. Sjöstrand UH. Review of the physiological rationale for and development of high-frequency positive pressure ventilation. Acta Anaesthesiol Scand 1977;64:7–27. 24. Courtney SE, Asselin JM. High-frequency jet and oscillatory ventilation for neonates: which strategy and when? Respir Care Clin North Am 2006;12(3):453–467. 25. Smith R. Ventilation at high respiratory frequencies. Anaesthesia 1982;37(10):1011–1018. 26. Walsh BK, Daigle B, Diblasi RM, Restrepo RD. AARC clinical practice guidelines: surfactant replacement therapy: 2013. Respir Care 2013;58(2):367–375. 27. Fredberg JJ, Glass GM, Boynton BR, Frantz ID III. Features influencing mechanical performance of neonatal high-frequency ventilators. J Appl Physiol 1987;62(6):2485–2490. 28. Taylor GI. Dispersion of matter in turbulent flow through a pipe. Proc R Soc Lond B Biol Sci 1954;223(1155):446–448. 29. Chunk HK. Mechanisms of gas transport during ventilation by high-frequency oscillation. J Appl Physiol 1984;56:553–563. 30. Boros SJ, Mammel MC, Lewallen PK, Coleman JM, Gordon MJ, Ophoven J. Necrotizing tracheobronchitis: a complication of high-frequency ventilation. J Pediatr 1986;109(1):95– 100. 31. Hoehn T, Busch A, Krause ME. Comparison of noise levels caused by four different highfrequency ventilators. Intensive Care Med 2000;26(1):84–87. 32. Been JV, Zimmermann LJI. What’s new in surfactant? Eur J Pediatr 2007;166(9):889–899. 33. Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362(21):1970–1979. 34. Diblasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: inhaled nitric oxide for neonates with acute hypoxic respiratory failure. Respir Care 2010;55(12):717–745.

CHAPTER

23 Extracorporeal Life Support for Respiratory Failure Desiree K. Bonadonna Craig R. Rackley

© Andriy Rabchun/Shutterstock

OUTLINE History of ECMO Use in Respiratory Failure ECMO Basics Indications and Contraindications ECMO Management ECMO Outcomes Complications Technological Advancements

OBJECTIVES 1. Understand the history and evolution of extracorporeal membrane oxygenation (ECMO) in practice. 2. Describe basic principles of ECMO. 3. Review common applications of ECMO and contraindications to its use. 4. Appraise data supporting the use of ECMO for acute respiratory failure. 5. Discuss ECMO management techniques.

6. Review common complications of ECMO support and their impact on patient outcomes. 7. Assess technological achievements and advancements of ECMO support and safety. 8. Describe other applications of ECMO, including PECLA, ECCO2R, and interhospital transport of ECMO patients.

KEY TERMS ECMO circuit extracorporeal carbon dioxide removal (ECCO2R) extracorporeal life support (ECLS) Extracorporeal Life Support Organization (ELSO) extracorporeal membrane oxygenation (ECMO) oxygenator pumpless extracorporeal lung assist (PECLA) sweep gas venoarterial (VA) ECMO venovenous (VV) ECMO

Introduction Despite continued advancements in conventional therapies, acute respiratory failure continues to carry a high disease burden. Globally, the mortality rate in adults with severe acute respiratory distress syndrome (ARDS) is greater than 45%.1 Among both adult and pediatric patients, ARDS survivors often face a prolonged recovery, long-term morbidity, and disability.2 Treatments for ARDS have centered on identification and treatment of the underlying cause (i.e., infection) and strategies aimed at minimizing ventilator-induced lung injury (VILI). Low tidal volume ventilation, prone positioning, and minimizing driving pressure all appear to improve outcomes in patients with ARDS.3–6 In some patients, gas exchange may be too compromised to allow for support of the patient without using injurious ventilator settings, further exacerbating their lung injury and ultimately leading to multiorgan failure and death. Extracorporeal methods of gas exchange represent a mechanism to provide life support with adequate gas exchange while mitigating VILI. Extracorporeal membrane oxygenation (ECMO) refers to the most common type of extracorporeal support, in which the patient’s blood is oxygenated and carbon dioxide is removed while the blood flows across an external gas exchange membrane. Venoarterial (VA) ECMO provides both cardiac and respiratory support, whereas venovenous (VV) ECMO provides support only for respiratory failure. Extracorporeal life support (ECLS) is a broader term that includes the shunting of blood through extracorporeal devices for hemodynamic or respiratory support. It includes temporary external ventricular assist devices without oxygenators in addition to ECMO. While ECMO may be used for either cardiac or respiratory indications, this chapter focuses primarily on ECMO for respiratory failure. Respiratory Recap Types of ECMO ∎ Venovenous (VV) ∎ Venoarterial (VA)

History of ECMO Use in Respiratory Failure Modern ECMO technology is based on the technology first used for cardiopulmonary bypass in the 1950s.7 Extended partial cardiopulmonary bypass as a successful support for severe respiratory failure was reported in 1972 in a young adult and a few years later in a neonate.8,9 In 1979, the first randomized trial of ECMO in adults with severe respiratory failure was published, and it reported equally dismal outcomes for both the ECMO and conventional arms.10 A repeat study 15 years later showed improved overall survival but failed to demonstrate a difference between ECMO and conventional management.11 In the face of these negative studies, ECMO use remained minimal in adults for many years. Meanwhile, ECMO for neonates with respiratory failure demonstrated promising outcomes, and the application of the technology in this population increased throughout the 1980s.12–15 A resurgence of interest in ECMO to support respiratory failure in adults occurred in 2009 in conjunction with two simultaneous events. The first was the outbreak of H1N1 influenza in 2008 and 2009, which affected a large number of young, healthy adults. Hospitals in many countries reported survival rates in young adults infected with H1N1 supported with ECMO exceeding 70% in a cohort of patients with a much higher predicted mortality.16,17 The second event was the publication of the Conventional Ventilatory Support Versus ECMO for Severe Adult Respiratory Failure (CESAR) trial.18 This study reported that adult patients with severe respiratory failure who were transferred to a single ECMO center had improved survival compared to those who remained at the referral center and received conventional therapy. Of note, 18% of the patients randomized to ECMO referral were not supported with ECMO because they were stabilized on conventional therapy. When patients who received ECMO were compared to those who did not, there was no difference in survival. Although this study demonstrated that patients with severe respiratory failure referred to a center with ECMO capability have improved outcomes, it failed to definitely demonstrate that ECMO was the reason for the more favorable outcomes. Following these two events demonstrating the feasibility and potential

benefit of ECMO in ARDS, the growth of ECMO utilization worldwide increased 360% from 2008 to 2017. This wider application occurred predominantly in adults, such that the number of adult ECMO cases now exceeds the number of neonatal ECMO cases for the first time since the technology’s introduction in the 1970s.16 Figure 23-1 shows the volume of ECMO cases reported to the Extracorporeal Life Support Organization (ELSO), which is an international organization that maintains a registry database that tracks ECMO volume and outcomes.

FIGURE 23-1 Yearly ECMO cases reported to the Extracorporeal Life Support Organization (ELSO) database. Data from the ECLS Registry Report. Ann Arbor, MI: Extracorporeal Life Support Organization; January 2018.

Description Despite the growth of ECMO utilization, clear evidence in adults demonstrating the effectiveness of this therapy for ARDS has been lacking. In 2018, the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial evaluated the use of ECMO in patients with severe ARDS.19 It was the largest, most well-designed ECMO trial to date. Although it failed to show a significant difference in mortality based on the intentionto-treat analysis, the investigators noted a significantly higher rate of death or treatment failure in the conventional arm compared to ECMO. With current advances in technology, the recent experience since 2009, and the exponential growth of ECMO utilization, it is likely that ECMO will remain a tool in the management of severe respiratory failure.

ECMO Basics ECMO is accomplished by inserting a large-bore cannula into a central vein, draining blood from the patient, pumping that blood through an artificial gas exchanger (oxygenator), and then returning the oxygenated blood to the patient. The oxygenator delivers pure oxygen or a mixture of oxygen with air or carbon dioxide (sweep gas) to provide gas exchange. Oxygen readily diffuses across the gas-permeable membrane of the oxygenator into the blood. Carbon dioxide removal occurs through passive diffusion across the gradient between the blood into the sweep gas (Figure 23-2). Blood may be returned either to the venous (VV ECMO) or arterial (VA ECMO) system (Figure 23-3). VV ECMO is the preferred method of support in respiratory failure, both for simplicity and for its more favorable safety profile.

FIGURE 23-2 Schematic of a simplified oxygenator. In a modern oxygenator, sweep gas flows through thousands of gas-permeable filaments (light blue) that are bathed in deoxygenated venous blood, allowing gas exchange to occur before the oxygenated blood is returned to the patient.

FIGURE 23-3 Basic cannulation strategies for ECMO. (A) VV ECMO using dual cannulation with venous drainage from the femoral vein and return to the right internal jugular vein. (B) VA ECMO with venous drainage from the femoral vein and return to the femoral artery. (C) VV ECMO through a dual-lumen cannula with venous drainage from the superior and inferior vena cavae and return to the right atrium.

Patients requiring VV ECMO can be cannulated using dual-site cannulation, in which the drainage cannula is placed in a different vessel than the return cannula, or via single-site cannulation using a dual-lumen catheter. Dual-site cannulation is often accomplished by placing a drainage cannula into a femoral vein and a return cannula in either the right internal jugular vein or the contralateral femoral vein. The duallumen catheter is usually placed in the right internal jugular vein but can also be placed in the left subclavian vein.20 Use of a double-lumen catheter allows for single-site cannulation, reduces vessel trauma and infection risk, and potentially allows for increased wakefulness and mobility. Ideally, this cannulation strategy is performed under direct visualization with fluoroscopy or transesophageal echocardiography. It cannot achieve the higher blood flow required in some patients with sepsis and severe hypoxemia, is more susceptible to flow interruptions, and is more expensive than dual site cannulation. For these reasons, single-site cannulation with a dual-lumen catheter should be reserved for patients with less severe hypoxemia with higher likelihood of mobility, such as those being bridged to a lung transplant.21,22 When VA ECMO support is indicated in adolescents and adults, the

most common arterial access is the femoral artery, but the axillary or subclavian arteries might also be utilized. The carotid artery is typically used for neonates and younger children requiring VA ECMO, either for cardiac support or inability to technically place a double-lumen venous catheter due to the small size of the internal jugular vein (in neonates). Open chest cannulations may also be performed with several different configurations depending on the patient’s pathology and surgical history.23 VA ECMO is typically reserved as a salvage technique for adult respiratory failure for many reasons, including risks of coronary, brain, and upper body ischemia; increased risk of stroke; and increased incidence of vascular complications. The remainder of this chapter focuses on VV ECMO support for respiratory failure, except where otherwise indicated. In adults, the blood flow through the VV ECMO circuit commonly ranges from 2 to 6 L/min depending on the cannulation strategy, the severity of pulmonary and/or cardiac impairment, and the needs of the individual patient. As a greater fraction of the patient’s cardiac output flows through the ECMO circuit, more oxygenated blood is returned to the patient and mixes with the circulating blood. Therefore, in a hypoxemic patient, increasing blood flow through the ECMO circuit typically improves oxygenation. The amount of blood flow achieved can be limited by the cannula size and location, so the clinician must consider the anticipated needs of the patient when deciding on the appropriate ECMO cannulation strategy. The sweep gas flow through the oxygenator can range from 0.1 to 10 L/min. The efficiency of oxygenation is high, such that blood leaving the oxygenator is typically fully saturated with oxygen, even at low sweep flows of 1 to 2 L/min.24 Increasing sweep gas flow does little to improve oxygenation but rather facilitates the removal of carbon dioxide. In a hypercarbic patient, increasing sweep gas flow will increase clearance of carbon dioxide. Stop and Think Which is the right patient for ECMO support? When should you consider ECMO? What patient factors increase mortality risk?

Indications and Contraindications In patients with severe hypoxemic or hypercarbic respiratory failure, the challenge for the clinician is to select the optimal therapy that will maximize benefits and minimize risks. Conceptually, like invasive mechanical ventilation, ECMO is intended to support patients while they recover from their underlying illness or insult. As such, ECMO should be reserved for patients with a reversible process, or in cases of end-stage lung disease, for patients who can be successfully bridged to lung transplant. The clinician must weigh the risks and benefits of ECMO versus the potential toxicities of conventional therapies when pondering the utility of ECMO. The most common indication for VV ECMO is treatment of severe ARDS. These patients often have a mix of respiratory acidosis due to a high dead space fraction and severe hypoxemia from alveolar flooding.16,18,19 VV ECMO has also been successfully used in patients with other reversible causes of inadequate gas exchange refractory to conventional management, including status asthmaticus, pulmonary embolism, airway compression due to mediastinal masses, air leak syndromes, persistent pulmonary hypertension of the newborn, and congenital airway anomalies. Patients with many of these disease processes experience the best outcomes with ECMO, as they may not have the multiorgan dysfunction that is frequently present with ARDSassociated hypoxemic respiratory failure.25,26 The optimal timing of initiation of ECMO remains unclear, as there is no defined point where the harm of invasive mechanical ventilation outweighs the harm of ECMO. Traditionally, ECMO has been used as a rescue therapy reserved for respiratory failure refractory to conventional therapy. However, the level of conventional support attempted prior to initiating ECMO varies widely. Much of this variation in ECMO timing reflects differing levels of experience and comfort with ECMO, as well as variable conventional practices and implementation of other rescue therapies. ELSO has published guidelines recommending initiation of ECMO once predicted mortality reaches 50% to 80%.16 This recommendation is arbitrary, however, and accurate mortality prediction scores are not

available specifically for ARDS. Patients with predicted mortality rates in the 50% to 80% range typically suffer from multisystem organ failure and may be less likely to benefit from ECMO. The oxygenation index, Murray Lung Injury Score, and PaO2/FIO2 ratio have all been used as criteria for initiation of ECMO in patients with ARDS. The oxygenation index ([P_aw × FIO2 × 100]/PaO2) accounts for both the FIO2 and the mean airway pressure required to achieve a particular PaO2. ELSO recommends initiation of ECMO in neonates for an oxygenation index of 20 to 40,16 and one study found a cutoff of oxygenation index ≥ 33 to be an indicator that the risk of lung injury outweighs the risk of ECMO in neonates.27 Similar oxygenation index values are commonly used as indications for ECMO initiation in children and adults.28–30 The Murray Lung Injury Score considers PaO2/FIO2, severity of infiltrates on chest x-ray, lung compliance, and positive end-expiratory pressure (PEEP). Based on the degree of abnormality, the score ranges from 0 to 4, with 4 being the most severe ARDS.31 This definition of severe ARDS was used in the CESAR trial, which enrolled patients with a lung injury score > 3.18 Most clinical trials in ARDS have used the PaO2/FIO2 ratio to define the severity of ARDS, including the EOLIA trial. However, recognizing that a patient may appear to have much more severe disease during the early period after initiation of invasive mechanical ventilation while the patient is being stabilized and undergoes lung recruitment, the EOLIA trial also incorporated time into its inclusion criteria. Patients with ARDS and a PaO2/FIO2 ratio < 80 for 6 hours or < 50 for 3 hours were selected for randomization.19 While no clear definitive guidelines have been established regarding when to initiate ECMO in patients with ARDS, low tidal volume ventilation, early neuromuscular blockade, prone positioning, and minimizing driving pressures all appear to reduce lung injury and improve outcomes in ARDS.3–6 Thus, if these proven lung-protective strategies do not meet the patient’s clinical goals, the clinician should consider ECMO. Both the CESAR and EOLIA studies used respiratory acidosis with a pH < 7.20–7.25 as an inclusion criterion.18,19 Generally, if a patient has refractory respiratory acidosis leading to hemodynamic compromise, then

ECMO should be considered for the management of respiratory acidosis irrespective of the patient’s degree of hypoxemia. Clinicians should also consider when irreversible lung injury has occurred prior to initiating ECMO. Current guidelines suggest that mechanical ventilation at high settings (FIO2 > 0.9, plateau pressure [Pplat] > 30 cm H2O) for 7 days or more is a contraindication to ECMO.16 While more than 7 days of mechanical ventilation has historically been used as an exclusion criterion for ECMO candidacy in many centers, emerging data suggest that the window of time to initiate ECMO may be increasing, likely due to improved lung-protective ventilation strategies. Recent studies report that mortality does not significantly increase until at least 10 to 14 days of pre-ECMO mechanical ventilation.26,32,33 Because survival may decrease with each additional day of mechanical ventilation prior to ECMO, however, identification of patients who require ECMO early in their disease course is an important goal.25,34 Furthermore, the level of ventilatory support may be more important than the duration of ventilation as providers attempt to determine the reversibility of lung injury. Absolute contraindications to ECMO are rare and relate to the ability to successfully initiate and manage the extracorporeal device. These contraindications may include irreversible coagulopathy and inability to cannulate the patient due to anatomic reasons. As with any medical therapy, futility should be considered an absolute contraindication to initiation or continuation of ECMO, but determination of futility in the acutely deteriorating patient can be challenging. As ECMO is a bridge therapy rather than a destination therapy, patients receiving ECMO should have the potential to recover or bridge to a destination therapy, such as lung transplantation. Severe neurologic injury and terminal diseases with short life expectancies are considered as contraindications to ECMO. Known risk factors for poor outcomes in ECMO patients should be considered when estimating disease reversibility and survivability. The RESP Score, which was derived from the ELSO registry, provides a predicted percent survival rate based on clinical factors and comorbidities that increase the risk of death in patients who receive ECMO.35 A final factor in the decision to initiate ECMO is resource allocation. ECMO is a resource-intensive therapy, in terms of both financial cost and

clinical staffing. Most centers are limited regarding the number of ECMO circuits they can run simultaneously. Thus, providers must consider the likelihood for meaningful survival when assessing patients for ECMO candidacy, and the potential for other patients who, in turn, may require but not be able to receive ECMO. Respiratory Recap Indications for ECMO for Respiratory Failure ∎ ARDS ∎ Status asthmaticus ∎ Pulmonary hemorrhage ∎ Pulmonary embolism ∎ Persistent pulmonary hypertension of the newborn ∎ Congenital diaphragmatic hernia ∎ Meconium aspiration syndrome ∎ Air leak syndromes ∎ End-stage lung disease as a bridge to transplant

Stop and Think How is a patient receiving ECMO managed differently from a typical patient with respiratory failure? What therapies can benefit the patient when provided in conjunction with ECMO? How do you know when it is time to discontinue ECMO support?

ECMO Management Blood flow and sweep gas flow are the main variables used to achieve goal oxygenation and carbon dioxide removal in a patient receiving ECMO. However, successful care of a patient on VV ECMO involves the interplay of multiple management considerations. ELSO has published guidelines regarding ECMO management, but those guidelines primarily focus on broad recommendations and leave room for individualization of therapy.16 As such, management of ECMO varies significantly across institutions and even between groups within individual institutions, and much of ECMO management is driven by experience and anecdote. The majority of published literature consists of retrospective reviews and small single-center trials.36 Increased standardization of ECMO, both within and across centers, is needed to better assess, study, and define those key strategic variables that can drive improved patient outcomes.37

Monitoring The healthcare team must monitor both the patient and the ECMO circuit closely to ensure ECMO is functioning appropriately and providing the level of support required. In addition to standard frequent vital sign monitoring, patient monitoring typically involves the placement of an arterial line and frequent blood sampling to ensure adequate gas exchange and monitoring of hemoglobin, platelets, and anticoagulation status. While no clear guidelines have been established on how often these measures should be monitored, the healthcare team must balance the need for adequate monitoring with the risk of cumulative blood loss from frequent phlebotomy. The patient should undergo a targeted physical examination at least daily and with any change in status. A neurologic examination should be conducted as the patient’s condition allows to monitor for neurologic complications of ECMO, such as stroke. Clinicians should pay special attention to the sites of cannulation to ensure secure positioning and to evaluate for bleeding, infection, or distal swelling that could indicate deep vein thrombosis (DVT) formation. Finally, clinicians should obtain a chest

radiograph to ensure appropriate internal positioning of the cannulas. ECMO circuit monitoring includes visual inspection of the circuit tubing, cannulas, and oxygenator for evidence of fibrin and clot formation and the integrity of connections and tubing. Additionally, some devices allow for continuous monitoring of pressures within the circuit. A change in pressure gradients within the circuit indicates increased resistance to flow, which can stem from a number of factors—for example, the volume status of the patient, the position of the cannulas, or clot formation within the circuit. In the absence of pressure monitoring, increased resistance manifests as a decrease in blood flow with no change in the pump’s revolutions per minute (RPM). Other monitoring components may include sonographic flow probes, continuous blood gas analyzers, bubble detectors to identify air emboli, and emergency clamps to stop flow if air is detected. A common problem is recirculation of oxygenated blood back through the circuit rather than to the patient for oxygen extraction. This is typically due to improper cannula positioning, hypovolemia, excess flows, or decreased cardiac output of the patient. Evidence of recirculation can be visually appreciated by evaluating the color of the blood in the venous drainage tubing relative to that in the return tubing. If blood in the venous drainage tubing is brighter red than on earlier inspection and is closer in color to the oxygenated blood in the return tubing, this finding may indicate recirculation. Recirculation can be detected with an increase in SvO2 on devices that provide continuous oxygen saturation monitoring of blood in the venous drainage catheter. Recirculation is significant when SpO2 decreases. Recirculation can often be remedied by decreasing the ECMO flow and confirming proper positioning of the cannula.

Anticoagulation When a patient is placed on ECMO, the immune system reacts to the foreign surfaces of the ECMO circuit and triggers an inflammatory response and coagulation cascade.38,39 As such, patients are typically maintained on systemic anticoagulation to reduce the risk of clot formation and consumptive coagulopathy associated with the cannulas and circuit. However, the risk of clot formation must be balanced with the

risk of hemorrhage, especially intracranial hemorrhage, which remains the most catastrophic complication of ECMO. The optimal agent and target level of anticoagulation remain unknown, and, in turn, the paucity of data drives practice variability. Heparin is the typical anticoagulant used given the long-term experience with this agent, its low cost, and the availability of a reversal agent (protamine). Direct thrombin inhibitors, such as argatroban or bivalirudin, may be used as alternative anticoagulants in the setting of heparininduced thrombocytopenia or heparin resistance and rarely as the primary anticoagulant.40–42 The ideal therapeutic level of anticoagulation is not clear and varies significantly among institutions.42 Higher levels of anticoagulation lead to more bleeding complications and fewer clotting complications, whereas lower levels of anticoagulation lead to more clotting and less bleeding.43 The significance of bleeding or clotting complications varies among patients, and the clinician must weigh these risks relative to the patient’s other comorbidities when selecting a target level of anticoagulation. Traditionally, anticoagulation was guided by activated clotting time, a test of whole blood clotting accounting for coagulation factors, platelets, procoagulants, and anticoagulants. ELSO recommends maintaining the activated clotting time (ACT) at 1.5 times the normal range.16 However, different ECMO centers use different techniques to monitor anticoagulation, such as activated partial thromboplastin time (aPTT), anti-Xa level, rotational thromboelastometry (ROTEM), and thromboelastography (TEG); they also vary significantly in their target levels of anticoagulation.42 The EOLIA trial used unfractionated heparin targeting an aPTT of 40 to 55 seconds or an anti-Xa level of 0.2 to 0.3 IU.19 While almost all patients receiving ECMO receive systemic anticoagulation, the biocompatible surface coating applied to ECMO circuit components allows providers to use no heparin for a limited time in the setting of refractory bleeding or invasive procedures. Some patients have been managed without systemic anticoagulation for prolonged periods of time—even for their entire ECMO course—without significant complications.44,45

Sedation The optimal level of sedation for patients requiring ECMO depends largely on the indication for ECMO and the severity of the underlying disease process. A patient with cystic fibrosis who is placed on ECMO primarily for treatment of respiratory acidosis as a bridge to lung transplantation may be awake, eating, and actively participating in physical therapy, whereas a patient with sepsis and very severe ARDS may require heavy sedation and neuromuscular blockade to adequately manage the respiratory failure. In general, patients on mechanical ventilation have improved outcomes when on lower levels of sedation, including less time on the ventilator and improved survival.46,47 Notably, however, those patients with severe ARDS have improved survival when treated with heavy sedation and neuromuscular blockade for the first 48 hours.4 This difference in outcomes is presumably due to these patients’ improved patient–ventilator interactions and less lung injury. When ECMO can fully correct the abnormality in the patient (i.e., respiratory acidosis or other airway obstruction), low levels of sedation and analgesia are often adequate, and patients may tolerate being fully awake and interactive. Conversely, patients with more severe disease may need a more deeply sedated state until they are stabilized. After stabilization, they should be allowed to be as awake and interactive as they can tolerate while still maintaining adequate support of organ dysfunction.

Fluid Administration Managing a critically ill patient on ECMO often involves balancing the complex interplay of intravascular and extravascular volume status, right ventricular dysfunction and pulmonary hypertension, and left ventricular dysfunction. Low intravascular volume impairs venous drainage into the ECMO circuit, especially when the patient is nearing a state of intravascular collapse. As a vessel collapses onto the drainage ports of the cannula, flow is decreased, and intermittent venous cannula occlusion results in chugging or chatter—that is, a bouncing motion visible on the drainage limb of the ECMO circuit. IV fluids or blood products are often administered to alleviate such interruptions in support.

Alternatively, the speed of the ECMO pump may be reduced, decreasing suction of the vessel, and maintaining a lower, but more consistent flow state. In patients with ARDS, a conservative fluid strategy has been shown to reduce ventilator days and ICU length of stay.48 In patients who require ECMO support, a positive fluid balance is an independent predictor of mortality.49 While the patient should be adequately resuscitated in the initial period of shock, the clinician should not administer additional fluids in the absence of clear volume depletion.

Mechanical Ventilation The management of mechanical ventilation during ECMO is controversial, and management strategies vary in different settings.50 It is generally accepted that proven strategies to minimize VILI in ARDS— such as maintaining low tidal volumes and limiting driving pressures and plateau pressures—should carry over to the management of patients with severe ARDS requiring ECMO. However, as the majority of gas exchange occurs through the ECMO circuit, these limits may be reduced once a patient goes on ECMO. Lung-protective strategies minimize the tidal recruitment/derecruitment and hyperinflation that occurs during mechanical ventilation. Therefore, most expert and consensus statements recommend keeping plateau pressures and tidal volumes low, but how low is unclear and often not defined due to a paucity of data.16,51 The amount of PEEP that should be applied for these patients is also uncertain. Higher levels of PEEP can lead to improved gas exchange, maintain alveolar recruitment, and improve left ventricular function. However, excessive PEEP may cause alveolar overdistention, reduce cardiac preload, and increase right ventricular afterload.52 Patients with severe ARDS managed with mechanical ventilation alone have improved survival with the use of higher levels of PEEP.53 Furthermore, patients with ARDS who are placed on ECMO are more likely to survive when they are managed with higher levels of PEEP during the first few days of ECMO.54 While the optimal strategy for managing mechanical ventilation in a patient on ECMO is unknown, the clinician should adhere to the principles of lung-protective ventilation. Patients should be managed using tidal volumes ≤6 mL/kg predicted body weight, driving pressures

≤15 cm H2O, and plateau pressures ≤30 cm H2O (and potentially even lower). The clinician should keep PEEP in a moderate range of 10 to 15 cm H2O to minimize atelectasis and maintain an open lung strategy. Whether patients should be completely liberated from mechanical ventilation while on ECMO to eliminate the risk of VILI and reduce the risk of respiratory muscle atrophy is also unclear and can be challenging in the setting of severe ARDS and critical illness.

Blood Transfusion Patients on ECMO require frequent blood draws and often have some degree of bleeding complications. Blood loss, in addition to impaired hematopoiesis related to critical illness, leads to patients on ECMO receiving frequent blood transfusions. The appropriate level of hemoglobin for this population has not been definitively established, and recommendations vary widely. ELSO recommends maintaining hemoglobin near the normal range.16 However, numerous studies in the setting of critical illness, sepsis, acute gastrointestinal bleeding, and cardiac surgery in high-risk patients have demonstrated that using a hemoglobin transfusion threshold of 7 to 7.5 g/dL leads to significantly less blood product utilization and either improved survival or no difference in survival compared to higher transfusion thresholds of 9 to 10 g/dL.55–58 Although these studies did not specifically address the issue of severe hypoxemia, the EOLIA trial, which is the largest ECMO trial in ARDS to date, suggested a hemoglobin transfusion threshold of 7 to 8 g/dL.19 Most patients requiring ECMO for respiratory failure likely can be managed with hemoglobin transfusion thresholds of 7 to 8 g/dL, which is in line with common clinical practice for other critically ill patients.

Timing of ECMO Decannulation When to liberate a patient from ECMO can be an even more difficult decision than whether to initiate ECMO. The decision to remove a patient from ECMO entails a risk–benefit analysis involving multiple factors. The most crucial question is, has the underlying or initial disease process improved sufficiently that the patient can be supported with conventional

management? Second, is the patient suffering undue morbidity or complications from ECMO, or is the patient stable without complications? The median duration of ECMO support for patients with ARDS ranges from 9 to 15 days.16,18,19 For other disease processes, such as asthma, patients often recover much more quickly and typically require shorter courses of ECMO.59 Outcomes for repeated courses of ECMO are poor, so it is generally preferable to remove a patient from ECMO on less than maximal support.26 Similarly, the avoidance of VILI—the primary advantage of ECMO—may be negated if the patient transitions from ECMO to toxic ventilator settings. Finally, if it becomes clear that the patient has no meaningful chance of survival, then the only ethical choice is to discontinue ECMO rather than continue to provide futile care. Determining that a patient with ARDS on ECMO has no meaningful chance of survival is very difficult. While the most appropriate length of time required to see recovery is unknown, ECMO support may still be warranted when patients have a potentially reversible process and have not developed multisystem organ failure, even after a prolonged ECMO course. Patients with respiratory failure are increasingly supported for more than 28 days on ECMO prior to decannulation and bridge to recovery.60,61

ECMO Outcomes Any complex technology has a steep learning curve to achieve optimal outcomes. An ECMO program requires an experienced and well-trained staff, coupled with the hospital infrastructure needed to support the complex patients. Patients managed at ECMO centers with more experience and greater annual ECMO volume have slightly better outcomes than those managed at centers with less experience.62 Cumulative survival for all respiratory ECMO patients is 61%, and survival rates decrease with age.16,25,26 Several studies have demonstrated a consistent mortality for ECMO patients over time, despite an increasingly complex patient population.25,26,63 While adult data are limited, when controlling for comorbidities and risk factors, the survival rate for children without comorbidities who receive ECMO has significantly increased, from 57% in 1993 to 72% in 2007.26 This improved survival is largely due to refinements in techniques and technological advancements.16, 25, 26, 64 Adult patients with severe ARDS managed in an ICU have a survival rate of approximately 54%.1 In the two major ECMO trials in ARDS, the survival rates of those who received ECMO were 56% (CESAR) and 60% (EOLIA).18,19 These patients had very severe ARDS, and their cases represent outcomes from experienced centers performing ECMO in this population, which provides a reasonable expectation of outcomes with current knowledge and technology. ECMO for near fatal asthma has excellent outcomes, with a survival rate of 84%.59 These patients tend to be younger, have single-organ dysfunction, and have a readily reversible cause, all of which typically lead to better outcomes.35 A small, but growing, population of patients receiving ECMO comprise individuals with end-stage lung disease as a bridge to lung transplant. Patients with end-stage lung disease requiring mechanical ventilation have historically had poor outcomes.65 Emerging data demonstrate improved outcomes in these patients using an awake and ambulatory ECMO strategy, especially at centers with higher transplant volume.66 Keeping patients awake helps avoid the negative effects of sedation and immobility. These awake patients may also participate in early

rehabilitation, which likely contributes to quicker recovery from critical illness.67 Stop and Think What are the major complications of ECMO? Are these complications directly attributable to the technology, or are they common in patients with respiratory failure in general?

Complications ECMO represents a complex system that is not without risk. Although some complications, such as bleeding, vascular injury, and catheterassociated infections, are directly related to ECMO, other organ dysfunction makes it difficult to differentiate the effects of the patient’s overall severity of illness from the complications specifically related to ECMO.

Bleeding Bleeding is the most frequent complication in ECMO patients, most commonly occurring at cannulation or other surgical site(s), and is typically manageable with local measures. Bleeding at other sites, including intracranial, gastrointestinal, and pulmonary locations, is associated with increased morbidity and mortality.16,25 Significant bleeding may be addressed by minimizing anticoagulation, replacing coagulation factors, and administering blood products, such as platelets, as indicated.

Neurologic Injury Complications involving the central nervous system carry the greatest risk of morbidity and mortality for ECMO patients, and this technology is associated with both ischemic and hemorrhagic stroke. Ischemic stroke tends to be more common in VA ECMO, contributing to approximately 9% of all deaths.68 In patients requiring VV ECMO for respiratory failure associated with H1N1 influenza infection, the rate of intracranial hemorrhage was approximately 9% and contributed to 43% of all deaths.16 However, in studies of VV ECMO for ARDS that did not exclusively include H1N1 patients, the overall rate of stroke did not differ in those who received ECMO compared to those who did not.18,19 While ECMO’s contribution to the risk of stroke remains uncertain, patients who require ECMO clearly have an increased risk of stroke, and this catastrophic complication often necessitates terminal discontinuation of ECMO.

Infection Patients receiving ECMO are at risk for infection given their severity of illness, ventilator status, risk of bacterial translocation from the gut, impaired immune response, and presence of large indwelling cannulas. Hospital-acquired infections during ECMO occur in 10% to 12% of patients, with the most important risk factor for their development being duration of ECMO support.69 Although some institutions advocate for prophylactic antibiotics, evidence is lacking to support their use in ECMO patients. Thus, antibiotics should be reserved for the treatment of active infections to reduce the risk of infection with multidrug-resistant organisms.

Vascular Injury and Thrombosis The placement of a large cannula for ECMO, often under emergent conditions, can lead to direct injury to the artery or vein being accessed or the surrounding tissue. An important consideration when accessing the arteries supplying blood to the limbs for VA ECMO is that the cannula has the potential to occlude the vessel and create limb ischemia. Limb ischemia has been reported in 17% of patients receiving VA ECMO, with 5% requiring amputation.70 This risk can be partially ameliorated by placing a distal perfusion catheter to provide blood flow to the artery distal to the ECMO catheter.71 VV ECMO carries much less risk of limb ischemia but does confer an important risk of thrombosis related to the cannula in the presence of a prothrombotic and inflammatory reaction to the ECMO circuit. The reported incidence of catheter-associated DVT varies but ranges as high as 85% of patients cannulated for VV ECMO having DVT present on ultrasound performed after decannulation.72 This risk highlights the need for vigilance in assessing for DVT and adjusting anticoagulation goals accordingly. Respiratory Recap Complications of ECMO ∎ Bleeding

∎ Neurologic injury ∎ Infection ∎ Vascular injury and thrombosis

Technological Advancements Since the application of ECMO for respiratory failure in the 1970s, several advances in circuit components have improved the reliability and ease of use of this technology. Previously, blood was pumped through the ECMO circuit using roller-head pumps, which can lead to significant mechanical shear on the circuit tubing and red blood cells. Roller-head pumps have largely been replaced by continuous-flow centrifugal pumps, which have fewer mechanical parts, resulting in smaller pumps and quicker setup times. Additionally, these newer devices may cause less red blood cell trauma and hemolysis.73 Newer cannulas and circuit tubing are often coated with heparin or other polymers to improve biocompatibility and circuit life by reducing the inflammatory response to ECMO. Modern cannulas are also reinforced with wire to prevent luminal occlusion and collapse under high negative pressure. Other cannula advancements include the development of percutaneously placed ECMO cannulas and double-lumen catheters that allow for simultaneous drainage from both the superior and inferior vena cavae and have directional outflow toward the tricuspid valve. Another component of a standard ECMO circuit that has undergone improvement is the oxygenator. The silicone rubber membrane oxygenators that served as the primary oxygenator for decades has largely been replaced by newer polymethylpentene hollow-fiber oxygenators. These modern oxygenators are smaller, have minimal plasma leakage and low resistance to blood flow, and are well suited for use with centrifugal blood pumps.74 All of these technical advances contribute to safer, lower-maintenance, and more-efficient ECMO circuits. Stop and Think How might extracorporeal support for respiratory failure change in the next few years?

Other forms of extracorporeal respiratory support are also being used in respiratory failure. The pumpless extracorporeal lung assist (PECLA) device uses the blood pressure gradient between arterial and

venous circulation as the driving force to push blood from the arterial system through a low-resistance membrane oxygenator and back to the central venous circulation. While outcome studies are lacking, the simplicity of the device makes the technology appealing.75 Another strategy is the use of low-flow extracorporeal carbon dioxide removal (ECCO2R). This technology typically uses a relatively small dual-lumen catheter, similar to a hemodialysis catheter. Blood is extracted through the catheter, flows through a gas exchanger, and then returns to the patient. This technology has been in use since the 1970s, having been studied as a way to minimize injurious ventilation in patients with ARDS.76 More recently, this technology has been employed to avoid invasive mechanical ventilation or facilitate early extubation in patients with an exacerbation of chronic obstructive pulmonary disease (COPD).77,78 Finally, in addition to allowing for ambulation on ECMO, the design of smaller and more portable ECMO circuits has allowed for transport of patients on ECMO between hospitals (Figure 23-4). Critically ill patients can now be placed on ECMO at the referring center, stabilized, and then transferred for continued management. Due to the resources needed to operate an ECMO program, support with ECMO remains limited to large hospitals and regional referral centers. The ability to move patients on ECMO between hospitals in an air or ground ambulance permits safer transport of patients who may have previously been deemed too unstable for transfer due to the severity of their respiratory failure.

FIGURE 23-4 The Cardiohelp System (Getingue, Gothenburg, Sweden), measuring less than 18 in (50 cm) in each dimension and weighing around 10 kg. Courtesy of Maquet Medical Systems.

Key Points Severe respiratory failure and ARDS impose a high global disease burden, and current treatments for these conditions are directed toward minimizing VILI. Extracorporeal gas exchange can provide life support and minimize VILI in the most severe forms of respiratory failure. ECMO is indicated in patients with reversible respiratory failure who cannot be managed with traditional lung-protective strategies. VV ECMO provides support for respiratory failure. VA ECMO provides support for cardiac and cardiopulmonary failure. ECMO utilization has grown exponentially since the late 2000s due to improvements in the technology, favorable outcomes in influenza pandemics, and positive results from clinical trials. Management of ECMO varies across institutions, and no clear, evidence-based guidelines for ideal management strategies have been established as yet. Predictors of mortality in patients receiving ECMO include increasing age, multiorgan dysfunction, and prolonged mechanical ventilation prior to ECMO. Bleeding is the most common complication related to ECMO. Technological advancements have made ECMO safer, easier, and more versatile. Mobile ECMO is becoming more common as a way to stabilize and transport critically ill patients with respiratory failure between hospitals.

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CHAPTER

24 Pulmonary Rehabilitation Neil R. MacIntyre Rebecca H. Crouch Anne M. Mathews

© Andriy Rabchun/Shutterstock

OUTLINE Mechanisms of Functional Deterioration in Patients with Chronic Lung Disease Program Structure The Process of Pulmonary Rehabilitation Outcomes from a Pulmonary Rehabilitation Program Reimbursement Issues Future Directions

OBJECTIVES 1. 2. 3. 4. 5.

Define pulmonary rehabilitation. List the team members who constitute a pulmonary rehabilitation program. Compare intensive programs, maintenance programs, and perioperative programs. Identify candidates for a pulmonary rehabilitation program. Describe the components of patient assessment in a comprehensive pulmonary rehabilitation program. 6. Describe the role of education in a pulmonary rehabilitation program.

7. Discuss the benefits of upper- and lower-extremity exercise training in a pulmonary rehabilitation program. 8. Explain the guidelines used to prescribe an exercise training program. 9. Discuss the roles of the following in a pulmonary rehabilitation program: respiratory therapies, psychological therapies, physical therapy, individualized instruction, nutrition counseling, and pharmacologic therapy.

KEY TERMS breathing retraining chronic lung disease exercise assessment exercise capacity exercise training exertional dyspnea healthcare utilization intensive program maintenance program perioperative program pulmonary rehabilitation Rating of Perceived Exertion (Modified Borg Scale)

Introduction Comprehensive pulmonary rehabilitation is a concept that has evolved steadily over the past 50 years.1–4 Prior to that time, the standard therapy for patients with chronic lung disease consisted of rest and avoidance of physical activity. In the early 1960s, however, studies challenged this approach by demonstrating that exercise training in patients with chronic obstructive pulmonary disease (COPD) not only resulted in training effects similar to those observed in normal subjects but also promoted a state of well-being.5–9 Numerous investigations followed that supported these initial findings. Almost universally, the early investigations supported three conclusions: 1. Exercise training in patients with COPD increases exercise capacity. 2. Exercise training improves the patient’s psychological state and quality of life. 3. Exercise training does not improve pulmonary function. As a consequence of these developments, the American College of Chest Physicians (ACCP) in 1974 and the American Thoracic Society (ATS) in 1981 both recognized the effectiveness of pulmonary rehabilitation and offered the following definition: Pulmonary rehabilitation is defined as an art of medical practice wherein an individually tailored multidisciplinary program is formulated, which, through accurate diagnosis, therapy, emotional support, and education, stabilizes or reverses both the physio- and psychopathology of pulmonary diseases and attempts to return the patient to the highest possible functional capacity allowed by his pulmonary handicap and overall life situation.1

Pulmonary rehabilitation programs have become multidisciplinary and comprehensive, incorporating psychological, nutritional, and vocational support; oxygen therapy; bronchial hygiene; education; and exercise.4,10,11 Along with this growth has come the development of professional societies devoted to such therapy (e.g., the American Association of Cardiovascular and Pulmonary Rehabilitation [AACVPR]), professional standards, accreditation and certification programs, and ongoing efforts to obtain proper third-party reimbursement.1–4,11

Respiratory Recap Pulmonary Rehabilitation ∎ Pulmonary rehabilitation is a multidisciplinary, multifaceted approach to chronic lung disease management. ∎ Pulmonary rehabilitation has been endorsed by all of the major respiratory societies.

Mechanisms of Functional Deterioration in Patients with Chronic Lung Disease Much of the research on functional deterioration in chronic lung disease has been done in patients with chronic obstructive pulmonary disease (COPD).12 These patients, unlike cardiac patients, tend to follow a slow downhill course often punctuated by exacerbations. The underlying chronic inflammation of COPD progressively damages lung tissue and airways and over a period of years, ultimately results in a depletion of ventilatory reserves.12 Complicating this deterioration are abnormalities in gas exchange and elevations in pulmonary vascular pressures that lead to right ventricular dysfunction. Evidence has demonstrated that an ongoing systemic inflammatory process from COPD can impair skeletal muscle function.13,14 These factors contribute to the sensation of dyspnea and the resultant limitation on physical activity. As dyspnea and exercise capacity worsen, the patient’s need for medical care increases, and his or her ability for self-care decreases. In turn, the patient faces a confusing combination of functional limitations, complex medical regimens, and dependence on others. The net effect is a profound sense of loss of control, with consequent depression and anxiety. These factors are further worsened by the vicious cycle of inactivity (Figure 24-1). This cycle begins when the patient starts to associate exertional dyspnea with the disease and no longer recognizes dyspnea as a normal response to exertion. In this setting, exertional dyspnea promotes increased levels of anxiety, depression, and fear of suffocation and death, which evolves into a generalized exertion phobia and a reduction in physical activity. The lack of exercise, in turn, leads to both central and peripheral deconditioning and, ultimately, to decreased endurance and weakness, and often to muscular atrophy.13,14 As a result of deconditioning, the patient experiences greater dyspnea, an even greater intolerance to exertion, and further loss of functional capacity. As the cycle continues, the patient’s exercise capacity spirals progressively downward, while the levels of fear, anxiety, and depression increase unabated. As the patient becomes progressively more physically and

psychologically incapacitated, the consumption of medical resources increases dramatically. The progressive loss of exercise capacity resulting from the vicious cycle of inactivity is superimposed on the underlying functional reduction caused by the lung disease.

FIGURE 24-1 The downward spiral of functional loss induced by lung disease and accelerated by resulting inactivity.

Other chronic lung diseases (e.g., interstitial lung disease, pulmonary hypertension), with different pathophysiologic mechanisms and at different disease trajectories, produce similar deteriorations in functional impairment over time. For this reason, patients with these non-COPD lung conditions are being increasingly referred for pulmonary rehabilitation.15–23 The goal of pulmonary rehabilitation is to improve the quality of life of patients with chronic lung disease by increasing their functional capacity

and sense of well-being. Central to achieving this goal is to break this cycle of inactivity through the institution of a lifelong exercise program. The comprehensive nature of pulmonary rehabilitation facilitates this fundamental lifestyle change not only by directing and encouraging formal exercise but also by maximizing all aspects of chronic lung disease management. In this sense, pulmonary rehabilitation can really be considered a lifelong disease management process. Respiratory Recap Goal of Pulmonary Rehabilitation ∎ Functional loss in chronic lung disease is multifactorial and involves respiratory dysfunction as well as cardiovascular, skeletal muscle, and metabolic factors. ∎ The goal of pulmonary rehabilitation is to improve functional capacity by addressing all of these factors.

Program Structure The basic elements of today’s pulmonary rehabilitation program have been formalized in the AACVPR guidelines and program certification process.4,11 Even within these established guidelines, however, the potential exists for diversity in the structure of pulmonary rehabilitation programs. This potential diversity results from consideration of several factors at the time the pulmonary rehabilitation program is under development, including the patient population, the available physical facilities, and the available pool of health professionals. The pulmonary rehabilitation team is usually a multidisciplinary team that consists of a pulmonary physician and a number of other health professionals, including respiratory therapists, physical therapists, psychologists, nutritionists, occupational therapists, social workers, and pulmonary nurses, among others. Although this implies the necessity for a large, diverse team, the recommended services for pulmonary rehabilitation may be provided by fewer personnel if those individuals are appropriately trained in the evaluation and management of patients with pulmonary disease. The ultimate providers of the essential services depend on the health professionals available to the program and the size of the facility and will likely vary from program to program. Pulmonary rehabilitation programs often provide at least two types of programs: (1) a short-term intensive program that provides an intense focus on pulmonary rehabilitation and (2) a long-term maintenance program that is less time consuming.

Intensive Programs Intensive programs generally provide two to five sessions per week for periods of 4 to 12 weeks. Such a program emphasizes exercise training, education, medication optimization, bronchial hygiene, and psychosocial support. In addition to respiratory therapists and physical therapists, healthcare specialists who contribute regularly to the program through the educational component include a pharmacist, nutritionist, pulmonary nurse, occupational therapist, and psychosocial counselor. Individual

consultations with specialists in nutrition, psychology, and smoking cessation are common. The intense focus of this program produces recognized benefits sooner than less intensive programs—a factor that enhances patient motivation.

Maintenance Programs Maintenance programs serve primarily as medically supervised facilityor home-based programs for patients with pulmonary disease who reside locally. Enrollment is usually limited to patients who have successfully completed the intensive program. Programs are generally open daily, and participants select their own schedules. Although such a program emphasizes exercise conditioning, all intensive program services are also available to these participants as needed. Major advantages of the maintenance program include long-term social interaction with peers and the formation of support groups.

Perioperative Programs Another type of program focuses on the perioperative management of patients receiving lung cancer surgery, lung volume reduction surgery, or lung transplantation.15–23 In perioperative programs, the preoperative period functions much like the intensive program described previously and is designed to optimize the patient’s functional status and education prior to surgery. In the postoperative period, these programs seek to restore and improve function as the patient recovers from the surgery. Respiratory Recap Pulmonary Rehabilitation Programs ∎ Pulmonary rehabilitation programs are based on exercise training, education, and psychosocial support. ∎ Pulmonary rehabilitation is a lifelong process, with formal programs usually being either several weeklong intensive programs or lifelong maintenance programs. ∎ In recent years, pulmonary rehabilitation programs focusing on perioperative patients have emerged.

The Process of Pulmonary Rehabilitation Patient Selection The clinical description of patients who potentially may benefit from pulmonary rehabilitation has broadened over the years. Any patient with stable chronic respiratory disease who is symptomatic and/or experiences dyspnea on exertion should be considered a candidate for pulmonary rehabilitation. In addition, candidates must be free of acute illness, including unstable medical conditions such as ischemic coronary disease, and motivated to lead a more active life. Multidisciplinary pulmonary rehabilitation programs can also prove valuable in the management of patients with restrictive and other pulmonary diseases.24,25 This should encourage acceptance of patients with nonCOPD pulmonary diseases as well as those with COPD into pulmonary rehabilitation programs. The observation that patients with limited ventilatory capacity may be unable to exercise with sufficient intensity to achieve a training effect has raised concerns over whether these individuals can derive benefits from a comprehensive pulmonary rehabilitation program. Although evidence of a true training effect in this group of patients remains controversial, at a minimum they can benefit from a program designed to improve coordination, muscle strength, functional activities, and a state of wellbeing. Even patients with limited ventilatory capacity may improve their exercise capacity, because the standard training effect is only one of several ways in which exercise capacity is known to increase.6,14,26 Concern that exercise might precipitate respiratory failure by overloading weakened respiratory muscles has led to speculation that exercise training might be contraindicated in hypercapnic COPD patients. Studies have shown, however, that hypercapnic COPD patients with severe ventilatory impairment and respiratory muscle weakness tolerate exercise and benefit significantly from intensive pulmonary rehabilitation.5–8 Similarly, exercise hypoxemia has been proposed as a contraindication to an exercise program. In such cases, appropriate supplemental oxygen and proper monitoring (e.g., pulse oximetry) can enable these patients to participate fully in all aspects of the exercise

program.27 Concerns about cardiac dysrhythmias and right ventricular dysfunction in patients with pulmonary hypertension have often limited these patients’ participation in pulmonary rehabilitation in the past, but appropriate exercise strategies and proper monitoring can allow such patients to benefit from pulmonary rehabilitation.24 Despite the broadening of criteria for participation in pulmonary rehabilitation, it appears that only a minority of eligible patients actually enter these programs.28,29 Moreover, many who enter the program fail to finish.29 One approach to increasing utilization of pulmonary rehabilitation has been to use the teachable moment of an exacerbation to introduce the concept of pulmonary rehabilitation and the associated disease management features of the program.30 Stop and Think You are caring for a patient with COPD who is considering enrolling in a pulmonary rehabilitation program. He asks you what is involved in the program. How would you respond?

Patient Assessment A comprehensive patient evaluation is essential to attaining the goals of pulmonary rehabilitation and is the foundation on which the individually tailored program is constructed. The healthcare team must identify and assess any condition or attitude that might potentially limit the patient’s ability to perform desired activities or grasp essential information and ultimately address it. All members of the rehabilitation team are vital participants in the process of gathering and evaluating information from patient questionnaires, interviews, and clinical evaluations. The first step in this assessment is to accurately diagnose the pulmonary problem and any complicating medical problems. The diagnosis should be confirmed by history, physical examination, pulmonary function testing (especially spirometry), and, as needed, chest radiograph and other laboratory tests. Other diseases or medical problems that may have a potential impact on the rehabilitation process must be identified as well. These include rhinitis/sinusitis, hypertension, gastrointestinal conditions, and arrhythmias or coronary artery disease.

Other potentially complicating diseases include diabetes, obesity, osteoporosis, and stroke. Once proper diagnoses are made, the team can establish an appropriate medication regimen. Exercise assessment of patients is a critical component prior to participants entering a rehabilitation program. These assessments quantify the level of disability and provide information for setting initial exercise loads and program expectations, and they provide insight into the various cardiorespiratory factors involved in the patient’s functional disabilities. Ultimately, they permit the healthcare team to select the appropriate focused therapies. For instance, a patient with exercise hemoglobin oxygen desaturation may need oxygen therapy, a patient with exercise bronchospasm can receive better bronchodilator therapy, and a patient with exercise cardiac dysrhythmias may require a more thorough cardiovascular exam. Incoming pulmonary rehabilitation patients should undergo a symptom-limited maximal exercise assessment.26 These tests detect hemoglobin oxygen desaturation with exercise in approximately one-third of patients. Among patients who do not require oxygen therapy, approximately one-fourth have ventilation limitations (exercise ventilation/maximal ventilatory volume > 0.7 or rising PaCO2), and approximately one-third have cardiovascular limitations (maximum heart rate > 80% of predicted maximum). This illustrates the wide variety of physiologic derangements of these patients and the importance of designing exercise therapy regimens appropriate to the patient’s limitations. Walk tests, especially the 6-minute walk test (6MWT), have become the method of choice to assess exercise capacity both before and after pulmonary rehabilitation.31 The 6MWT is simple to perform at the rehabilitation site, and walk distance is closely linked to functional performance. In addition, the clinician can assess the patient’s heart rate, pulse oximetry, blood pressure, perceived exertion, and ventilation response during the test. Because patients with chronic lung disease commonly have psychological disturbances, psychosocial assessment is important prior to their engagement with a pulmonary rehabilitation program.32–34 The most common emotional consequences of COPD are depression and anxiety, which can further reinforce social isolation and inactivity.

Cognitive function has also been shown to be impaired in these patients, perhaps as a consequence of chronic hypoxemia. Medications and psychotherapy can be provided as necessary, but no formal guidelines or recommendations have been developed to incorporate psychotherapeutic interventions into pulmonary rehabilitation. Other assessments necessary prior to beginning pulmonary rehabilitation include physical therapy evaluations, nutritional evaluations, occupational therapy evaluations (especially activities of daily living), and an educational assessment for the patient’s knowledge and understanding of the disease process and its management. A particularly important assessment is tobacco usage. Although current smokers may be allowed to participate in a rehabilitation program, formal efforts should be made to persuade the patient to discontinue smoking through participation in smoking cessation-counseling sessions with program staff. These may be done on either an individual or group basis. Stop and Think You are asked to provide patient education as part of a pulmonary rehabilitation program. What information would you cover, and what strategies would you use to maximize the effectiveness of your teaching?

Education A primary purpose of the educational component of pulmonary rehabilitation is to provide the framework for self-care. Through an educational process of instruction, supervision, and practice, patients can acquire an awareness of their disease and its management that allows them to take responsibility for their own care. A spouse, family member, or close friend who participates in the educational activities can provide familial understanding of the disease process and can reinforce the recommended self-care techniques in the home setting. The educational process consists of a combination of lectures, discussions, demonstrations, and practice sessions.35 During all program activities, the educator continually reinforces the patient’s knowledge and ability to perform self-management techniques. Topics typically covered in formal lectures and discussion sessions include the anatomy and

physiology of the lung, the pathophysiology of chronic lung disease, pulmonary medications, nutrition, physiologic responses to exercise, sexual concerns, travel concerns, coping with chronic lung disease, early recognition and management of infections and exacerbations, and psychosocial issues. Medication management is a critical component of the educational process. Many patients find the array of inhaled medication options bewildering. Their confusion is further amplified by the complexity of the aerosol delivery systems associated with proprietary medications. Considerable education time may be required to ensure that patients have a good working knowledge of their medication regimens. Another key educational component is the management of COPD exacerbations.36–38 The cost of treating exacerbations is the single most expensive aspect of caring for the patient with COPD. Importantly, patients can be taught to recognize signs and symptoms of an impending exacerbation. An action plan under these circumstances can include transient increased dosing of bronchodilators, prompt initiation of antibiotics, and pulse steroid therapy. Aborting an exacerbation early can lead to reduced need for hospitalizations and a faster return to baseline function. Respiratory therapy and physical therapy techniques are presented in either individual or group demonstrations and in practice sessions. Topics covered include cleaning and care of equipment, proper use of inhalers, airway clearance therapy, stress management, and supplemental oxygen therapy. Educational materials in the form of pamphlets, booklets, and books are available from a multitude of sources, including various websites and the American Lung Association. This additional information is used to support and reinforce the information the patient receives in the lectures, discussions, and demonstrations. Breathing retraining is a key aspect of the educational component of a pulmonary rehabilitation program.4,35 Pursed-lip breathing, diaphragmatic breathing, and paced breathing are commonly used to reduce shortness of breath and improve gas exchange. By using pursedlip breathing, patients may be able to maintain adequate oxygenation without necessitating supplemental oxygen. The success of the program’s educational process is assessed by providing testing on didactic information before and after instruction and

by requiring each patient to satisfactorily demonstrate the recommended management techniques.

Exercise In general, the exercise training experience provided by the pulmonary rehabilitation program should expose the patient to a balance of three types of exercise: stretching and flexibility exercises, strengthening exercises, and endurance exercises. Stretching and flexibility exercises are part of a floor exercise routine that improves range of motion and provides a general warm-up. Strength training is part of the floor exercise routine and includes exercises utilizing dumbbells, cuff weights, or a stretch band. Pulmonary patients also do well with free weights and weight machines for strength training. When patients first begin the program, strengthening exercises should be prescribed at lower weights and higher repetitions. General endurance training involves exercises that produce a cardiopulmonary stress that results in an elevated heart rate (HR) and ventilation. Such exercises include walking, rowing, swimming, water aerobics, cycling (arm or leg), and stair climbing. Endurance training is of lower intensity and higher frequency. Interval training, with higher work intensities alternating with rest breaks, results in lower perceived exertion scores and improved exercise continuity while demonstrating comparable exercise training to continuous endurance training.39 The benefits of exercise training are, for the most part, specific to the muscles and tasks involved in training.4–7,40 A walking program produces significant improvement in walking performance but not in swimming or biking performance. It is important, therefore, to consider the mode of exercise in conjunction with the patient’s needs and goals. If a patient has a stated goal that requires improvement in stair climbing, this should be one of the modes of exercise in the prescription. Walking is considered an essential exercise because of its prevalence in daily activities. For that reason, most exercise training prescriptions use predominantly lower-extremity exercises. Many patients with chronic airway obstruction experience marked dyspnea when they use their arms for even simple tasks. Arm exercise may result in dyspnea by contributing to ventilatory muscle fatigue, by

placing a load on an already stressed system, and by placing a nonventilatory demand on shoulder girdle muscles that have been recruited to act as accessory muscles of respiration. Improvements in upper-extremity function as a result of specific upper-extremity exercises have been reported in patients with COPD.4,40 Such improvements can then carry over to self-care, leisure, and other arm activities. Combining arm and leg exercises in a training program for patients with chronic airway obstruction not only increases exercise performance in both upper and lower extremities but also improves patients’ state of well-being, which is greater in combined training than in either arm or leg training alone.4,40 Upper-extremity exercise training may be accomplished through activities that use the arms at or above shoulder height (e.g., passing an object overhead) or gravity-resistive exercises (e.g., lifting objects to chest level or overhead and walking a short distance). Upper-extremity strength training may be achieved by performing exercises with free weights, pulley systems, or weight machines. Arm endurance training may be accomplished with an arm ergometer, rowing machine, combined arm/leg bicycle, or cross-country ski machine. Guidelines exist for prescribing the intensity of endurance exercise for normal persons as well as for cardiac patients. These guidelines are based on target exercise heart rates expressed as a percentage of the predicted maximum HR. These guidelines may not be appropriate for pulmonary patients, however, because gas exchange and/or ventilatory impairments may prevent the patient from reaching the predicted maximum HR.6,7,41 The initial load prescription should be of sufficiently low intensity such that the patient can accomplish it without discomfort. Nothing destroys a patient’s motivation faster than failure to complete the initial exercise or experiencing significant discomfort during or after the first exercise session. Should a symptom-limited stationary bicycle Graded Exercise Test (GXT) be performed prior to program entry, the initial exercise prescription workloads are normally based on the maximum workloads achieved during that test. A reasonable prescription is 50% to 80% of the maximum watts achieved for the stationary bicycle workload and 30% to 40% for the arm ergometer prescription. Other approaches to the exercise prescription rely on perceived

physical exertion and breathing effort (dyspnea). Perceived physical exertion and breathing effort are quantified using the Modified Borg Scale, a visual analogue scale that patients can readily understand (Figure 24-2).42 Because this scale is used to rate both perceived physical exertion and breathing effort, it is important to instruct the patient on the difference between the two. Separating perceived physical exertion and breathing effort allows for a more complete assessment of patient difficulties when performing exercise and allows therapies to be more focused. If perceived physical exertion and breathing effort fall between 4 and 6 on the Modified Borg Scale, the patient’s effort and exercise prescription are considered adequate.

FIGURE 24-2 The Modified Borg Scale for Rating of Perceived Exertion or breathing effort (dyspnea).

The exercise prescription in pulmonary patients must also consider the patient’s cardiac response (i.e., heart rate) and oxygenation status. Training intensity should be pushed to a training effect (i.e., as much as 70% to 80% predicted maximal heart rate) if possible.7 Even patients with

ventilatory or gas exchange limitations who cannot reach these target heart rates will benefit from higher (rather than lower) levels of exercise. Finally, all exercise training should be performed under conditions of adequate arterial oxygenation (PaO2 > 55 mm Hg, SpO2 > 88%).3,4 This ensures patient safety as well as allows the hypoxemic patient to exercise for a longer duration at a higher intensity, enhancing the exercise’s beneficial effects. If the initial patient assessment has determined that the patient’s resting oxygenation is low or that significant desaturation occurs with exertion, the patient should receive supplemental oxygen so as to maintain adequate oxygen saturation. Patients with severe exercise hypoxemia may require oxygen reservoir systems. When adequate oxygenation cannot be maintained, either the intensity of the exercise must be reduced, or the patient must be instructed to stop exercising until oxygenation returns to an adequate level. An interesting additional application for supplemental oxygen may be in patients who have some degree of rest or exercise hemoglobin desaturation, but whose values do not fall to critical levels that impair cardiac function or oxygen delivery (i.e., PaO2 values remain >60 mm Hg or SpO2 values remain >90%). In this group, oxygen therapy will have little impact on cardiac function or oxygen delivery but may reduce carotid body (i.e., oxygen receptor) output, thereby reducing dyspnea and allowing exercise training at a higher level.27 The recommended minimum duration and frequency of endurance exercise are no less than 20 minutes 3 times per week.3,4 Increasing the duration and frequency beyond this minimum must take into consideration the motivation and goals of the patient and balance the time spent in training against the benefits derived from a more intense, and less frequent, training regimen. When transitioning from lower initial loads to higher target loads, the clinician should use the Modified Rating of Perceived Exertion (Modified Borg Scale) as a measure of perceived stress and the exercise heart rate and oxygen saturation as a measure of cardiopulmonary stress.20 Using these parameters, if the patient is capable of performing a given load for the duration of the exercise session (e.g., 20 minutes), the Modified Borg Scale values are 1 year), particularly in combination with frequent courses of oral corticosteroid therapy, may be associated with adverse growth

effects.

Long-Acting ß2-Agonists LABAs are used to provide a longer duration of airway smooth muscle relaxation. This class of medications is not intended for relief of acute bronchospasm or for monotherapy (delivery without an ICS). LABAs have a bronchodilation duration of approximately 12 hours but require a longer onset of action than SABAs for peak bronchodilatory protection. Medications in this class include salmeterol and formoterol (see Table 321). LABAs relax smooth muscle by stimulating β2 receptors, thereby increasing production of cyclic adenosine monophosphate (cAMP). Because it is lipophilic, cAMP remains bound within the muscle cell wall. These medications work well as an adjunct therapy to anti-inflammatory medications in the long-term control of symptoms.48 LABAs work exceptionally well at controlling symptoms that occur at night39 and at minimizing the risk of exercise-induced exacerbations. The complications of LABAs are controversial. Reports have cited sudden severe asthma attacks that could have been worsened or initiated with the use of salmeterol.50 Two studies that examined this issue in a large cohort of patients found a slight increase in deaths in patients who were taking salmeterol compared to those who were not.51,52 On the basis of these data, clinicians need to pay close attention to properly educating patients who are using LABAs. LABAs should be used only as a supplement to inhaled corticosteroids and never as a quickrelief medication. The EPR-3 recommendations for the use of LABAs are as follows:1 LABAs are used as an adjunct to ICS therapy for providing long-term control of symptoms. LABAs are not recommended as monotherapy for long-term control of persistent asthma. The use of LABAs is not recommended to treat acute symptoms or exacerbation of asthma. LABAs may be used before exercise to prevent exercise-induced bronchoconstriction, but frequent and chronic use of these agents for

exercise-induced bronchoconstriction may indicate poorly controlled asthma, which should be managed with daily anti-inflammatory therapy.

Long-Acting Muscarinic Antagonists LAMAs, commonly used in the management of COPD, have a role in asthma control. GINA describes the use of tiotropium as an add-on therapy for adult and adolescent patients with a history of exacerbations.2 This agent modestly improves lung function and increases time to severe exacerbation.

Methylxanthines Theophylline is an alternative—but not preferred—therapy in patients with mild to moderate persistent asthma. Slow-release theophylline is used primarily as adjuvant therapy for nocturnal asthma (see Table 32-1). The mechanism of action of methylxanthines in asthma is not well established.53,54 Theophylline acts as a nonselective phosphodiesterase inhibitor: It increases levels of cyclic guanosine monophosphate and cAMP, which inhibit inflammation cells and produce bronchodilation. Recent studies indicate that low serum concentrations of theophylline may act as a mild anti-inflammatory medication.55 This effect most likely reflects decreased mediator release from mast cells and reactive oxygen species and inhibition of neutrophil activity. Theophylline requires frequent monitoring of serum drug levels so that therapeutic, but not toxic, levels are achieved. Serum drug levels are affected by a patient’s comorbidities and the presence of smoking; in consequence, managing asthma through theophylline intervention often proves difficult or impractical. Potential toxic side effects of this medication include tachycardia, nausea and vomiting, central nervous system stimulation, arrhythmias, headache, seizures, hyperglycemia, and hypokalemia. The therapeutic serum range is 5 to 15 mg/L to limit potential toxic effects. Pay close attention to other medications that patients using theophylline are receiving (e.g., antibiotics, β2-blockers, quinolones).

Leukotriene Modifiers Leukotriene modifiers are also employed as controller medications. This class of medications acts on the inflammatory cells known as leukotrienes. Leukotrienes are mediators released from mast cells, eosinophils, and basophils; they are responsible for airway bronchoconstriction, inflammatory cell recruitment, increased vascular permeability, and secretion production. Montelukast is a leukotriene receptor antagonist (LTRA) that blocks the receptor sites on inflammatory cells for leukotrienes. LRTAs appear to work best in patients who have mild to moderate persistent asthma. These medications are an alternative, but not preferred, therapy to lowto medium-dose ICS. Patients typically experience greater improvement in lung function and symptom scores with the use of ICS versus LRTA.56 Regardless, LRTAs improve lung function, diminish asthma symptoms, and decrease the need for SABAs, particularly in patients with allergies.57

Biologics Anti-Immunoglobulin E Omalizumab (Xolair) is a recombinant DNA-derived monoclonal antibody that inhibits the binding of IgE to the IgE receptor on the surface of mast cells and basophils.58 When omalizumab binds to the IgE receptors, the amount of surface-bound IgE is reduced, which leads to decreases in the activation of mast cells and the release of inflammatory mediators. Omalizumab is an alternative, but not preferred, drug for the treatment of moderate to severe persistent asthma in patients who have a positive skin test to aeroallergens and whose symptoms are inadequately controlled with ICS. It has been approved only for patients 12 years or older. Omalizumab is administered subcutaneously, with the dose being based on both IgE level and patient weight. This biologic must be administered only in a closely observed clinic, and the patient must remain in the clinic for a period of observation following injection, because a rare adverse effect is anaphylaxis. Omalizumab has been shown to decrease the incidence of asthma exacerbations and emergency department visits, has increased efficacy in patients with severe persistent allergic asthma who are already on high-dose ICS and

LABA, and improves quality of life scores. Aside from its adverse effects, another drawback to omalizumab is its cost.1

Anti-Interleukin-5 Some patients with moderate to severe asthma have specific eosinophilic phenotypes that appear in elevated levels in their sputum or blood. IL-5 is the primary cytokine that recruits, activates, and maintains eosinophils through IL-5 pathway inhibition.59 Mepolizumab and reslizumab are monoclonal antibodies (mAb) that bind and inhibit IL-5, thereby preventing IL-5 from binding to its receptor on eosinophils and reducing downstream eosinophilic inflammation.60 Mepolizumab (Nucala) is an add-on therapy for patients with severe asthma who are 12 years of age or older and have an eosinophilic phenotype. Reslizumab (Cinqair) is an add-on therapy for patients with severe asthma who are 18 years of age or older and have an eosinophilic phenotype. Benralizumab (Fansera) is a mAb that binds the alpha subunit of the IL-5 receptor on eosinophils and basophils, preventing IL-5 binding and the subsequent recruitment and activation of eosinophils.61,62 This biologic is an add-on therapy for patients with severe asthma who are 12 years of age or older and have an eosinophilic phenotype. Dupilumab (Dupixent) is a mAb that targets the IL-4 alpha receptor and blocks signaling of both IL-4 and IL-13, key cytokines that promote production of IgE and recruitment of inflammatory cells in addition to stimulating goblet cell hyperplasia and modulating airway hyperresponsiveness and airway remodeling.63 This agent is an add-on therapy for patients with moderate to severe asthma who are 12 years of age or older and have an eosinophilic phenotype or corticosteroiddependent asthma. Table 32-2 summarizes dosing of anti-interleukin medications. TABLE 32-2 Dosing of Anti-Interleukin Medications

Description

Quick-Relief Medications Short-Acting ß2-Agonists SABAs are used predominantly to relieve airway bronchoconstriction and symptoms of cough, chest tightness, and wheezing. These agents are the first-line medications for treating an acute asthma exacerbation and for preventing exercise-induced bronchoconstriction.64,65 Given the focus on the role of airway inflammation in the chronic management of asthma, SABAs are utilized as quick-relief medications. The most commonly used SABA is albuterol (Table 32-3). TABLE 32-3 Quick-Relief Medications Medication

Dose

Frequency

Pressurized metered-dose inhalers Racemic albuterol (Ventolin HFA, Proventil HFA, Pro-Air HFA) Levalbuterol (Xopenex HFA)

90 µg/puff 45 µg/puff

prn; q4h–q6h prn, q6h

Dry powder inhaler (Respiclick)

90 µg/inhalation

prn; q4h–q6h

Nebulization Racemic albuterol (Ventolin, Proventil, generic) Levalbuterol (Xopenex) Metaproterenol (Alupent)

2.5 mg 0.63–1.25 mg 0.31 mg and 0.63 mg

prn, q4h–q6h prn, q6h–q8h prn; q4h–q6h

Short-Acting a2-Agonists

Oral tablets Albuterol (Repetabs, Volmax) Metaproterenol

2 and 4 mg 10 and 20 mg

prn; q4h–q6h

Syrup Albuterol Metaproterenol

2 mg/5 mL 10 mg/5 mL

prn; q4h–q6h

Subcutaneous injection Terbutaline

1-mg/mL injection

prn; q4h–q6h

Pressurized metered-dose inhaler Ipratropium (Atrovent)

18 µg/puff

bid–qid

Nebulization Ipratropium bromide (Atrovent)

500-µg solution

bid–qid

Anticholinergics

bid, twice a day; HFA, hydrofluoroalkane; prn, as needed; qid, four times a day; q4h, every 4 hours; q6h, every 6 hours.

SABAs act by relaxing smooth airway muscle and quickly resolving airway obstruction. Bronchodilation occurs primarily through β2adrenergic receptor stimulation in bronchial smooth muscle. These receptors are also present in airway epithelium, airway smooth muscle, mucous glands, and mast cells. The onset of action for a SABA is approximately 5 to 15 minutes under most circumstances of mild to moderate acute exacerbations. Complications from SABA use are usually mild and self-limiting on stopping the medication. Potential side effects include tachycardia, nausea, vomiting, tremors, headache, palpitation, paradoxical bronchospasm, and hypokalemia. Potential complications from high use or prolonged use of SABAs over time include sub-sensitivity (reduction in bronchodilation effect), increased airways hyperreactivity, and lifethreatening episodes with overuse. The frequency of SABA use or prescription refills can be used as a marker of disease worsening or to indicate increased risk of death or near death. Patients should be cautioned to use SABAs only as needed. If the patient uses a SABA more often than twice per week, this frequency indicates decreased asthma control. A red flag is if the patient uses more

than one canister of SABA per month, as this pattern indicates that the patient has used the SABA approximately 3 times per day. The need for this much SABA suggests worsening of the underlying inflammation, and the patient should seek medical attention in this event.

Short-Acting Muscarinic Antagonists SAMAs, also called anticholinergics, are used primarily as quick-relief medications and adjuncts to SABAs in acute severe exacerbations of airway bronchoconstriction in the emergency department. Their mechanism of action involves airway smooth muscle tone relaxation through cholinergic innervation. Ipratropium is the key asthma medication in the SAMA class. A derivative of atropine, it lacks the side effects of atropine (see Table 32-3). The effectiveness of ipratropium in the management of asthma remains controversial.66,67 Its effectiveness for long-term asthma management has not been demonstrated. Adult patients who have asthma and a component of COPD apparently experience some beneficial outcomes. Studies in children have demonstrated that the use of ipratropium in combination with a SABA in patients with exacerbations or severe airway obstruction may have benefits. Routine administration of this combination therapy does not appear to be helpful except during moderate to severe airflow obstruction.67,68

Systemic Corticosteroids Systemic corticosteroids are usually combined with SABAs to provide a quick resolution of airway obstruction in an emergency department or hospital setting.69 These drugs are given either orally or intravenously. The normal dosage in this setting is 2 mg/kg every 6 hours, up to a maximum dose of 120 mg. The mechanism of action for systemic corticosteroids is the same as that for inhaled corticosteroids. The administration of a systemic corticosteroid can help prevent or ease the onset of the delayed (phase 2) asthmatic response that occurs secondary to the event that led the patient to present to the emergency department. If not given a systemic corticosteroid, the patient may present to the emergency department again following discharge with more severe bronchospasm and inflammation than during the initial admission.

For outpatient use, systemic corticosteroids are prescribed for shortterm burst therapy (once a day for 3 to 10 days). The clinician should prescribe the lowest possible dose (0.5 to 2 mg/kg/day). The maximum dose is usually restricted to 60 mg daily for outpatient use. If chronic use of systemic corticosteroids is needed, a study has documented improved efficacy when the medication is given at 3 PM instead of in the morning. Respiratory Recap Asthma Quick-Relief Medications ∎ Short-acting β2-agonists ∎ Short-acting muscarinic antagonists ∎ Systemic corticosteroids

Aerosol Therapy The main routes of delivery for asthma medications are systemic or inhaled. Systemic delivery includes oral (ingested) and parenteral (subcutaneous, intramuscular, or intravenous) routes.1 Oral medications are mainly in pill or liquid form. Use of parenteral medications is usually limited to patients who either are in the emergency department or are admitted to the hospital. The inhaled route is more convenient and commonly used because it has fewer side effects and a quicker onset of action. The disadvantages of this route are associated with the delivery device and the factors that affect drug penetration and deposition in the lungs. The main factors affecting penetration and deposition are physical (sedimentation, inertial impaction, and diffusion) and clinical (particle size, ventilatory pattern, and lung function) in nature.70 Jet nebulizers, ultrasonic nebulizers, mesh nebulizers, pMDIs (with or without spacer or valved holding chamber), and dry powder inhalers (DPIs) are used for inhaled medications. Opinions vary on the best and most efficient method, but available evidence suggests that the devices are equally effective in treating asthma.71

Nebulizers The small-volume jet nebulizer (SVN) is most commonly used to deliver medications to small children and patients requiring hospitalization. Mesh or ultrasonic nebulizers can also be used. Although aerosol delivery and deposition in an asthmatic airway may improve with a less dense gas (heliox),72,73 use of nebulizers powered by heliox is associated with several potential problems.74 Consequently, heliox is best reserved for severe exacerbations that are refractory to conventional therapy.75 A number of factors affect jet nebulizer performance.76–78 Deposition of appropriate particle size in the lower respiratory tract depends on the patient’s ventilatory pattern. To ensure optimal deposition, a slow inhalation through the mouth to total lung capacity with an end-inspiratory breath hold is ideal. With proper breathing technique, aerosol delivery

with an SVN is equally effective with a mask or mouthpiece, although a mouthpiece is preferred when possible—the nose filters out 40% of the delivery aerosol when a mask is used.

Continuous Aerosolized Bronchodilators In a severe asthma attack, aggressive intermittent aerosol therapy may fail to relieve symptoms. Studies have demonstrated that continuous bronchodilator therapy is as effective or more effective than intermittent therapy. Continuous aerosol bronchodilator therapy has become an accepted alternative to intermittent therapy in emergency departments for patients who fail to respond to less aggressive therapy. Current evidence supports the use of such therapy in patients with severe acute asthma who present to the emergency department to increase their pulmonary function and reduce hospitalization,79 and it is safe and well tolerated. Stop and Think In a hospitalized patient with asthma, do you think a jet nebulizer or pMDI should be used? Why?

Pressurized Metered-Dose Inhalers The pMDI is the device most commonly used to deliver medications in an ambulatory setting and can also be used in hospitalized patients and emergency department treatment. To activate the canister, the patient compresses it into a mouthpiece, which causes a metered dose of the drug to be delivered for inhalation. A number of factors can affect pMDI performance and drug delivery.80 One factor that may interfere with the desired delivery is using medications from one manufacturer with an actuator from another manufacturer. Most of the factors that affect optimal delivery involve patient technique, especially with very young or elderly patients. Factors critical in the effectiveness of pMDI performance include timing of actuation, lung volume, pMDI position to the mouth (without a spacer), inspiratory flow, and the ability to perform a breath hold. Each pMDI has

specific instructions on priming, so respiratory educators must read the package insert to learn how many times a pMDI needs to be primed and how and when to clean the pMDI actuator, with this information then being taught to the patient.

Spacers and Valved Holding Chambers If patients find it difficult to use a pMDI correctly or if they have been prescribed an ICS pMDI, they should use a spacer or valved holding chamber to enhance optimal drug delivery. A spacer is a cylindrical or cone-shaped chamber that receives the pMDI actuator on one end and has a mouthpiece on the other end. A valved holding chamber is a spacer with a one-way valve at the mouthpiece end that prevents the patient from exhaling into the chamber with subsequent loss of dose. Several of these devices also incorporate a flow signal (an audible sound) if the patient is inhaling too fast. With optimal pMDI delivery technique, the same level of deposition may be achieved (even by children) with or without a spacer device. When used with a spacer or valved holding chamber, the pMDI is actuated into the chamber, and the patient breathes the medication from a mouthpiece or mask attached to the chamber. A notable factor that may affect the amount of drug delivered with a spacer device is a static charge that occurs from washing the chamber. The device should be disassembled and washed in soapy water, rinsed, and allowed to air-dry before use. Antistatic chambers have also been developed.

Respimat The Respimat is a propellant-free soft-mist inhaler that utilizes mechanical energy in the form of a tensioned spring to generate a soft aerosol plume.81 Energy created by turning the device’s base to the right for one-half turn draws a predetermined metered volume of solution from the medication cartridge through a capillary tube into a micro-pump. When the operator depresses the dose release button, energy from the spring forces solution to the mouthpiece, creating a soft aerosol plume that lasts approximately 1.5 seconds.64

Dry Powder Inhalers Two types of DPIs exist: single-dose devices (e.g., Spiriva Handihaler) and multidose devices (e.g., Advair Diskus, Pulmicort Flexhaler, Asmanex Twisthaler, Ellipta). DPIs are breath-activated devices that generate a high inspiratory flow at the mouthpiece. Because they require a high inspiratory flow for actuation, DPIs are not indicated for use in children younger than 12 years. Several instructions are common to all types of DPIs. For example, the DPI must be kept level during inhalation, it must be kept in a dry location to prevent clumping of the powder, and the patient must not exhale into the DPI. Multidose DPIs have dose counters to alert the patient as to the number of doses remaining in the device. Respiratory Recap Aerosol Delivery Devices for Patients with Asthma ∎ Jet, ultrasonic, and mesh nebulizers ∎ Pressurized metered-dose inhaler ∎ Pressurized metered-dose inhaler with accessory device ∎ Dry powder inhaler

Adjunctive Treatments Heliox Helium is a gas that is less dense than air, which may be beneficial in the treatment of asthma. It is not a stand-alone therapy to treat a severe asthma exacerbation but rather a supportive therapy that allows time for bronchodilators and corticosteroids to take effect. Helium concentrations in the range of 60% to 80% are used for this indication. The therapeutic benefits of heliox are controversial.82,83 Reports of these benefits of heliox are isolated primarily to the management of pediatric asthma or the management of adult patients who present to the emergency department with respiratory acidosis and/or a short duration of symptoms. Given the safety profile of heliox and the short time necessary to achieve a positive response, a brief trial of heliox may serve as a therapeutic bridge until corticosteroid therapy has taken effect. The EPR-3 recommends consideration of heliox-driven albuterol nebulization for patients who have life-threatening exacerbations and for those patients whose exacerbations remain in the severe category after 1 hour of intensive conventional therapy.1,75

Magnesium Sulfate Magnesium sulfate is an alternative treatment for a severe asthma exacerbation.83 The EPR-3 recommends intravenous magnesium sulfate in patients who have life-threatening exacerbations and in those whose exacerbations remain in the severe category after 1 hour of conventional therapy.1 The mechanisms of action associated with this therapy include calcium-channel blockade in the airway smooth muscle and inhibition of acetylcholine and histamine release. Magnesium may promote bronchodilation that would improve SABA delivery. A study comparing nebulized magnesium to albuterol demonstrated a similar response for both therapies,84 but nebulized magnesium does not consistently have this bronchodilator effect. Other studies have reported no improvement in FEV1 in patients who were treated with intravenous magnesium.85,86 The dose for intravenous magnesium is 2 g in adults and from 25 to

75 mg/kg up to 2 g in children administered over 30 minutes. The onset of action for magnesium can occur within minutes of its administration. Side effects are usually minor (facial warmth and flushing). Magnesium can be toxic with high serum levels; signs of magnesium toxicity include hypotension, dysrhythmias, areflexia, and muscle weakness. Magnesium sulfate is not recommended as a first-line therapy for severe exacerbations. This agent has no value in exacerbations of lesser severity.1

Noninvasive Ventilation The use of noninvasive positive pressure ventilation (NIV) is considered in patients who are at high risk for intubation and mechanical ventilation. Some evidence supports the use of NIV in patients with acute asthma,86–88 but it is not sufficiently robust to warrant its inclusion in clinical practice guidelines.89 The use of aerosolized medications with NIV is feasible.90 Stop and Think When would you recommend the use of noninvasive ventilation for a patient with severe acute asthma?

Invasive Ventilation Invasive ventilation of patients with asthma is a treatment of last resort for patients experiencing respiratory failure because of severe airflow obstruction, increased mucus production, and severe airway inflammation.91,92 Asthma resulting in intubation and mechanical ventilation is not a common event, occurring in less than 5% of patients. Box 32-6 lists the general indications for mechanical ventilation in the patient with asthma. The obstructive nature of a severe exacerbation of asthma produces a ventilation-perfusion mismatch and increased work of breathing but rarely leads to severe hypoxemia. The more difficult issue in the patient with acute asthma is optimizing the pH and PaCO2 because of bronchoconstriction, air trapping, and increased dead space.82

BOX 32-6 Indications for Mechanical Ventilation of the Patient with Asthma PaCO2 > 40 mm Hg (especially if increasing) Refractory hypoxemia (PaO2 < 60 mm Hg or FIO2 ≥ 0.5) Mental status deterioration Decreased or loss of breath sounds Apnea

With intubation of a patient with acute asthma, full support is usually provided (i.e., no spontaneous breathing). This allows optimization of the patient–ventilator interface under the best conditions. The principal goal of mechanical ventilation of the patient with asthma is to provide acceptable gas exchange while avoiding air trapping (auto-PEEP). With auto-PEEP, alveolar overdistention may occur with concomitant hypotension and barotrauma. The choice of ventilator mode is often based on clinical preference or institutional bias. Either volume or pressure control can be used. With volume control, auto-PEEP results in increased plateau pressure and alveolar overdistention. With pressure control, auto-PEEP results in decreased tidal volume and respiratory acidosis. In patients with asthma with severe airflow obstruction, clinicians may find it difficult to deliver an adequate tidal volume with pressure control. Regardless of the mode chosen, healthcare providers must closely monitor auto-PEEP and plateau pressure. When selecting the tidal volume in patients with severe asthma exacerbation, the clinician seeks to avoid overdistention. Tidal volume is set at 4 to 8 mL/kg predicted body weight and adjusted to minimize overdistention (i.e., to avoid a plateau pressure of more than 30 cm H2O). This often results in a ventilator strategy of permissive hypercapnia. With permissive hypercapnia, PaCO2 is allowed to rise, and an acidic pH is tolerated. Although the limits of safe PaCO2 and pH continue to be debated, general consensus suggests that a PaCO2 level of 80 to 100 mm Hg and a pH level of 7.15 to 7.20 are acceptable. The use of positive end-expiratory pressure (PEEP) when ventilating the patient with asthma is controversial. PEEP is not necessary to prevent atelectasis or collapse but has been used to combat auto-PEEP.

The clinician tries to counterbalance auto-PEEP by applying PEEP so that the patient will be better able to trigger the ventilator. Care must be taken to avoid increased overdistention with the application of PEEP. PEEP has little role in counterbalancing auto-PEEP in the patient who is not attempting to trigger the ventilator. One study observed three different responses to PEEP in the setting of auto-PEEP.93 In the biphasic response, expiratory flow and lung volume remained constant during progressive PEEP steps until a threshold was reached, beyond which overinflation ensued. In the classic overinflation response, any increment of PEEP caused a decrease in expiratory flow and overinflation. In the paradoxical response, a drop in functional residual capacity during PEEP application was commonly accompanied by decreased plateau pressures and total PEEP, with increased expiratory flow. Generally, no more than 10 cm H2O PEEP is used to counterbalance auto-PEEP. Some auto-PEEP that occurs during mechanical ventilation of the patient with asthma may not be measurable because of complete airway closure during the expiratory phase. The inspiratory-to-expiratory (I:E) ratio in a patient with airflow obstruction is important to avoid air trapping. The I:E ratio is determined by the inspiratory time (flow and tidal volume for volume control) and respiratory rate. When setting I:E ratio in patients with asthma, the clinician seeks to allow adequate expiratory time to minimize auto-PEEP. Use of prolonged expiratory times requires a low respiratory rate and a shortened inspiratory time in the range of 0.8 to 1.2 seconds (high flow). Typically, a respiratory rate of 15 breaths per minute or less is used. Aerosol administration by either nebulizer or pMDI is an effective means of delivering medication to ventilated patients.94,95 Many factors in intubated patients affect optimal aerosol delivery and deposition. In particular, higher-than-standard doses may be necessary to elicit a desired response because of potential barriers involved with mechanically ventilated patients. Respiratory therapists must pay sufficient attention to detail, including the use of an efficient nebulizer or pMDI adapter, and proper placement and operating method, to ensure optimal delivery. The role of heliox during mechanical ventilation remains unclear.82 Inhalational anesthetics (e.g., enflurane, sevoflurane, or isoflurane) have a bronchodilatory effect and are used rarely in the most severe cases.

Major complications of mechanical ventilation of the patient with asthma include overdistention, pneumothorax, hypotension, air trapping, and patient–ventilator asynchrony. Stop and Think What can be done to minimize air trapping in the mechanically ventilated patient with asthma?

Respiratory Recap Mechanical Ventilation of the Patient with Asthma ∎ Avoid strategies that cause air trapping and auto-PEEP. ∎ Consider PEEP to counterbalance auto-PEEP, but avoid hyperinflation. ∎ Avoid a plateau pressure greater than 30 cm H2O. ∎ Permissive hypercapnia may be necessary. ∎ Inhaled bronchodilators can be administered using nebulizers or pMDIs.

Respiratory Recap Adjunctive Treatments for Asthma ∎ Heliox ∎ Magnesium sulfate ∎ Noninvasive ventilation ∎ Invasive ventilation

Education Asthma education begins at diagnosis and should be reinforced with each visit to the healthcare provider. Indeed, patient education is a critical part of the nonpharmacologic treatment of asthma. The ability to modify morbidity and resource consumption through education has been well documented in patients with asthma. Many programs and formats have been designed and implemented to demonstrate that asthma education is a major component of the overall successful management of the disease. The items in Box 32-7 should be included in asthma education programs.1 BOX 32-7 Educational Recommendations of the NAEPP Teach basic facts about asthma. Teach the necessary medication skills (techniques, delivery devices, and dosing regimens). Teach self-monitoring skills: symptom-based, peak flow monitoring. Teach relevant environmental control/avoidance strategies. Provide a written asthma exacerbation treatment plan. Modified from National Asthma Education Program, National Heart, Lung, and Blood Institute. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. Full report 2007. NIH Publication 08-4051. Bethesda, MD: National Institutes of Health; 2007.

Educational interventions may be provided in a multitude of settings: ambulatory clinics, allergy or pulmonary specialty clinics, emergency departments, hospitals, patient homes, and asthma camps. The impact of educational interventions has been evaluated regarding readmission rates, hospitalizations, compliance, emergency department visits, clinic follow-up rates, test scores, and behavior changes. The asthma education program needs to take a proactive approach. Such a program should provide education to the patient with asthma as well as all potential caregivers (spouses, parents, older children, day-care providers, teachers, coaches, group leaders, and counselors). The National Cooperative Inner City Asthma Study (NCICAS) reported that often a child has several care providers in the home.96 This pediatric study demonstrated the importance of involving as many caregivers as

possible in the asthma education to ensure consistent management. It also identified additional educational barriers related to pediatric asthma. For example, education providers often overlook the child and instead concentrate their educational efforts on the caregivers. Children as young as 2 years can begin learning about their asthma and its management. As children age, the scope and the depth of the information will need to continue to grow. As children grow into adolescents, they should receive all asthma information themselves.97 Age-Specific Angle Children as young as 2 years can begin learning about asthma and its management.

Asthma education information should be repeated several times for maximum effect, and educational objectives should be reinforced with age-appropriate written materials. Self-management education should be modified to fit the needs of the individual patient. Educators should discuss cultural beliefs and harmful practices with sensitivity and understanding. They should attend to and document the concerns of the patient and the family regarding medications and asthma management. Addressing concerns and explaining the rationale for treatment may be the overriding factor in patient adherence for chronic asthma management. Asthma educators also must be prepared to intervene and problem solve in the areas of medications, level of treatment, trigger avoidance, adherence, and self-management skills. One indicator related to any chronic condition is the ability to modify or reduce morbidity and mortality risks through patient education. Asthma is a chronic disease condition for which this ability has a key role. Healthcare providers have a number of approaches or interventions at their disposal to ensure that they provide effective and efficient asthma education to patients and their families. Although one method might not be truly better than another, the most important consideration is to provide the resources and information at diagnosis and consistently thereafter to each patient with asthma individually.

Case Studies Case 1. Ambulatory Asthma Management A 43-year-old woman with asthma presents to an inner-city emergency department (ED) with coughing, wheezing, and shortness of breath. She reports a respiratory viral infection within the past week that resolved with use of over-the-counter medicines in 3 or 4 days. Her initial physical examination reveals the following: respiratory rate of 36 breaths/min, labored; heart rate of 120 beats/min; blood pressure of 120/80 mm Hg; pulse oximetry of 93% on room air; inspiratory and expiratory wheezing upon auscultation; equal air exchange bilaterally; moderate intercostal retractions; and peak expiratory flow (PEF) of 290 L/min (60% of predicted). The initial treatment consists of 6 puffs of albuterol, administered via a pMDI with a holding chamber. Each puff is given with the appropriate technique. Post-treatment PEF is 300 L/min (62% of predicted). The patient reports that she stopped taking her Advair about 2 months before this visit. The following additional information is acquired: Reported medications: Advair 1 inhalation twice a day, and albuterol 2 puffs as needed and before exercise Treatment before arrival: None Peak flow meter diary: None Unscheduled ED/MD visits in the past month: 0 Unscheduled ED/MD visits in the past year: 3 Hospital admissions in the past year: 1 Prior ICU admissions: 0 Cough or wheeze frequency: Two times per week Activity limitations: Occasionally Nocturnal cough or wheeze: Two to three times per week Work absenteeism: 6 days per year Approximately 20 minutes after the initial treatment, the patient receives a second treatment consisting of 6 puffs of albuterol via pMDI and holding chamber. The patient is also given 60 mg of prednisolone.

Post-treatment assessment reveals a respiratory rate of 24 breaths/min; heart rate of 100 beats/min; SpO2 95% breathing room air; inspiratory and expiratory wheezing upon auscultation; equal air exchange bilaterally; mild intercostal retractions; and PEF of 315 L/min (65% predicted). Approximately 20 minutes after the second treatment, a third treatment of albuterol (6 puffs) is administered, along with 2 puffs of Atrovent. Post-treatment assessment reveals a respiratory rate of 16 breaths/min; heart rate of 80 beats/min; SpO2 95% breathing room air; faint end-expiratory wheezes with auscultation and bilateral equal air exchange; no intercostal retractions; and PEF of 365 L/min (75% predicted). The next SABA treatment is withheld, and the patient is reassessed in 60 minutes. The response is sustained, and the healthcare team readies her for discharge. Based on the self-reported asthma history, the woman’s chronic asthma is determined to be moderate persistent asthma. The asthma educator instructs her to continue her albuterol treatments with 2 puffs every 4 to 6 hours for the next several days. She also is told to resume her Advair therapy of 1 inhalation twice a day for chronic inflammatory control. She is given a peak flow meter and instructed in its proper use. The asthma educator also instructs the patient in the use of an asthma action plan with a peak flow diary that illustrates meter readings in three color-coded zones to assist her in selfmanagement. Finally, the patient is instructed to call her primary care physician and to schedule a follow-up visit in the next week to 10 days.

Case 2. Life-Threatening Asthma Management A 10-year-old boy with asthma presents to an inner-city ED with dyspnea at rest, talking in phrases, agitated, and dusky in color. The boy’s mother reports having administered three nebulizer treatments before arrival in the ED. The child’s initial physical examination reveals the following: respiratory rate of 48 breaths/min, labored; heart rate of 170 beats/min; blood pressure of 160/100 mm Hg; SpO2 of 89% breathing room air; breath sounds muffled to inaudible; severe intercostal and substernal retractions; and inability to perform a PEF. The patient is started on continuous albuterol delivered with 100%

oxygen. The clinician places an IV and gives the patient 60 mg methylprednisolone. During the aerosol treatment, an asthma history is taken from the boy’s mother. She reports that her child had been outside playing basketball with his friends for most of the afternoon. Before this episode, he was in good health. The following information is acquired: Reported medications: Albuterol 2 puffs as needed before exercise Treatment before arrival: 3 nebulized treatments with albuterol Peak flow meter diary: None Unscheduled ED/MD visits in the past month: 0 Unscheduled ED/MD visits in the past year: 1 Hospital admissions in the past year: 1 Prior ICU admissions: 1 (3 years ago) Cough or wheeze frequency: With respiratory infections Activity or play limitations: Always Nocturnal cough or wheeze: 1 to 2 times per week School absenteeism: 3 to 4 days per year While receiving continuous albuterol, the child is assessed every 20 minutes. The clinician continuously monitors the electrocardiography and pulse oximetry. After the initial 20 minutes, 0.5 mg of ipratropium is added to the aerosol. After 35 minutes, the patient’s status is a respiratory rate of 20 breaths/min, labored; heart rate of 80 beats/min; blood pressure of 200/100 mm Hg; SpO2 of 88% on continuous nebulizer; inaudible breath sounds; severe intercostal and substernal retractions; inability to perform PEF; and lethargy and drowsiness. Arterial blood gas results are pH 7.29, PaCO2 52 mm Hg, PaO2 60 mm Hg, HCO3– 26 mmol/L, and oxygen saturation 87%. The healthcare team decides to intubate the child. After atropine, ketamine, and succinylcholine are administered, he is intubated with a 6mm cuffed endotracheal tube. On arrival in the pediatric ICU, he is placed on the following settings: volume control continuous mandatory ventilation (VC-CMV), tidal volume 350 mL (7 mL/kg), PEEP 3 cm H2O, mandatory breath rate 10 breaths/min, I:E ratio 1:5, and FIO2 0.50. After 1 hour on the ventilator, the arterial blood gas results are as follows: pH 7.32, PaCO2 46 mm Hg, PaO2 120 mm Hg, HCO3– 22 mmol/L, and oxygen saturation 99%. The FIO2 is reduced to 0.4. The patient is

ventilated with permissive hypercapnia to prevent auto-PEEP and overdistention. Continuous ventilator waveform analysis is used to detect auto-PEEP, and the flow is increased to allow a longer expiratory time. The patient is kept moderately sedated, and paralysis is not necessary. The child is given albuterol and Atrovent through the ventilator circuit with a mesh nebulizer. The patient remains on IV methylprednisolone. After 6 hours of this therapy, the albuterol treatments are changed to a frequency of every hour. After 12 hours of mechanical ventilation and pharmacologic therapy, blood gas results are pH 7.42, PaCO2 33 mm Hg, PaO2 95 mm Hg on FIO2 0.25, HCO3– 24 mmol/L, and oxygen saturation 99%. The patient is awake and triggering at a rate of 6 to 10 breaths/min above the mandatory rate. A spontaneous breathing trial is successful, and the patient is extubated to a 2-L/min nasal cannula, 5 mg nebulized albuterol every hour, ipratropium 0.5 mg every 6 hours, and IV methylprednisolone.

Key Points Asthma is a common chronic disease that is increasing in prevalence and severity. The pathophysiology of asthma is largely related to inflammation, hyperresponsiveness, and airway obstruction. The most readily identified predisposing factor for the development of asthma is atopy. Nocturnal symptoms of asthma are common. Exercise-induced asthma is characterized by transient airway obstruction after strenuous exercise. Occupational asthma is characterized by variable airway hyperresponsiveness in the workplace. The NAEPP has developed a four-tier system to classify asthma disease severity. Asthma exacerbation is characterized by increased symptoms and acute decrease in airflow. The NAAEPP has developed a protocol for assessing exacerbation severity and an algorithm for care in the ED, ward, and ICU. The most common ways to diagnose and monitor airflow obstruction in asthma are spirometry and peak flow meters. Asthma medications are classified as either long-term controllers or quick-relief medications. Inhaled medications are delivered by nebulizer, pressurized metered-dose inhaler, or dry powder inhaler. The cornerstones of therapy for asthma consist of oxygen, inhaled β2-agonists, and corticosteroids. Mechanical ventilation is the treatment of last resort for patients with asthma and respiratory failure. Asthma education begins with diagnosis and should be reinforced with each visit.

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CHAPTER

33 Chronic Obstructive Pulmonary Disease Dean R. Hess

© Andriy Rabchun/Shutterstock

OUTLINE Definitions Diagnosis, Symptoms, and GOLD Stages Etiology of Chronic Obstructive Pulmonary Disease Pathophysiology of Chronic Obstructive Pulmonary Disease Outpatient Care of Stable Chronic Obstructive Pulmonary Disease Surgery and Bronchoscopic Interventions Managing Exacerbations Palliative and End-of-Life Care Case Studies

OBJECTIVES 1. 2. 3. 4. 5.

Define chronic obstructive pulmonary disease (COPD). Describe the epidemiology, pathogenesis, and pathophysiology of COPD. Use the GOLD guidelines in the care of a patient with COPD. Discuss therapeutic strategies for stable patients with COPD. Discuss the surgical and bronchoscopic approaches to improve lung function in patients with COPD.

6. Describe the approach to managing patients with COPD exacerbation. 7. Compare the use of noninvasive ventilation in patients with COPD exacerbation and in patients with stable COPD. 8. Describe the medications used in the treatment of COPD. 9. Identify important aspects of palliative and end-of-life care for patients with COPD.

KEY TERMS air trapping alpha1-antitrypsin (AAT) deficiency BODE index bullae bullectomy chronic bronchitis chronic obstructive pulmonary disease (COPD) COPD Assessment Test (CAT) COPD exacerbation corticosteroid dynamic airway compression dynamic hyperinflation electronic cigarette (e-cigarette) emphysema hyperinflation intrinsic positive end-expiratory pressure (auto-PEEP) long-acting beta-agonist (LABA) long-acting muscarinic antagonist (LAMA) long-term oxygen therapy (LTOT) lung transplantation lung volume reduction surgery (LVRS) Modified Medical Research Council (mMRC) dyspnea scale nicotine replacement therapy noninvasive ventilation (NIV) overlap syndrome phosphodiesterase inhibitor pulmonary rehabilitation short-acting beta-agonist (SABA) short-acting muscarinic antagonist (SAMA) smoking cessation

Introduction Chronic obstructive pulmonary disease (COPD) is a major health condition, affecting an estimated 80 million people worldwide. In the United States, more than 16 million people have a formal diagnosis of COPD, and millions more may have the disease but have not yet been diagnosed.1 Respiratory therapists have the needed expertise to intercede at all stages of COPD to improve patients’ functional status, quality of life, and the outcome of their disease. COPD is the fourth leading cause of death in the United States and around the world.2,3 In the United States, the mortality rate from COPD has declined since 1999 in men and some age groups but appears to be still rising in women, albeit at a reduced pace.4 Moreover, COPD is a systemic disease, not just a pulmonary disease, and increases the risk of pneumonia, heart disease, metabolic syndrome, and lung cancer.5,6 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report2 is accepted as the guide to COPD management, and this chapter is written to be consistent with that document.

Definitions COPD is a common, preventable, and treatable disorder characterized by progressive symptoms and flow limitation that is not fully reversible by bronchodilator or anti-inflammatory therapy.2 Flow limitation is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, especially cigarette smoking. COPD also produces systemic inflammation and important nonpulmonary consequences such as cachexia, skeletal muscle dysfunction, cardiovascular disease, osteoporosis, depression, fatigue, and cancer. The flow limitation stems from a combination of destruction of lung parenchyma (emphysema) and small airways disease (obstructive bronchiolitis), with the relative proportions of each varying in individual patients. Other specific causes of chronic flow limitation—such as cystic fibrosis, asthma, bronchiolitis obliterans, and bronchiectasis—are not categorized as types of COPD. Airways disease is used to define the pathologic and physiologic abnormalities observed in the airways of patients with COPD because these changes occur in both central (bronchi) and small airways (bronchioles). The historical categorical term chronic bronchitis is no longer preferred because it incorrectly limits the focus to inflammatory changes observed in pathologic examinations of central airways (bronchi). In addition, this term creates more confusion because it defines a clinical condition wherein patients have a productive cough for at least 3 months of the year for 2 or more successive years. Some patients with chronic bronchitis diagnosed clinically might not have spirometric evidence of flow obstruction and, therefore, do not meet the definition of COPD. The terminology of airways disease recognizes that mucus hypersecretion occurs in the proximal airways but that the site of increased airways resistance in COPD is the peripheral, small airways, where inflammation results in fibrosis and airway distortion. The specific causative factors of flow limitation in peripheral airways, however, have not been clearly defined, as indicated by the poor correlation between pathologic changes observed in the bronchioles and the degree of measured flow limitation. Some degree of emphysema occurs in nearly all patients with COPD,

although the extent observed varies widely among patients. Emphysema is a pathologic, rather than a clinical, term. This condition is diagnosed by histopathologic examination of lung tissue or by imaging studies, such as high-resolution computed tomography (HRCT), that can detect emphysema-related pathologic changes.7 Emphysema is characterized by abnormal enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis (Figure 33-1). This irreversible airspace enlargement occurs in the alveoli, alveolar duct, and respiratory bronchiolar regions of the lung where gas exchange occurs. Structural abnormalities in these regions cause uneven distribution of ventilation and hypoxemia, hypercapnia, and decreased lung diffusion as measured by the diffusing capacity for carbon monoxide (DLCO).

FIGURE 33-1 Schematic models showing the airways and lung parenchyma of normal individuals (A and C) and patients with COPD (B and D). Airways in COPD patients are characterized by hyperplasia of surface mucous cells, enlargement of tracheobronchial submucosal glands, excess mucus, loss of cilia and ciliary dyskinesia, and the presence of inflammatory cells. Compared with patients with normal lungs (C), patients with COPD have permanently enlarged airspaces distal to terminal bronchioles caused by alveolar wall destruction (D).

Description Airspace enlargements larger than 1 cm in diameter are termed bullae (Figure 33-2). Bullae progressively enlarge and compress

adjacent lung tissue, further impairing respiratory function. Emphysema contributes to flow limitation by decreasing lung elastic recoil. During exhalation, positive intrathoracic pressure compresses airways that are no longer tethered open by surrounding normal lung tissue. This process, termed dynamic airway compression, results in air trapping and hyperinflation (Figure 33-3). Hyperinflation with increased lung volumes may be apparent on chest radiography (Figure 33-4) and chest computed tomography (CT) scans.

FIGURE 33-2 Computed tomography scan of a patient with severe emphysema. Note the multiple bullae throughout the lung parenchyma, which appears hyperlucent, indicating generalized loss of lung tissue and hyperinflation.

FIGURE 33-3 Schematic model demonstrating the morphologic changes associated with dynamic airway compression in patients with COPD. The loss of parenchymal tethering external to airways causes airway collapse during forced expiration. Maximal expiratory effort (A) creates more compressing pressure around airways and produces more dynamic compression as compared with moderate expiratory effort (B).

Description

FIGURE 33-4 Chest radiograph of a patient with emphysema showing hyperinflation as evidenced by the flattening of the diaphragm, best observed on the lateral view, and hyperlucent lung fields.

Respiratory Recap Definition of COPD ∎ COPD is a preventable and treatable disorder characterized by progressive flow limitation that is not fully reversible by bronchodilator or anti-inflammatory therapy. ∎ The term chronic bronchitis incorrectly limits the focus of COPD to inflammatory changes observed in pathologic examinations of central airways (bronchi). ∎ Some degree of emphysema occurs in nearly all patients with COPD.

Diagnosis, Symptoms, and GOLD Stages Patients who develop COPD from smoking have a prolonged initial subclinical course. Cough and dyspnea with exertion represent early symptoms that patients often ascribe to expected consequences of smoking rather than to an underlying lung disease. Many patients are first diagnosed when they experience an exacerbation and present with increased cough, dyspnea, and sputum production that may require hospitalization. Others present with a complication such as pneumonia. Patients may also present with an associated disorder such as cancer or heart disease. Because early diagnosis helps patients consider smoking cessation and emerging data suggest that therapy may alter the course of the disease,8 patients older than age 40 years with respiratory symptoms (Box 33-1) who smoke should undergo spirometry. However, the role of mass screening with spirometry is controversial.9 Once diagnosed by spirometry, patients who continue to smoke have an accelerated decline in FEV1 (forced expiratory volume in the first second of expiration) as compared with nonsmoking, age-matched individuals. Patients with moderate to severe COPD commonly experience exacerbations. Patients who have COPD onset early in life or in the absence of smoking history should be evaluated for alpha1-antitrypsin deficiency. BOX 33-1 Symptoms That Suggest a Diagnosis of COPD Dyspnea that worsens over time, increases with exercise, persists on a daily basis, and feels to the patient like an increased effort to breathe, heaviness, or gasping Chronic cough that may be persistent, intermittent, and/or nonproductive Chronic sputum production of any pattern or nature of sputum History of risk factors of tobacco smoke, occupational dusts or chemicals, and/or smoke from home cooking or heating fuels Reproduced with permission of the American Thoracic Society. Copyright © American Thoracic Society. Modified from Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176(6):532– 555.

Limitation of maximal expiratory flow is the cardinal abnormality associated with COPD and serves both to diagnose the presence of the disease and to stage its severity. Measures of postbronchodilator FEV1 and the ratio of FEV1 to forced vital capacity (FEV1/FVC) are the best measures of expiratory flow limitation, with flow obstruction defined by a post-bronchodilator FEV1/FVC of less than 0.70,2 which is an abnormal finding in nearly all age groups. This FEV1/FVC threshold, however, may over-diagnose COPD in elderly patients because of the decrease in lung volume and flow that occur with aging. The GOLD report uses spirometry to classify the severity of COPD into four grades (Table 33-1).2 TABLE 33-1 Spirometric Grades of COPD Severity Based on Postbronchodilator FEV1 GOLD 1: Mild

FEV1/FVC < 0.70 FEV1 ≥ 80% predicted

GOLD 2: Moderate

FEV1/FVC < 0.70 50% ≤ FEV1 < 80% predicted

GOLD 3: Severe

FEV1/FVC < 0.70 30% ≤ FEV1 < 50% predicted

GOLD 4: Very severe

FEV1/FVC < 0.70 FEV1 < 30% predicted

FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

FEV1 and FVC alone, however, do not correlate well with severity of dyspnea and functional performance, survival, or response to therapy. Because hyperinflation has important effects on lung function, lung volume measurements, such as the ratio of the inspiratory capacity to the total lung capacity, are better predictors of survival than FEV1. It is also recognized that the systemic nonpulmonary manifestations of COPD have important effects on prognosis. Symptom burden is measured by the Modified Medical Research Council (mMRC) dyspnea scale (Figure 33-5) or the COPD

Assessment Test (CAT) (Figure 33-6). The mMRC assesses the degree of dyspnea, whereas the CAT assesses symptoms beyond dyspnea. Using assessments of dyspnea or symptoms and exacerbation history, the severity of COPD is classified into four groups: A, B, C, D (Figure 337). The BODE index (body mass index, flow obstruction, dyspnea, and exercise capacity) is a multidimensional measure of disease severity, prognosis, and response to therapy (Table 33-2).10 Some sources have combined the BODE index with spirometry to stage COPD (Table 33-3).

FIGURE 33-5 Modified Medical Research Council dyspnea scale. Reproduced from Fletcher CM. Standardized questionnaire on respiratory symptoms: a statement prepared and approved by the MRC Committee on the etiology of chronic bronchitis (MRC breathlessness score). BMJ 1960;2:1662.

Description

FIGURE 33-6 COPD Assessment Test. Reproduced from Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J 2009;34(3):648– 654.

Description

FIGURE 33-7 GOLD assessment. Reproduced from Gold teaching slide test, https://goldcopd.org/gold-teaching-slide-set.

Description TABLE 33-2 BODE Index

Description TABLE 33-3 Classification of COPD Severity Based on BODE Index and Spirometry At risk

FEV1/FVC < 0.70 FEV1 ≥ 80% predicted

Mild

FEV1/FVC < 0.70 FEV1 < 80% predicted BODE index 0–2

Moderate

FEV1/FVC < 0.70 FEV1 < 80% predicted BODE index 3–4

Severe

FEV1/FVC < 0.70 FEV1 < 80% predicted BODE Index 5–6

Very severe

FEV1/FVC < 0.70 FEV1 < 80% predicted BODE index 7–10 Data from Celli BR. Update on the management of COPD. Chest 2008;133(6):1451–1462, with permission from the American College of Chest Physicians.

Etiology of Chronic Obstructive Pulmonary Disease Epidemiologic and experimental evidence demonstrates that smoking is the major cause of COPD. Nevertheless, nonsmokers may also develop COPD when exposed to other risk factors11—for example, passive exposure to cigarette smoke and nontobacco inhalational factors such as occupational dusts and chemicals and both indoor and outdoor air pollution. There is increasing interest in classifying diseases by their phenotypes, endotypes, and genotypes.12–15 A large study, the COPDGene project, is currently under way to investigate the genetic factors underlying COPD. Phenotypes are observed clinical characteristics of an individual. COPD is phenotypically heterogeneous, as patients may have primarily bronchitis or primarily emphysema, frequent exacerbations or few exacerbations, and exercise limitation or no exercise limitation, to name a few possibilities. Endotypes are groups of patients who share observed characteristics because of shared underlying biology. Biomarkers may be useful to identify endotypes. Once an endotype is identified, personalized treatment approaches can target those endotypes.15 The best-characterized genetic risk factor for COPD is alpha1antitrypsin (AAT) deficiency.16,17 This hereditary condition almost always occurs in Caucasians and results from abnormal function or insufficient production of AAT. Patients with AAT deficiency demonstrate an abnormal antiprotease response to pro-inflammatory effects of tobacco smoke. The resultant activation of proteases and toxic O2 metabolites results in accelerated lung destruction and emphysema in early life. Individuals with AAT may remain healthy throughout their lives, but even nonsmokers with AAT deficiency may develop COPD symptoms, usually late in life. The gene that is most commonly abnormal for AAT is the Z allele; normal genes are labeled M. The most common genotype associated with AAT is ZZ (also referred to as PiZ). Approximately 100,000 people have the ZZ phenotype in the United States.

Males and females have an equivalent prevalence of COPD, although some studies suggest the risk of COPD is greater among women smokers.18 Prevalence of COPD is greater in smokers with lower socioeconomic status,19 but this observation may result from associated differences in living conditions, exposure to environmental toxins, or smoking behaviors. Various occupational dusts, including coal and grain dusts, air pollution, indoor air pollution caused by cooking fuels or cigarette smoke, and childhood respiratory infections are additional risk factors for the development of COPD. Stop and Think You are explaining COPD to a member of your family. What would you say is the major risk factor for developing this disease?

Although asthma and COPD are correctly considered separate diseases, some patients can have features of both. Asthma–COPD overlap syndrome (ACOS) is characterized by persistent flow limitations plus several features usually associated with asthma and several features usually associated with COPD.2 ACOS is identified by the features that it shares with both asthma and COPD. This syndrome usually presents after age 40 years, but the patient may have experienced symptoms as a child or young adult. Respiratory symptoms including exertional dyspnea are persistent but may vary dramatically. The flow limitations associated with ACOS are not fully reversible. Their presence often demonstrates current variability or variability in the past but becomes persistent over time. Patients may also have physiciandiagnosed asthma, allergies, family history of asthma, and noxious exposures. Symptoms are partly but significantly reduced with treatment. Progression usually occurs, however, and patients’ treatment needs are high.

Pathophysiology of Chronic Obstructive Pulmonary Disease Recognition of the pathogenetic importance of impaired antiprotease defenses in AAT deficiency led to the protease–antiprotease theory for the etiology of smoking-related COPD. In this model, smoking and other noxious inhalants overwhelm the lungs’ antioxidant and antiprotease defense mechanisms, allowing proteolytic digestion of lung tissue. Different COPD-like phenotypes have been generated in animal models by targeting the immune system or causing disturbances of apoptotic control in pulmonary endothelium.20 These observations have expanded the pathophysiologic understanding of COPD beyond protease– antiprotease mechanisms to include multiple immunogenetic disturbances that can combine in varying ways to produce unique COPD phenotypes in different patients. The convergence of these different mechanisms may explain why the COPD population has diverse clinical expressions. The structural abnormalities that produce respiratory symptoms and functional limitations in COPD occur in the central airways, peripheral airways, and lung parenchyma. The central airways are the site of most of the increased mucus production in patients who raise excess sputum and carry the clinical diagnosis of chronic bronchitis. Mucous glands below the epithelial basement membrane in central airways secrete mucus that serves, in healthy individuals, as a mechanical host defense mechanism against environmental particulate inhalants. Some patients with COPD have moderate enlargement of mucous glands, which correlates with cough and sputum production. Mucus-secreting goblet cells are nested among epithelial cells along all segments of the conducting airways. These goblet cells may proliferate in the central airways of patients with COPD and contribute to excess mucus production. Ciliary dyskinesia, loss of cilia, and epithelial metaplasia have also been observed in the central airways of patients with COPD. Inflammation is present in the form of neutrophils, macrophages, and lymphocytes within the epithelium and submucosa of central airways and

neutrophils and eosinophils within airway secretions.18 Eosinophils are found in the airway submucosa during exacerbations of COPD. Nodules rich in both T and B cells develop in regions of abnormal lung tissue, lending support to an immunogenic etiology to COPD.19 Altered T- and Bcell responses are also observed in the peripheral blood, indicating the systemic nature of the disease and the presence of immunodysregulation in nonpulmonary organs. In COPD, most of the increase in airways resistance occurs in the peripheral airways, where multiple pathologic changes occur. Early in the course of COPD, brown-pigmented macrophages aggregate in the respiratory bronchioles. As COPD progresses, a low-grade inflammatory response develops in the membranous bronchioles, characterized by a modest influx of neutrophils, macrophages, and lymphocytes. In some patients, smooth muscle enlargement, minimal fibrosis, squamous cell metaplasia of airway epithelial cells, and goblet cell metaplasia develop. These changes, in combination with abnormalities of smooth muscle and connective tissue, result in a narrowed caliber of the airway lumen both from thickening of the airway walls and a decrease in cross-sectional total airway diameter. Although these pathologic abnormalities in peripheral airways contribute to the expiratory flow limitations observed in COPD, they do not entirely explain the increased airways resistance. Other contributory factors—such as the loss of airway tethering caused by decreased elastic recoil of the lung parenchyma, airway secretions, changes in the properties of airway lining fluid, and smooth muscle contraction—interact in complex and poorly understood ways. Among these factors, loss of elastic recoil plays an important role. Elastic recoil refers to the lungs’ natural tendency to deflate after inspiration. It is expressed visually by plotting lung volume as a function of transpulmonary pressure. Figure 33-8 shows the comparative pressure-volume curves of a normal adult and a patient with emphysema. With loss of pulmonary elasticity from destruction of alveolar and interstitial structures, the patient with emphysema has increased lung compliance, as shown by a shift of the pressure-volume curve up and to the left. Increased lung compliance results in attenuation of the tethering effect that normal lung parenchyma has on the airways, which usually causes them to resist airway narrowing during expiration. Consequently,

the airways of patients with COPD decrease in caliber and resist expiratory flow to a greater degree than normal. Dynamic airway compression then occurs during expiration as the expiratory muscles contract and intrathoracic pressure increases, with this compressional force being transmitted to the external walls of conducting airways. The relationship of flow to pressure during inspiration and expiration at a given lung volume is shown in Figure 33-9.

FIGURE 33-8 Volume–pressure relationships of individuals with normal lungs and patients with emphysema. Patients with emphysema experience a small increase in pressure (ΔP) with an increase in volume (ΔV) while breathing at low lung volumes. In contrast, patients with

emphysema have large increases in pressure (ΔP′) for a similar change in volume (ΔV′) when breathing at high lung volumes, at which point their lungs become hyperinflated and stiff. Patients with emphysema have heterogeneous distribution of emphysema, so that normal regions of lung follow the normal volume–pressure curve and emphysematous regions follow the emphysema curve.

Description

FIGURE 33-9 Relationship of flow to pressure during inspiration and expiration at a given lung volume. This relationship is linear during inspiration, but dynamic airway compression (arrow) causes expiratory flow to reach an early maximal value that does not increase with further increases in alveolar pressure.

Description Expiratory flow-volume curves graphically depict these relationships (Figure 33-10). Individuals with normal lung function increase their expiratory flow during forced expiratory maneuvers until dynamic airway compression occurs, at which point flow does not increase with increased effort. During tidal breathing, expiratory flow is much lower than during a maximal, forced expiration, indicating that patients in good health have considerable ventilatory reserve available for increasing minute ventilation ( E).

FIGURE 33-10 Expiratory flow–volume curves of a patient with severe COPD compared with an individual with normal lungs. The patient with COPD reaches maximal expiratory flow during tidal breathing.

Description In patients with COPD, the decreased diameter of the conducting airways decreases the maximal expiratory flow at all lung volumes compared with normal individuals. Because of the loss of lung elasticity and the collapsibility of airways in patients with emphysema, dynamic airway compression occurs at lower intrathoracic pressures. In patients with severe COPD, maximal flow may be reached during minimal exercise and eventually at resting tidal breathing. When maximal flow is

reached during tidal breathing, patients faced with increased ventilatory demands from exercise cannot increase flow to recruit a larger tidal volume (VT). Thus, to respond to exercise demands, they must increase E by generating a higher respiratory rate. An increased respiratory rate decreases expiratory time, which promotes air trapping and increased intrathoracic pressures and further aggravates dynamic airway compression. As air trapping progresses, intra-alveolar pressure at end-expiration may remain positive rather than equilibrating with ambient pressure, as occurs in healthy patients. This condition is termed intrinsic positive end-expiratory pressure (auto-PEEP). Auto-PEEP creates an inspiratory threshold load that increases the work of breathing because patients must contract inspiratory muscles to negate auto-PEEP before they can generate the negative alveolar pressure necessary to initiate inspiration. These changes result in patients breathing with a decreased VT and increased respiratory rates at higher lung volumes. Higher lung volumes at end-expiration increase the inspiratory work of breathing because patients must overcome the increased elasticity of the chest wall and lungs that begin inspiration in an already expanded anatomic configuration. The clinician can assess hyperinflation by measuring lung volumes, which demonstrate increased total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) in patients with COPD. As FEV1 and FVC decrease with progressive COPD, lung volumes will increase in a corresponding fashion. The severity of emphysema and flow limitations in small airways varies among different regions of the lung. This heterogeneity causes regional variations in the distribution of ventilation, which results in ventilation-perfusion mismatch. Although emphysematous regions of the lungs are under-ventilated, perfusion is more severely decreased, so that ventilation-perfusion ratios ( ) increase. Consequently, the emphysematous regions of the lung have increased dead space that leads to hypoxemia and hypercapnia. In other regions of the lungs, increased resistance or partial obstruction of airways that ventilate relatively normal alveolocapillary units generates decreased ratios that cause venous admixture and hypoxemia. The combination of lung regions with high and low alters gas exchange and places demands on the ventilatory capacity of patients, thereby increasing respiratory

work. Worsening abnormalities eventually result in hypoxemia and, if ventilation is markedly impaired, hypercapnia; both of these imbalances are associated with a poor prognosis in patients with COPD. Shunts are notably absent in stable COPD, indicating the efficiency of collateral ventilation and hypoxic pulmonary vasoconstriction and the absence of complete airway obstruction. Patients with COPD also experience abnormalities in the coordination of respiratory muscle function. During exercise and voluntary hyperventilation, patients experience fatigue of the exercising muscle groups combined with asynchrony of respiratory muscles with poor coordination of rib cage and diaphragm-abdominal muscles. Hypercapnia and untreated hypoxia can cause pulmonary hypertension and cor pulmonale, which is characterized by right ventricular hypertrophy. As the severity of COPD progresses, patients become aware of the effort to breathe. When this effort is perceived as work, patients experience dyspnea. Dyspnea related to COPD derives from alterations in ventilatory mechanics. Patients with early COPD and mildly increased flow limitation respond to abnormalities in gas exchange by increasing respiratory drive and E through recruitment of a larger VT to normalize PaCO2 and PaO2. With more severe disease, increasing VT causes too much work, so E is maintained by increasing the respiratory rate. To increase the respiratory rate, patients must shorten their inspiratory time (TI), resulting in a decreased fractional duration of inspiration (TI/TTOT) and an increased mean inspiratory flow (VT/TI). An increased respiratory rate eventually decreases expiratory time to such a degree that alveolar emptying cannot occur and further hyperinflation develops. Worsening hyperinflation shifts the pressure– volume curve of emphysematous lung units upward and to the left, adding a restrictive pulmonary defect to the underlying flow limitation. This produces the rapid and shallow respiratory pattern commonly observed in patients with severe COPD. Rapid and shallow breathing places greater demands on respiratory muscles in terms of both the amount of pressure they need to generate for breathing (Pbreath) and the proportion of the respiratory cycle during which muscle contraction is required to occur (TI/TTOT). Progressive dyspnea correlates both with increasing Pbreath and TI/TTOT. As Pbreath

approaches the maximal pressure that the respiratory muscles can generate (PImax), patients function near their limits of ventilatory reserve and fatigue threshold. Further demands on respiratory muscles, such as an exacerbation of COPD with increased airways resistance, can overburden compensatory mechanisms and cause acute respiratory failure. Lung volume is more closely associated with dyspnea and functional limitations of patients with advanced disease than is FEV1. As patients exercise, E increases and expiratory flow limitations produce dynamic hyperinflation, as expressed as the ratio of inspiratory capacity to total lung capacity. This ratio has been shown to predict survival better than does FEV1. Additionally, improvements in exercise capacity and dyspnea produced by inhaled bronchodilators, pulmonary rehabilitation, and lung volume reduction surgery are less closely associated with improvements in FEV1 and more tightly linked to delaying dynamic hyperinflation. Stop and Think You are assisting in the care of a patient with COPD. What are the treatment goals for this patient?

Respiratory Recap Pathophysiology of COPD ∎ Most of the increase in airways resistance occurs in the peripheral airways. ∎ Loss of pulmonary elasticity is due to destruction of alveolar structures. ∎ Decreased diameter of the airways lowers the maximum expiratory flow at all lung volumes. ∎ Flow limitation results in dynamic hyperinflation. ∎ Lung volume is more closely associated with dyspnea and functional limitation than are spirometry data.

Outpatient Care of Stable Chronic Obstructive Pulmonary Disease An integrated outpatient approach to the management of COPD provides opportunities to reduce symptoms and improve quality of life, slow the decline in lung function, prevent complications, avoid or minimize adverse effects of therapy, and prolong survival. Such a comprehensive strategy incorporates drug therapy, surgical interventions, rehabilitation, education, prophylactic measures, and supplemental O2. Chronic disease management models—including those for COPD—recommend collaborative care, wherein the clinician partners with patients to ensure self-reliance and high personal esteem. Preventive care is a cornerstone of COPD therapy, including immunization with pneumococcal vaccine and yearly influenza vaccinations. Unfortunately, considerable gaps exist in primary care management of patients with COPD, with many patients being both underdiagnosed and undermanaged. Goals of treatment center on preventing deterioration of lung function, enhancing quality of life by diminishing symptoms, managing complications, and prolonging meaningful life. Survival benefits have been demonstrated with the implementation of smoking cessation, longterm O2 therapy for hypoxemic patients, lung volume reduction surgery for patients with upper lobe emphysema and poor exercise capacity, and noninvasive ventilation (NIV) in selected patients. Drug therapy improves symptoms and lowers the risk of exacerbations. Other therapies, such as lung transplantation and pulmonary rehabilitation, can improve function, symptoms, and quality of life for patients with advanced COPD.21

Smoking Cessation Smoking cessation is the only healthcare intervention clearly shown to slow the accelerated decline of FEV1 in patients with COPD. Although most smokers want to quit, they face multiple barriers to doing so, including physicians’ self-reported lack of training in smoking cessation interventions. Respiratory therapists and other caregivers can assist

patients in stopping smoking by addressing the issue, providing brief advice, and guiding patients toward smoking cessation resources. Although brief interventions during hospitalization have negligible effects, referral to counseling programs represents a more effective tobacco use treatment strategy.22,23 While delivering respiratory care to hospitalized patients, respiratory therapists and others should discuss the health benefits that smoking cessation can provide at any patient age (Box 332). BOX 33-2 Health Benefits of Quitting Smoking Longer life Decreased risk for lung cancer, other types of cancers, heart attack, and stroke Reduction in risk for cardiac events Improved circulation Chronic cough improves Lung function improves within 3 months Dyspnea improves within 1 to 9 months Improved sense of smell and taste Improved functional abilities such as walking and climbing stairs

Combining pharmacotherapy with behavioral therapy and other interventions increases success rates for patients who are motivated to stop smoking (Box 33-3). Nicotine replacement therapy reduces symptoms related to nicotine withdrawal and produces smoking cessation rates of 17% at six months as compared with 10% among control groups.24 Only limited data support combination nicotine replacement therapy as being superior to a single route of nicotine replacement.25 Other than cost, no differences exist in efficacy among the various forms of nicotine replacement therapy. BOX 33-3 Pharmacologic Interventions to Assist Smoking Cessation Nicotine Replacement Therapy Gum: Increases cessation rates about 1.5 to 2 times control rates at 6 months 24-hour patch: Increases cessation rates about 1.5 to 2 times control rates at 6 months Nasal sprays: Increase cessation rates about 1.5 to 2 times control rates at 6 months Inhaler: Increases cessation rates about 1.5 to 2 times control rates at 6 months Lozenges: Increase cessation rates about 1.5 to 2 times control rates at 6 months

Bupropion Oral sustained-release formulation: Increases cessation rates about 2 times control rates at 1 year

Varenicline Oral tablet: Increases cessation rates more than 3.5 times control rates and almost 2 times bupropion rates at 12 weeks

Bupropion reduces cravings for cigarettes through unknown mechanisms. Insufficient comparative data with nicotine replacement therapy exist, but one study reported a doubling of smoking quit rates at one year with bupropion as compared with the nicotine patch.26 Varenicline reduces cravings for cigarettes by binding to a nicotine receptor associated with the relaxing effects felt by smoking. Clinical trials of varenicline as compared with placebo or bupropion demonstrated higher abstinence rates for varenicline.27 Limited evidence of efficacy exists for clonidine, nortriptyline, naltrexone, alprazolam, silver acetate, mecamylamine, and lobeline, and these agents have not been cleared by the Food and Drug Administration (FDA) for smoking cessation. Clonidine and nortriptyline are recommended as second-line therapy for patients who fail first-line therapy or have contraindications to first-line drugs. The role, if any, for electronic cigarettes (e-cigarettes) in smoking cessation is controversial. One study reported that e-cigarettes were more effective for smoking cessation than was nicotine replacement therapy.28 A consideration is that adult use of e-cigarettes exposes children to vapors and displays an addictive behavior.29 E-cigarettes are designed for pulmonary delivery of nicotine through an aerosol, usually consisting of propylene glycol, nicotine, and flavorings.21 These devices heat the nicotine solution using a battery-powered circuit and deliver the resulting vapor into the lungs. Although e-cigarettes appear to be safer than smoking combusted tobacco, they have their own inherent risks, which are poorly characterized and largely unregulated. Given the dearth of evidence regarding their long-term safety, their use should be discouraged.

Drug Therapy

Symptomatic patients with COPD can benefit from pharmacologic therapy. Oral and inhaled medications are directed toward relieving symptoms, improving functional capacity and quality of life, decreasing hyperinflation, and preventing or reversing exacerbations and worsening of lung function. The approach to pharmacotherapy in COPD is informed by the GOLD report (Figure 33-11 and Figure 33-12).30 Mild disease with intermittent symptoms responds to occasional use of short-acting bronchodilators, either a short-acting beta-agonist (SABA) or a shortacting muscarinic antagonist (SAMA) or a combination of both. Maintenance bronchodilator therapy with a long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA),31 and inhaled corticosteroids (ICS) is added for patients with more advanced disease.32 Long-term monotherapy with ICS is not recommended. Combining drugs from different classes (β2-agonists, muscarinic antagonists, ICS) has additive beneficial effects. Oral phosphodiesterase inhibitors (theophylline and roflumilast) and macrolides can also be used in selected patients.

FIGURE 33-11 GOLD suggestions for treatment of COPD. CAT, COPD Assessment Test; ICS, inhaled corticosteroids; LABA, long-acting agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; SABA, short-acting agonist; SAMA, short-acting muscarinic antagonist. Modified from Medical Research Council, CAT: COPD Assessment Test. From Hess MW. The 2017 Global Initiative for Chronic Obstructive Lung Disease report and practice implications for the respiratory therapist. Respir Care 2017;62(11):1492–1500.

Description

FIGURE 33-12 Choosing inhaler therapy for patients with stable COPD based on the Global Initiative for Chronic Obstructive Lung Disease grouping. Treatments highlighted in green are preferred. From Burkes RM, Donohue JF. An update on the Global Initiative for Chronic Obstructive Lung Disease 2017 guidelines with a focus on classification and management of stable COPD. Respir Care 2018;63(6):749–758. Permission conveyed through Copyright Clearance Center, Inc. Republished with permission of Daedalus Enterprises, Inc.

Description Short-acting bronchodilators are used for quick relief of symptoms. Either a SAMA, a SABA, or a combination can be used. In patients with COPD, a SAMA (ipratropium) or SABA/SAMA (albuterol/ipratropium) is preferred, although a SABA (albuterol) can also be used. These medications are administered by nebulizer, pressurized metered-dose inhaler (pMDI), dry powder inhaler (DPI), or Respimat. They are usually well tolerated with minimal side effects. Levalbuterol is the R-enantiomer

of albuterol, which has not been shown to have advantages as compared with racemic albuterol, which has both the R- and S-enantiomers. LAMA and LABA are used for maintenance therapy in patients with persistent symptoms and moderate to very severe COPD. LABA are available as twice-a-day (salmeterol, formoterol, arformoterol) or oncedaily (indacaterol, olodaterol) formulations. Available LAMA include twicedaily (glycopyrrolate, aclidinium) and once-daily (tiotropium, umeclidinium, revefenacin) formulations. Compared with LABA, LAMA produce better bronchodilation and greater improvements in dyspnea.33 Inhaled corticosteroids have airway anti-inflammatory effects and provide opportunities to improve symptoms and the clinical course of patients with COPD while avoiding many of the side effects associated with oral corticosteroids. These medications lower the rate of progressive loss of quality of life and the frequency of exacerbations among patients with advanced COPD.8,31,34 Although patients with COPD treated with inhaled corticosteroids have a higher risk of developing pneumonia, no increase in pneumonia-related deaths is observed.32 Combination medications are available as ICS/LABA (fluticasone/salmeterol, budesonide/formoterol, and mometasone/formoterol), LABA/LAMA (vilanterol/umeclidinium, olodaterol/tiotropium, indacaterol/glycopyrrolate, formoterol/glycopyrrolate, formoterol/aclidinium), and ICS/LABA/LAMA (fluticasone/vilanterol/umeclidinium). A large multicenter trial (the TORCH trial) demonstrated that salmeterol added to fluticasone improves FEV1, exacerbation rate, and quality of life as compared with either drug alone, which is consistent with previous studies that examined the effects of adding inhaled corticosteroids to β2-agonists.35 A reanalysis of the TORCH trial data determined that the combination of salmeterol and fluticasone slowed the annual decline of FEV1, although salmeterol had similar benefit in this study when given alone.8 Combination LABA/LAMA therapy is more effective at preventing exacerbations than either of the singular components and decreases exacerbations more than LABA/ICS combinations.30 Trials of triple therapy (ICS/LABA/LAMA) versus monotherapy or dual therapy (ICS/LABA) have reported a significant and meaningful improvement in lung function and quality-of-life scores in patients using triple therapy.36 Triple therapy is also superior in reducing exacerbations compared to monotherapy or dual therapy.37,38

The phosphodiesterase inhibitor theophylline has moderate bronchodilation effects. It is available in sustained-release formulations for once- or twice-daily dosing. Theophylline has a narrow therapeutic window, however, and can cause serious adverse effects including cardiac arrhythmias and seizures, which may be the initial manifestations of toxicity.39 Theophylline is a third-line therapy for patients with inadequate responses to inhaled bronchodilators and for patients who cannot use inhaler therapy optimally. Target drug serum concentrations are in the range of 8 to 13 mg/dL, which is achieved in most patients with a 300- mg dose once daily at bedtime. Roflumilast is an oral phosphodiesterase-4 inhibitor that decreases inflammation and may promote smooth muscle relaxation.39 It has an FDA-cleared indication for the reduction of exacerbations in patients with chronic bronchitis, severe or very severe flow limitation, and a history of exacerbations. Whether roflumilast provides additional benefits when combined with other inhaled medications to reduce COPD exacerbation frequency is unknown. Short-term administration of systemic corticosteroids for 5 to 14 days has a role in managing patients with exacerbations of COPD, but for patients with stable COPD, no measurable benefit is achieved by longterm use of oral corticosteroids. Moreover, corticosteroid therapy causes multiple adverse effects. A trial of oral corticosteroids does not predict which patients with COPD will benefit from inhaled corticosteroids. Antibiotics are reserved for patients with COPD exacerbations characterized by fever, leukocytosis, purulent sputum, or chest radiographic changes consistent with bronchitis. Chronic use of antibiotics for stable patients does not preserve lung function or prevent exacerbations. If patients have frequent exacerbations despite optimal therapy for COPD including bronchodilators and anti-inflammatory agents, clinicians should consider prescribing antibiotic prophylaxis with the macrolide azithromycin.39,40 Mucokinetic agents are intended to reduce mucus viscosity and assist with the mobilization of airway secretions. In patients with COPD, however, these agents have marginal benefits. Thus, drugs such as iodinated glycerol and N-acetylcysteine are not recommended. In the largest study conducted to date, oral N-acetylcysteine did not demonstrate efficacy.41 Inhaled dornase alfa provides no benefit in COPD

and might result in worse outcomes. Therapy for AAT deficiency consists of alpha-1 protease inhibitor.17 Four commercial alpha-1 protease inhibitor preparations are available in the United States. These medications are administered intravenously to augment the serum and alveolar epithelial lining fluid concentrations of AAT. The current administration of once-weekly intravenous augmentation therapy is burdensome and costly for individuals living with and caring for patients with AAT deficiency. Augmentation therapy is used only for patients with AAT deficiency and not for those with other forms of COPD. Stop and Think You are asked to see a patient in the clinic who is having difficulty correctly using her COPD drugs. How would you assess for proper medication administration?

Long-Term Oxygen Therapy Long-term oxygen therapy (LTOT) for hypoxemic patients with COPD prolongs survival.42 Patients treated with LTOT for an average of 19 hours per day have a slower progression of pulmonary hypertension compared with those treated with 12 hours per day or less, suggesting a positive effect on pulmonary vasculature as the basis for improved survival. The Long-Term Oxygen Treatment Trial (LOTT)43 evaluated the benefit of O2 on all-cause mortality or hospitalization in patients with COPD with moderate resting SpO2 (89–93%) or exertional desaturation not exceeding 90%. In this study, the investigators did not find any benefit of O2 supplementation on the primary outcome of first hospitalization or death, or secondary outcomes of quality of life, depression, anxiety, or functional exercise performance. Patients are selected for O2 therapy on the basis of indications derived from clinical and laboratory findings (Box 33-4). Demonstration of hypoxemia should occur after a four-week period in which patients are stable, receive full medical therapy, and do not smoke. Subsequent monitoring of oxygenation is performed on an individual basis. Reassessment after several months of stability identifies an appreciable

portion of initially eligible patients who are no longer eligible for O2 therapy, thus reducing program costs to public funders without adverse consequences on quality of life, mortality, or other resource use.44 BOX 33-4 Indications for Long-Term Oxygen Therapy for Stable COPD Continuous Oxygen Therapy PaO2 ≤ 55 mm Hg or SpO2 ≤ 88% at rest while breathing room air PaO2 between 56 and 59 mm Hg or SpO2 of 89% at any time during breathing of room air with one or more of the following: Polycythemia (Hct > 56%) Pulmonary hypertension as evidenced by right heart dysfunction

Noncontinuous Oxygen Therapy PaO2 ≤ 55 mm Hg or SpO2 ≤ 88% during exertion or sleep while breathing room air

Stop and Think To what target SpO2 should oxygen be delivered during COPD exacerbation? Why?

Vaccinations Vaccinations are a central preventive measure in the management of patients with COPD. All caregivers interacting with patients should counsel them regarding their annual vaccination with trivalent influenza vaccine. All caregivers of patients with COPD should also receive the influenza vaccine. Pneumococcal vaccination is recommended for patients with COPD regardless of age.

Ventilatory Support The benefits of intermittent NIV in the outpatient management of patients with severe stable COPD have not been clearly defined. The purpose of ventilator support is to unload respiratory muscles and treat or prevent muscle fatigue. A systematic review of 15 studies of NIV observed that

six available randomized controlled trials (RCTs) demonstrated no improvement in gas exchange.45 By contrast, nine non-RCTs did report some clinical improvements, including health-related quality of life and dyspnea. The authors of the review concluded that a subset of patients on maximal medical treatment for severe stable COPD might benefit from NIV. The Medicare guidelines for reimbursement for NIV for patients with COPD are listed in Box 33-5. BOX 33-5 Guidelines for Medicare Reimbursement for Noninvasive Positive Pressure Ventilation in Patients with COPD 1. Symptomatic despite optimal medical therapy. 2. Abnormal gas exchange: a. PaCO2 ≥ 52 mm Hg and b. Nocturnal hypoventilation with SpO2 < 89% for ≥5 consecutive minutes while breathing usual FIO2 3. Obstructive sleep apnea excluded at least on clinical grounds. If obstructive sleep apnea exists, CPAP is indicated initially. 4. NIV can be considered with repeated hospital admissions for hypercapnic respiratory failure.

High-intensity NIV is an approach that uses high inspiratory pressure and a high backup rate with the goal of normalizing the patient’s PaCO2.46 An RCT reported improved survival of patients with stable COPD when healthcare providers used a high-intensity approach.33 Use of a high-flow nasal cannula (HFNC) in patients with stable COPD has attracted increasing attention from clinicians. One study reported that 6 weeks of treatment with HFNC (20 to 40 L/min) improved health-related quality of life and reduced hypercapnia in patients with stable hypercapnic COPD.47

Management of Sleep-Related Abnormalities Patients with COPD are at risk for sleep-related disorders characterized by poor sleep quality and worsening hypoxemia and hypercapnia at night.48,49 Although the prevalence of sleep-related disorders among patients with varying severity of COPD is unknown, many normoxic

patients with COPD develop oxyhemoglobin desaturation during sleep, and nearly half of hypercapnic patients with COPD experience a 10-mm Hg increase in PaCO2 at night.50 Many factors contribute to sleep-related breathing disorders in COPD, with alveolar hypoventilation being the predominant mechanism. Sleep-related increases in upper airway resistance, worsening of , and changes in O2 consumption, CO2 production, and cardiac output most likely have contributory roles. Alterations in sleep-related breathing patterns create greater changes in respiratory function for patients with COPD as compared with normal subjects because COPD patients have more physiologic dead space at baseline. Patients with COPD also have abnormal respiratory system mechanics—characterized by hyperinflation and diaphragmatic flattening —that amplify the effects of altered breathing patterns during sleep. Sleep-disordered breathing, including obstructive sleep apnea (OSA), and COPD are common in the general population, and many patients have both disorders. This overlap syndrome is associated with more severe nocturnal hypoxemia than either COPD or OSA alone.51 Patients with COPD and OSA have a greater risk of morbidity and mortality, compared to those with either COPD or OSA alone. Treatment consists of continuous positive airway pressure (CPAP) and O2 as needed. NIV may be helpful in patients with overlap syndrome but has not been well studied to date.

Pulmonary Rehabilitation Enrollment of patients with moderate to severe COPD in outpatient pulmonary rehabilitation programs provides opportunities to restore patients to the highest possible level of independence and functioning in the community. Components of an effective, multidisciplinary rehabilitation program include exercise training and conditioning, physical therapy, education for patients and family (e.g., nutrition, O2 use, inhaler techniques), instruction in airway clearance techniques, energy conservation, vocational counseling, and psychological support. A systematic review of evidence concluded that pulmonary rehabilitation is beneficial for patients with COPD.52

Airway Clearance Therapy Evidence supporting the use of airway clearance therapy in patients with stable COPD is either weak or lacking.53 Most patients with COPD are able to clear secretions without any additional therapy. If airway therapy is used, evidence does not show that any therapy is superior to the others. The GOLD report does not mention airway clearance therapy as a treatment option for stable COPD.2 Respiratory Recap Outpatient Care of the Patient with COPD ∎ Smoking cessation is indicated for all smokers. ∎ Encourage exercise and vaccinations for all patients. ∎ Provide drug therapy for symptomatic patients, with additional drugs being prescribed as functional impairment worsens. ∎ Long-term O2 therapy improves survival. ∎ NIV improves outcomes for exacerbations; the benefit of its chronic use in stable patients is uncertain. ∎ Sleep-disordered breathing should be considered. ∎ Pulmonary rehabilitation is beneficial. ∎ Evaluate patients with advanced disease for surgical and bronchoscopic options.

Surgery and Bronchoscopic Interventions Giant Bullectomy Giant bullae represent an unusual complication of emphysema that can cause pulmonary decompensation as bullae expand and compress adjacent functioning lung tissue. Patients are selected for bullectomy by estimating the degree of lung compression and the functional status of the compressed lung to determine the amount of improvement that bullectomy may provide. Patients with giant bullae who have limited amounts of potentially functioning compressed lung tissue, called vanishing lung syndrome, will not gain any benefit from bullectomy. CT scans can assess the size of bullae, the amount of compressed lung, and the severity of diffuse emphysema. Pulmonary function tests (PFTs) determine the severity of underlying emphysema. Appropriate candidates for surgery will have a restrictive (rather than obstructive) PFT pattern because of lung compression by the bullae. A severe obstructive pattern suggests the presence of advanced diffuse emphysema that will not improve with bullectomy. To calculate the gas volume of giant bullae, subtract the total lung volume (TLC) determined by helium dilution (which does not measure the volume of bullae) from the TLC measured by plethysmography (which includes the volume of bullae).

Lung Volume Reduction Surgery Lung volume reduction surgery (LVRS) refers to surgical resection of the regions of lung tissue most severely affected by emphysema. After removal of 20% to 30% of an emphysematous lung, the remaining lung expands beyond its previous boundaries and gains increased recoil elasticity. The lung, chest wall, and diaphragm demonstrate improved mechanics, with higher expiratory flow and less air trapping.54,55 The National Emphysema Treatment Trial (NETT) reported improved short-term outcomes in carefully selected patients with COPD.56 Patients with a heterogeneous upper lobe distribution of emphysema and low exercise capacity experienced improved long-term survival following LVRS as compared with continued medical therapy. Patients without

these preoperative characteristics did not benefit from LVRS and had either worse or similar survival as compared with medical management. In secondary subgroup analyses, patients with upper lobe distribution of emphysema and poor exercise capacity had improved quality of life and exercise capacity. Improved lung function and gas exchange for some patients has been reported to last as long as 24 to 36 months after surgery.57 Complications of LVRS include prolonged air leak, pneumonia, respiratory failure, postoperative ileus and colonic or cecal perforation, and cardiac ischemia.

Lung Transplantation COPD is the most common indication for lung transplantation. In the absence of contraindications, patients are selected for transplantation if they have advanced COPD with an estimated survival of less than 2 years. It is difficult to estimate the survival of individual patients, but markers of high near-term mortality include an FEV1 less than 25% to 30% of predicted, a rapid decline in lung function, and severe hypoxemia, hypercapnia, and secondary pulmonary hypertension despite maximal medical therapy. Both single- and double-lung transplantations are performed for COPD, but single-lung procedures occur most commonly because of the limited availability of donor lungs. Similar postoperative exercise functional capacities result from either procedure, but data suggest improved survival with double-lung transplantation. Double-lung transplantation also produces greater improvement in spirometric measures. Coexistence of bronchiectasis with associated purulent airway secretions requires double-lung transplantation to prevent infection of the allograft. Single-lung transplantation is usually performed through a lateral thoracotomy incision, whereas bilateral lung transplantation typically involves a median sternotomy or transverse thoracosternotomy clamshell incision. Bilateral lung transplantation may require cardiopulmonary bypass in 20% of patients. The 1-year survival rate for patients undergoing lung transplantation for COPD is 90%, with 1-year survival rates ranging from 40% to 50%. Although lung transplantation in COPD has not been subjected to randomized trials to determine its effect on survival, analyses of

retrospective data controlled for independent risk factors of death indicate improved survival compared with patients with severe COPD who have not received transplants. In contrast, some other retrospective analyses have reported similar survival for patients who received lung transplants and those who remained on the transplant list. The primary rationale for lung transplantation centers on improvement of functional status and quality of life rather than survival benefits. Patients experience improved pulmonary function, exercise capacity, and quality of life after transplantation. Complications of lung transplantation may include infection, early allograft dysfunction that may progress to acute lung injury, hemorrhage, dehiscence of the bronchial anastomoses, and acute and chronic lung rejection. The development of acute postoperative allograft edema that requires mechanical ventilation in patients who have undergone singlelung transplantation complicates ventilator management. The overexpansion of the highly compliant native lung compared with the lowcompliant allograft may necessitate independent lung ventilation with a double-lumen endotracheal tube.

Bronchoscopic Interventions Some patients are not candidates for surgical treatment but might benefit from bronchoscopic interventions (Figure 33-13).54 These procedures include bronchoscopic insertion of endobronchial valves. Endobronchial valves utilize unidirectional air flow to collapse regions of the lung with heavy emphysema involvement.

FIGURE 33-13 Overview of surgical and bronchoscopic treatments for COPD. Abbreviations: BLVR, Bronchoscopic Lung Volume Reduction; EBV, Endobronchial Valve; LVRS, Lung Volume Reduction Surgery; LVRC, Lung Volume Reduction Coil; VA, Vapor Ablation. Reproduced from Gold teaching slide test, https://goldcopd.org/gold-teaching-slide-set.

Description A multicenter RCT evaluated the effectiveness and safety of the Zephyr endobronchial valve in patients with heterogeneous emphysema with little to no collateral ventilation in the treated lobe.58 The Zephyr valve provided clinically meaningful benefits in lung function, exercise tolerance, dyspnea, and quality of life for at least 12 months, with an acceptable safety profile in patients with little or no collateral ventilation in the target lobe. The Chartis Pulmonary Assessment System is used to measure interlobar collateral ventilation during bronchoscopy. Chartis consists of a balloon catheter, combined with flow and pressure sensors. The balloon is placed in the target lobe orifice to block the airway and direct flow through its central lumen. A valve in the console allows only expiratory flow, simulating complete valve occlusion of the target lobe. Continuous expiratory flow greater than 5 minutes, or a total exhaled volume greater than 1 L, suggests refilling of the lobe through collateral channels, whereas gradual decline followed by eventual cessation of flow suggests

the absence of collateral ventilation.

Managing Exacerbations Patients with COPD are at risk for exacerbations that may require hospitalization. A COPD exacerbation is an acute worsening of respiratory symptoms that requires additional therapy. Viral respiratory infections precipitate most exacerbations, but bacterial infection, environmental pollutants, and other undefined precipitants may also play a role.59 Severe exacerbations are frequent in patients with COPD and may lead to significant mortality depending on the severity of acute respiratory failure and the number of comorbid conditions.60 Recognition of the importance of severe exacerbations is an essential step in improving outcomes for patients with COPD.61 Exacerbations may be mild and respond to outpatient modifications of therapy, or they may become severe and require ventilatory support. Mild exacerbations can be managed with home therapy in the absence of severe COPD, clinically important acute or chronic comorbidities, or other factors that increase the risk of hypercapnic respiratory failure. Patients should be encouraged to maintain adequate fluid intake to avoid dehydration and should monitor their ability to cough and raise secretions. Patients will benefit from a written action plan to manage their medications and alert them to when they should contact their physician or go to the emergency department. In the event of an exacerbation, inhaled SABA should be increased to their maximum dosages. An inhaled SAMA can be added to the medication regimen if the patient is not already taking one, although evidence of the efficacy of combined therapy in exacerbations is not consistent. SABAs, but not LAMAs, may transiently worsen hypoxia through pulmonary vascular effects. The role of antibiotics in mild exacerbations remains uncertain because of the heterogeneity of existing clinical trial designs. At least one-third of respiratory infections that underlie exacerbations are viral in etiology and, therefore, would not be expected to respond to antibiotics. Nevertheless, a meta-analysis concluded that antibiotics reduce mortality and treatment failures in those patients who require hospitalization.62 The American Thoracic Society (ATS) guidelines recommend initiation of antibiotics for COPD exacerbations.63 An oral antibiotic should be

selected that has activity against the common pathogens in COPD exacerbations—namely, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Patients with severe COPD are at risk for infection with gram-negative bacteria, including Pseudomonas aeruginosa. A systematic review observed equivalent clinical outcomes between drug trials that compared quinolones, macrolides, and amoxicillin-clavulanate.64 Prednisone therapy may provide for a more rapid and greater degree of improvement in oxygenation and FEV1 and fewer treatment failures in patients with exacerbations. Guidelines recommend a dose of 40 mg of prednisone per day for 5 days.2 Oral corticosteroids are as effective as intravenous administration, and ICS might be effective in some patients, including therapies utilizing the increased intensity of combination ICS/LABA.2 Severe exacerbations may occur in patients with moderate, severe, and very severe COPD and commonly alter gas exchange, which may result in acute respiratory failure. In such a case, baseline worsens, intrapulmonary shunts develop, and hyperinflation increases with the onset or worsening of auto-PEEP. These pathophysiologic factors require careful evaluation of patients regarding the need for hospitalization or admission to the ICU. The inpatient mortality of patients hospitalized for COPD exacerbations remains substantial, ranging from 6% to 30%.62 Markers of increased mortality include advanced age, need for mechanical ventilation, ventricular dysrhythmia, atrial fibrillation, acute or chronic cardiac disease, associated nonpulmonary organ failure, high APACHE (Acute Physiology and Chronic Health Evaluation) III score, poor nutritional status, poor baseline health status, and an alveolar–arterial O2 gradient on room air greater than 40 mm Hg or a low PaO2/FIO2. Alternative diagnoses (Box 33-6) should be considered and excluded if suggestive findings exist. Of note, 25% of patients with COPD hospitalized for severe exacerbations of uncertain etiologies have pulmonary emboli. BOX 33-6 Conditions That May Simulate a COPD Exacerbation Pneumonia

Pulmonary emboli Myocardial infarction or ischemia Congestive heart failure Dysrhythmia Pneumothorax Aspiration Neuromuscular weakness Rib or vertebral body fractures Metabolic acidosis or other electrolyte disturbance Pleural effusion Sedating drugs or beta-blocking drugs Inappropriate use of O2 with hyperoxia and retained CO2 Other organ dysfunction, such as renal failure or gastrointestinal hemorrhage

Severe exacerbations should prompt acceleration of the outpatient therapy. Supplemental O2 should be administered routinely and titrated to a flow to maintain PaO2 at greater than 60 mm Hg and SpO2 at greater than 90% (Figure 33-14). Sampling of arterial blood gases is indicated within 30 to 60 minutes to ensure adequate oxygenation and the absence of progressive hypercapnia. Either a nasal cannula or an air entrainment mask is an acceptable O2 delivery device, depending on patient tolerance.

FIGURE 33-14 Algorithm for the management of supplemental O2 in patients hospitalized for an exacerbation. ABGs, arterial blood gas values; PaCO2, partial pressure of arterial carbon dioxide; SpO2, arterial O2 saturation by pulse oximetry.

Description

A meta-analysis of randomized trials did not support the use of methylxanthine bronchodilators, such as aminophylline or theophylline, for the treatment of COPD exacerbations.65 Administration of methylxanthines was noted to increase the adverse events of nausea and vomiting, without demonstrating any improvement of respiratory endpoints. The GOLD guideline, however, recommends methylxanthines as second-line therapy for patients who have inadequate response to SABAs.2 Hospitalized patients with exacerbations may present with acute respiratory failure or develop respiratory failure after initial medical management. A common scenario occurs when patients with moderate to severe airway obstruction increase their E and work of breathing in response to increased airways resistance due to worsening airway inflammation, edema, bronchospasm, and secretions. The increasing respiratory rate shortens expiratory time and causes dynamic hyperinflation and auto-PEEP. Other factors—such as pulmonary hypertension, poor nutrition with muscle weakness, disadvantageous chest wall mechanics from hyperinflated lungs, and baseline hypercapnia —may lower ventilatory reserve. As work of breathing continues to increase, the patient develops fatigue, and acute respiratory failure ensues. Patients with acute respiratory failure have fatigued respiratory muscles and may benefit from ventilatory assistance. Goals of assisted ventilation include unloading of respiratory muscles to allow recovery from muscle fatigue, reduction of air trapping, and maintenance of PaCO2 at or near the patient’s baseline. Many patients develop acute respiratory failure in the setting of chronic compensated respiratory acidosis. For this reason, the clinician should adjust ventilatory support to the patient’s baseline PaCO2, which can be estimated by the patient’s serum bicarbonate level at admission or during a previous period of stability. Overventilation to a normal PaCO2 if the patient is chronically hypercapnic will result in renal loss of bicarbonate and uncompensated respiratory acidosis when the patient returns to the baseline level of hypercapnia during discontinuation of ventilatory support. NIV is considered first-line therapy for COPD exacerbation. In a metaanalysis, this approach yielded a survival benefit in patients with COPD exacerbation.66 Clinical practice guidelines recommend the following:67

NIV should not be used in patients with hypercapnia who are not acidotic in the setting of a COPD exacerbation. NIV should be used for patients with acute or acute-on-chronic respiratory acidosis (pH ≤ 7.35) due to COPD exacerbation. A trial of NIV should be considered in patients who require endotracheal intubation and mechanical ventilation, unless the patient is immediately deteriorating. NIV should be considered when pH ≤ 7.35, PaCO2 > 45 mm Hg, and respiratory rate > 24 breaths/min despite standard medical therapy. NIV is the preferred intervention for patients with COPD who develop acute respiratory acidosis during hospital admission. There is no lower limit of pH below which a trial of NIV is inappropriate; however, the lower the pH, the greater the risk of failure. Patients must be very closely monitored, with rapid access to endotracheal intubation and invasive ventilation being implemented if they do not improve. NIV may be delivered with either an oronasal mask, a total face mask, or a nasal mask. A comfortable mask fit is important for patient adherence. Patients who fail NIV or have immediately life-threatening respiratory failure (severe hypoxemia, hypercapnia, hemodynamic instability, altered mental status, or impending apnea) require intubation and invasive mechanical ventilation. The role of HFNC during COPD exacerbation is unclear. Although HFNC is often more comfortable for patients compared to NIV, whether it is equally effective remains unknown. The low level of expiratory pressure might counterbalance auto-PEEP in patients with COPD, and the flushing of CO2 from the upper airway may reduce the minute ventilation requirement. Whether this translates into an outcome benefit is unknown. Some patients poorly tolerate NIV, and HFNC might be useful when patients are given short breaks off of NIV.68 The clinician should adjust the mode of ventilation, VT, respiratory rate, and inspiratory flow rate to ensure that the patient’s fatigued respiratory muscles are adequately unloaded and dynamic hyperinflation improved or eliminated (Box 33-7). The greatest risks associated with invasive ventilation in patients with COPD are air trapping and autoPEEP. These effects result in alveolar overdistention (increased plateau pressure), patient–ventilator asynchrony, barotrauma (e.g.,

pneumothorax), and hemodynamic instability. and hemodynamic instability. Overdistention increases dead space, which may paradoxically increase PaCO2 with further increases in E. Auto-PEEP also increases inspiratory effort due to the negative intrathoracic pressure necessary to trigger the ventilator. BOX 33-7 Guidelines for Ventilator Settings for Patients with COPD Set the respiratory rate low, at 12–15 breaths/min. Set the tidal volume at 6–8 mL/kg. Set FIO2 to achieve an SpO2 of 90% to 92%. Adjust PEEP to manage ventilator triggering and auto-PEEP. Set the peak flow high to provide adequate expiratory time. Avoid over-ventilation and target the baseline PaCO2. The clinician can choose either volume-control or pressure-control; no high-level evidence indicates that one is superior to the other. Monitor auto-PEEP, peak pressure, and plateau pressure. Consider early extubation to NIV. FIO2, fraction of inspired O2; PaCO2, partial pressure of arterial CO2; PEEP, positive endexpiratory pressure.

The clinician should set the ventilator so as to minimize auto-PEEP.69 The respiratory rate, VT, inspiratory flow waveform, and inspiratory-toexpiratory (I:E) ratio should allow for a sufficient expiratory time. Some patients with extreme air trapping require sedation and paralysis to allow tolerance of a low respiratory rate that provides a longer expiratory time and permits less air trapping. In the presence of auto-PEEP, the patient must produce enough effort to overcome the auto-PEEP before the ventilator triggers (Figure 33-15). Application of PEEP may counterbalance auto-PEEP and make it easier to trigger the ventilator. without contributing to over-distention (Figure 33-16) For an intubated patient with COPD and missed trigger efforts, the clinician should increase the PEEP until the patient can comfortably trigger the ventilator, as illustrated in Figures 33-15 to 33-17. In the presence of auto-PEEP, flow trigger and pressure trigger will be equally ineffective until the patient can generate enough effort to overcome the auto-PEEP and meet the pressure or flow trigger set on the ventilator.

FIGURE 33-16 In the presence of auto-PEEP with flow limitation, the addition of external PEEP counterbalances auto-PEEP and decreases the effort required to trigger the ventilator.

Description

FIGURE 33-15 Waveforms of flow, airway pressure, and esophageal pressure in an intubated patient with severe COPD. The arrows indicate the presence of missed triggers. Note the upward

deflection in the expiratory flow waveform with each missed trigger.

Description

FIGURE 33-17 Flow and pressure waveforms in an intubated patient with severe COPD. With PEEP set at zero (top), the end-expiratory hold indicates about 10 cm H2O of auto-PEEP. When the PEEP is increased to 8 cm H2O (bottom), there is no change in peak inspiratory pressure or plateau pressure, suggesting that the external PEEP is counterbalancing auto-PEEP.

Description Pressure support can result in trigger or cycle asynchrony in patients

with COPD.70 Trigger asynchrony results from auto-PEEP, whereas cycle asynchrony is due to the flow cycle setting. With high airways resistance (e.g., COPD), the rate of flow decreases slowly with pressure support. The result is a prolonged inspiratory time unless the flow cycle criterion is increased. Thus, the clinician should set the flow cycle to greater than the usual 25% to prevent a prolonged inspiratory phase and active exhalation to terminate the inspiratory phase. Patients with COPD exacerbation who require intubation might benefit from 24 to 48 hours of full support. After that, ventilator liberation can be assessed with a spontaneous breathing trial (SBT). Because continuous positive airway pressure can counterbalance auto-PEEP and pressure support unloads respiratory muscles, the SBT is ideally performed without CPAP or pressure support. Because patients with COPD are at risk for extubation failure, it is recommended that they be extubated to NIV.67 If the SBT is performed with pressure support and/or CPAP, the patient should be extubated to NIV. Respiratory Recap Goals of Invasive Mechanical Ventilation in the Patient with COPD ∎ Unload ventilatory muscles and allow the patient to rest and recover from fatigue. ∎ Provide an adequate expiratory time to avoid auto-PEEP and dynamic hyperinflation. ∎ Prevent overventilation and respiratory alkalosis. ∎ Prevent patient–ventilator asynchrony.

Respiratory Recap COPD Exacerbations ∎ Mild exacerbations can be managed at home. ∎ Inhaled β2-agonists are the first-line therapy. Inhaled anticholinergics may be added, but evidence of added benefit is limited. ∎ A 5- to 14-day course of systemic corticosteroids is standard practice. ∎ Antibiotics are used for patients with increased sputum volume or purulence and/or dyspnea. ∎ Titrate O2 to maintain an SpO2 of 90% without aggravating CO2 retention. ∎ NIV is useful in the management of COPD exacerbation.

∎ Life-threatening respiratory failure requires intubation and mechanical ventilation.

Readmissions One in five patients hospitalized for COPD exacerbation will require rehospitalization within 30 days.71 COPD is part of Medicare’s Hospital Readmissions Reduction Program, which penalizes hospitals for excess 30-day, all-cause readmissions after a hospitalization for COPD exacerbation. A number of interventions can be implemented to reduce readmissions, thereby avoiding the Medicare penalty: Patient self-management Inhaler device training Outpatient follow-up within 30 days after discharge Pulmonary rehabilitation Telehealth Filling of all respiratory medications prior to hospital discharge Pharmacist-supervised medication reconciliation Note that many of these interventions represent an opportunity for respiratory therapists.72,73 In one hospital, a respiratory therapist COPD disease management program was associated with fewer readmissions, fewer ICU days, and shorter hospital stays with exacerbations.73

Palliative and End-of-Life Care Patients with COPD experience progressively worsening symptoms and quality of life as their disease becomes more severe. Palliative care provides opportunities to prevent and relieve suffering by managing symptoms and providing support to both patients and their families. Caregivers of patients with COPD should understand the rationale for palliative care and have a willingness to consult with palliative care specialists to assist with special patient needs. Most patients hospitalized for COPD exacerbations survive to hospital discharge. A subgroup of patients, however, present with acute respiratory failure as the terminal event. Intubation and life support are burdensome for this group of patients and may prolong their dying process. Unfortunately, clinical and laboratory findings at the time of admission cannot discriminate between those patients who will survive their hospitalization and those who will not recover. In such circumstances, clinicians should have a clear understanding of their patients’ end-of-life wishes and decisions about the withdrawal of life support. Patients can formulate their own decisions about the acceptability of life support by blending their life goals and values with their physicians’ estimates of anticipated outcome from life support interventions. This process centers on a patient’s ability to provide informed decision making and requires an ongoing dialogue among patients, families, and caregivers. Patients with severe COPD who choose to forgo life-supportive care in the terminal phases of their disease need continuous reassurance from all caregivers that they will not be medically or emotionally abandoned. Intensive comfort care and close monitoring to detect a need for aggressive pain, anxiety, and dyspnea relief are fundamentally important. In such settings, the principle of double effect ethically, morally, and legally allows the administration of sufficient sedatives and analgesics to relieve pain and suffering even if drug therapy accelerates the patient’s death, as long as the intent is to relieve suffering.74 COPD is recognized as a condition warranting hospice services by the National Hospice Organization, which has published guidelines to identify patients who qualify for hospice care (Box 33-8).

BOX 33-8 Parameters to Identify Patients Who Qualify for Hospice Services Patients will be considered to be in the terminal stage of pulmonary disease (life expectancy of 6 months or less) if they meet the following criteria. 1. Severe chronic lung disease as documented by both: a. Disabling dyspnea at rest, poor response, or unresponsive to bronchodilators, resulting in decreased functional capacity (e.g., bed-to-chair existence), fatigue, and cough. (Documentation of FEV1, after bronchodilator, less than 30% of predicted is objective evidence for disabling dyspnea, but is not necessary to obtain.) b. Progression of end-stage pulmonary disease, as evidenced by increasing visits to the emergency department or hospitalizations for pulmonary infections and/or respiratory failure or increasing physician home visits before initial certification. (Documentation of a serial decrease of FEV1 > 40 mL/year is objective evidence for disease progression but is not necessary to obtain.) 2. Hypoxemia at rest on ambient air, as evidenced by PaO2 less than or equal to 55 mm Hg; or SpO2 less than or equal to 88% on supplemental O2 as determined by either arterial blood gases or SpO2; or hypercapnia, as evidenced by PaCO2 ≥ 50 mm Hg. These values may be obtained from recent (within 3 months) hospital records. 3. Right heart failure secondary to pulmonary disease (cor pulmonale) (e.g., not secondary to left heart disease or valvulopathy). 4. Unintentional progressive weight loss of greater than 10% of body weight over the preceding 6 months. 5. Resting tachycardia > 100/min. Adapted from Lanken PN, Terry PB, Delisser HM, Fahy BF, Hansen-Flaschen J, Heffner JE, et al. An official American Thoracic Society clinical policy statement: palliative care for patients with respiratory diseases and critical illnesses. Am J Respir Crit Care Med 2008;177(8):912–927. Reproduced with permission of the American Thoracic Society. Copyright © American Thoracic Society.

Case Studies Case 1. Initial Presentation of Chronic Obstructive Pulmonary Disease During a routine physical examination, a 62-year-old woman complains of increasing shortness of breath with exertion. She has a 40-year smoking history and presently smokes one pack of filtered cigarettes per day. She reports occasional nonproductive cough but denies ever having symptoms compatible with a COPD exacerbation. Physical examination reveals bilateral breath sounds with no adventitious sounds. Respiratory rate and pattern are normal at rest. No cyanosis or edema is present, and the remainder of the history and physical examination are unremarkable. She is referred to the pulmonary clinic for consultation, pulmonary function testing, and arterial blood gas analysis. Results of pulmonary function testing are an FVC of 2.10 L (80% predicted), FEV1 of 1.20 L (65% of predicted), and FEV1/FVC of 58%. After administration of an inhaled β2-agonist, the patient’s FEV1 increases to 1.35 L (73% of predicted). Lung volumes (residual volume, functional residual capacity, and total lung capacity) reveal mild hyperinflation. Single-breath DLCO is 70% of predicted. Arterial blood gases when breathing room air are pH 7.42, PaCO2 39 mm Hg, and PaO2 72 mm Hg. A chest radiograph is unremarkable, other than the suggestion of mild hyperinflation. The patient is counseled about the importance of stopping smoking and referred to a smoking cessation program. She receives influenza and pneumococcal vaccinations. A SABA/SAMA combination is prescribed every 4 to 6 hours as needed to relieve symptoms, and the patient is told to use the SABA/SAMA before exertion. A respiratory therapist instructs the patient in the proper use of SABA/SAMA by Respirmat. Pulmonary rehabilitation is arranged. The patient is scheduled for a follow-up at 2 months to evaluate her symptoms and exercise capability after smoking cessation and rehabilitation. If she remains exercise limited, a long-acting SABA or SAMA will be prescribed to improve her symptoms and quality of life and to prevent exacerbations.

Case 2. Exacerbation of Chronic Obstructive Pulmonary Disease A 72-year-old man with a history of severe COPD is admitted to the emergency department with progressively increasing dyspnea over the past 48 hours. He uses continuous home O2 at 2 L/min. He also uses an inhaled SABA, LABA/ICS, and LAMA. His sputum became purulent 3 days ago, and his primary care physician prescribed antibiotic therapy (azithromycin). The patient has a respiratory rate of 30 breaths/min with use of accessory muscles and pursed-lip exhalation. Breath sounds are distant, but no adventitious sounds are present. The chest is hyperinflated. Mild neck vein distention and ankle edema are present. The electrocardiogram is normal, with the exception of a mild tachycardia (110 beats/min). The patient appears dyspneic, but he cooperates with the physical examination. Arterial blood gas values are obtained with the patient breathing O2 at 2 L/min: pH 7.28, PaCO2 78 mm Hg, and PaO2 52 mm Hg. A nebulizer treatment has been administered with SABA/SAMA. Prednisone is given at a dose of 40 mg, and an antibiotic (moxifloxacin) is started. NIV is initiated. An oronasal mask is necessary because of the patient’s dyspnea and inability to maintain a closed mouth. After 30 minutes of ventilation, the patient’s accessory muscle use decreases, his respiratory rate improves, and he reports his dyspnea has improved. Inspired O2 is titrated to maintain an SpO2 of 88% to 90%. Preparations are made to admit the patient to the ICU. Two hours later, the patient is in the ICU. He continues on NIV but appears more comfortable. Arterial blood gas values at this time are pH 7.36, PaCO2 65 mm Hg, and PaO2 66 mm Hg. Four hours later, the patient asks to have the mask removed. He initially appears comfortable, but after 1 hour he has increasing dyspnea and accessory muscle use. NIV is resumed at the previous settings, but with the use of a nasal mask instead of the oronasal mask. This pattern of failed attempts to discontinue NIV continues for the next 36 hours, at which time the patient remains comfortable after removal of the mask. Six hours after discontinuation of NIV, the patient’s arterial blood gas values when breathing 2 L/min of O2 by nasal cannula are pH 7.37, PaCO2 60 mm Hg, and PaO2 62 mm Hg. The patient is transferred from

the ICU to a general ward. The following day, he continues to do well, and plans are made for discharge home. Options related to future exacerbations are discussed with the patient and his wife. He decides that NIV may be used for future exacerbations, but he elects not to be intubated or receive other resuscitative measures if he fails NIV. He completes a living will and advance directive for healthcare and ensures that his healthcare providers have future access to this information.

Key Points Chronic obstructive pulmonary disease is a common cause of death in the United States, and its prevalence is increasing worldwide. Flow limitation defines the presence of COPD. In most patients, COPD is caused by smoking, and the prognosis of COPD is improved at any age with smoking cessation. Although existing clinical practice guidelines stage the severity of COPD based on FEV1, patients’ quality of life and prognosis relate more closely to multidimensional measures that assess both respiratory and systemic features of COPD. The GOLD guidelines categorize COPD based on symptoms and exacerbations. COPD is a treatable disease. Management is directed toward reducing symptoms and improving quality of life, reducing decline in lung function, preventing complications, preventing or minimizing adverse effects of therapy, and prolonging survival. Depending on disease severity, SAMA, SABA, LAMA, LABA, ICP, and combination therapies can be used to treat COPD. Smoking cessation prolongs life in patients with COPD. O2 therapy prolongs life in patients with COPD and severe hypoxemia. Pulmonary rehabilitation is an important part of COPD management. Surgical and bronchoscopic procedures may be beneficial in some patients. The role of NIV in patients with stable COPD is controversial. Corticosteroids, and often antibiotics, have a role in the treatment of COPD exacerbations. NIV improves outcomes of patients with COPD exacerbations. For patients requiring mechanical ventilation, the clinician should set the ventilator to minimize auto-PEEP. Palliative care and end-of-life planning are important components of the management of patients with all stages of COPD.

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CHAPTER

34 Interstitial Lung Disease Stephen P. Bergin Lake D. Morrison

© Andriy Rabchun/Shutterstock

OUTLINE Pathophysiology Classification Clinical Presentation and Diagnostic Evaluation Pathology Prognosis Management Selected Interstitial Lung Diseases

OBJECTIVES 1. Describe the precipitating causes, clinical manifestations, radiographic, laboratory, and pathophysiologic findings of interstitial lung disease. 2. Describe the spectrum of diseases associated with interstitial lung disease. 3. Review the prognosis of interstitial lung disease. 4. Describe the management of interstitial lung disease.

KEY TERMS

chronic hypersensitivity pneumonitis connective tissue disease (CTD) cryptogenic organizing pneumonia (COP) eosinophilic granuloma idiopathic pulmonary fibrosis (IPF) interstitial lung disease (ILD) pulmonary alveolar proteinosis (PAP) respiratory bronchiolitis sarcoidosis

Introduction Interstitial lung disease (ILD) encompasses more than 200 distinct diseases in which the interstitium is altered by some combination of inflammation and fibrosis. The interstitium of the lung includes the alveolar walls, pulmonary microvasculature, interstitial macrophages, fibroblasts, myofibroblasts, and matrix components of the lungs (Figure 34-1). The inflammatory and fibrotic derangements of ILD can affect any of these components. The resulting infiltration of the acinar region by cellular and extracellular elements may distort the alveolar and bronchiolar architecture (Figure 34-2).

FIGURE 34-1 Schematic of lung illustrating components of the interstitium.

Description

FIGURE 34-2 Micrographs showing (A) normal lung and (B) interstitial lung disease. In contrast to the normal lung, the interstitium is thickened with an accumulation of inflammatory cells. The stain is hematoxylin and eosin at a magnification of approximately 100.

ILD comprises an extremely diverse group of both acute and chronic disorders. Common clinical, radiographic, and pathophysiologic features form the basis for collective reference to this complex group of disorders as interstitial lung disease (Box 34-1). Most often the patient complains of dyspnea and cough, a chest radiograph shows abnormal markings, and lung function tests demonstrate a loss of function including decreased volumes and reduced diffusing capacity. To make the diagnosis of ILD, the clinician must integrate the patient’s clinical presentation, radiographic findings, pulmonary function test results, laboratory values, and sometimes lung biopsy findings. In many cases, a definitive diagnosis cannot be made without a biopsy. BOX 34-1 Key Diagnostic Features of Interstitial Lung Disease Dyspnea at rest and/or with exertion Bilateral interstitial infiltrates on chest radiograph Physiologic abnormalities of a restrictive lung defect: decreased lung volumes, decreased diffusing capacity for carbon monoxide (DLCO) Hypoxemia breathing room air at rest and/or with exertion Histopathologic features of inflammation and/or fibrosis of the pulmonary parenchyma

Pathophysiology A common sequence of events resulting in ILD begins when either a recognized or an unidentified insult induces alveolitis or vasculitis (Box 34-2). Persistence of this inflammatory state results in alveolar, capillary, and parenchymal cell injury. Cytokines released by cellular injury propagate the inflammatory response and trigger abnormal repair, leading to proliferation of mesenchymal cells and ultimately the production of excess collagen and other extracellular matrix connective tissue elements. Importantly, no single unifying pattern of histologic abnormality (other than abnormal interstitial space) is associated with ILD. Histologic findings vary significantly depending on the subtype of lung injury. Alterations of the interstitium may range from a highly cellular inflammatory infiltrate with little fibrosis to a complex fibrotic and relatively acellular abnormality. In the advanced stages of ILD, the normal architecture of the lung may be replaced by cystic spaces separated by thick bands of fibrous tissue, a condition called honeycomb lung. BOX 34-2 Pathophysiology of Interstitial Lung Disease

Although the end stage of the lung injury is histologically similar in many types of ILDs, the alveolitis stage often has distinctive characteristics because of the number and influence of various inflammatory and immune effector cells present, such as neutrophils, eosinophils, and lymphocytes. Oxidants (generated both exogenously and endogenously) and neutrophil proteases (e.g., elastase, collagenase, and cathepsins) are assumed to mediate some portion of tissue injury in many of these disorders. The alveolar macrophage has been implicated in the coordination of this injury because of its release of reactive oxygen species, chemoattractants for neutrophils, and growth factors for mesenchymal cells, including fibronectin, platelet-derived growth factor, and insulin-like factor 1, which are involved in the progression to fibrosis. Nevertheless, cells other than alveolar macrophages residing in the lower respiratory tract have a similar capacity to elaborate these same mediators and coordinate an inflammatory and fibrotic response to numerous agents.

Classification A universally accepted classification system for ILD has not been developed, and consensus guidelines continue to evolve as new research becomes available.1 For practical and therapeutic purposes, it is helpful to categorize the disorders based on the presence (or not) of an identified exogenous cause or associated connective tissue disease (Box 34-3). It is also important to rule out causes of diffuse parenchymal lung disease that mimic ILD (Box 34-4). BOX 34-3 Classification of Interstitial Lung Disease Exposure or Environmental Cause Inhalational exposure Inorganic dusts: silicosis, asbestosis, talcosis, berylliosis, coal worker’s pneumoconiosis, siderosis, baritosis Microbial antigens: farmer’s lung, humidifier lung, bird fancier’s lung, moldy/water damaged environment Fumes: lung injury from exposure to chlorine gas, sulfuric acid, hydrochloric acid, nitrogen dioxide, or ammonia Cigarette smoke: eosinophilic granuloma, desquamative interstitial pneumonitis (DIP), or respiratory bronchiolitis ILD (RB-ILD) Drug toxicity Radiation exposure or prior radiotherapy treatment

Systemic Disease Association Connective tissue diseases Rheumatoid arthritis Systemic sclerosis Systemic lupus erythematosus (SLE) Idiopathic inflammatory myopathies (polymyositis and dermatomyositis) Sjögren disease Mixed connective tissue disease Vasculitides Granulomatosis with polyangiitis (GPA) Microscopic polyangiitis (MPA) Eosinophilic granulomatosis with polyangiitis (EGPA) Congenital and metabolic causes Lipoidoses: Gaucher disease, Niemann-Pick disease Storage disorders: Hermansky-Pudlak syndrome Amyloidosis Graft-versus-host disease (hematopoietic stem cell transplant recipients) Tuberous sclerosis

Ataxia telangiectasia

Unknown Cause Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Acute interstitial pneumonia Idiopathic pulmonary fibrosis Sarcoidosis Idiopathic pulmonary hemosiderosis Cryptogenic organizing pneumonia Pulmonary alveolar proteinosis Lymphangioleiomyomatosis (LAM)

BOX 34-4 Mimics of Interstitial Lung Disease Infection Bacteria (Legionella pneumophila, Bordetella pertussis, Mycoplasma species, Mycobacterium species) Viruses (cytomegalovirus, human immunodeficiency virus, respiratory syncytial virus, adenovirus, influenza, parainfluenza, measles) Fungi (Aspergillus species, Pneumocystis jirovecii pneumonia) Parasites Neoplasm Bronchoalveolar cell carcinoma Leukemia Hodgkin disease Non-Hodgkin lymphoma Lymphangitic carcinomatosis Congestive heart failure Chronic aspiration Lipoid pneumonia Bronchiolitis

An alternative method for classification of ILD is based on the pattern of histologic lung parenchymal abnormality or the presence (or not) of granulomatous inflammation, although this method of classification is very limited by substantial disease overlap. For example, the systemic connective tissue disease rheumatoid arthritis can manifest as ILD with patterns of usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and organizing pneumonia (OP). Additionally, many exposures and underlying disorders are associated with each specific histologic pattern of ILD. UIP can be caused by drug toxicity, connective

tissue diseases (e.g., systemic sclerosis, polymyositis), or, if no underlying cause is identified, idiopathic pulmonary fibrosis (IPF).

Clinical Presentation and Diagnostic Evaluation Symptoms and Signs Although some forms of ILD can present in an acute fashion, the most common presentation of ILD is the insidious onset of slowly progressive dyspnea and a nonproductive cough. Dyspnea is present only with exertion at first but may progress to dyspnea at rest. The history is the most important tool in identifying a cause of ILD. A thorough history limits the differential diagnosis and may preclude the need for biopsy. Despite a detailed history, a causative agent or systemic disease association is not identified in at least one-third of ILD patients.2 To determine the cause of the ILD, the clinician must ask detailed questions and note specific symptoms. The clinician should compile a list of all medications the patient has been taking in an effort to detect drugrelated causes of ILD. A detailed medication history should focus on prior exposure to chemotherapy, chronic antibiotics, and antiarrhythmic agents. A detailed occupational history can help define exposures to dusts, fumes, and antigens associated with ILD. Note any hobbies and environmental exposures (e.g., pigeon breeding, home saunas, contaminated heating and air-conditioning units) that may be associated with the disease. Knowledge of the agents that can cause ILD can serve as a guide to the areas that should be emphasized in the occupational and environmental history. Ask the patient about use of illicit recreational drugs, as these agents may contribute to the development of ILD. In addition, evaluate the patient for risk factors for infection with the human immunodeficiency virus (HIV). The review of systems must include attention to systemic symptoms such as fevers, chills, night sweats (e.g., hypersensitivity pneumonitis, vasculitis), arthralgia and myalgia (ILD associated with connective tissue disorders), sinusitis, and hemoptysis (vasculitis and alveolar hemorrhage syndromes). The medical history should specifically include questions about prior pneumothorax. Review the family history carefully for any inherited disorders known to cause ILD, such as IPF, tuberous sclerosis, and rheumatoid arthritis. A history of cigarette smoking is important in the pathogenesis of some ILDs, especially eosinophilic granuloma,

desquamative interstitial pneumonitis, and respiratory bronchiolitis-ILD. The physical examination is frequently less helpful than the history in determining a specific diagnosis for a patient with ILD (Table 34-1). Bilateral, end-inspiratory, basilar crackles are a feature in many forms of ILD, including IPF, ILD with collagen vascular diseases, and drug toxicity. Wheezes are rare except in eosinophilic granulomatosis with polyangiitis (EGPA). Other findings on the physical examination can assist in the differential diagnosis. Patients who have experienced severe disease for a protracted period may show evidence of pulmonary hypertension and right heart failure on the physical examination. TABLE 34-1 Physical Examination Findings with Interstitial Lung Disease Finding

Associated Disease

Digital clubbing

Idiopathic pulmonary fibrosis

Cutaneous lesions

Sarcoidosis, tuberous sclerosis, systemic vasculitis, dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis

Ocular signs

Sarcoidosis, ILD in systemic vasculitis, ILD with Sjögren syndrome or other connective tissue disorders

Polyarthritis

Sarcoidosis, ILD in systemic vasculitis, ILD with Sjögren syndrome, rheumatoid arthritis, or other connective tissue disorders

Peripheral lymphadenopathy

Sarcoidosis, lymphoid interstitial pneumonia, ILD with connective tissue disorders

Hepatosplenomegaly

Sarcoidosis, amyloidosis, eosinophilic granuloma, chronic cor pulmonale from advanced ILD

Neurologic manifestations

Tuberous sclerosis, systemic vasculitis, sarcoidosis, eosinophilic granuloma

ILD, interstitial lung disease.

Respiratory Recap

Clinical History for Evaluation of Interstitial Lung Disease ∎ Dyspnea on exertion or at rest ∎ Cough ∎ Fevers, chills, and night sweats ∎ Medications taken ∎ Detailed work history ∎ Hobbies ∎ Environmental exposures ∎ Risk factors for infection with the human immunodeficiency virus (HIV) ∎ History of pneumothoraces ∎ Family history of interstitial lung disease ∎ Cigarette smoking

Pulmonary Function Testing The initial evaluation of pulmonary function in the patient with ILD should include spirometry, measurement of lung volumes and diffusing capacity (DLCO), maximum voluntary ventilation, exercise oxygen saturation, and occasionally arterial blood gas measurements. These studies characteristically reveal restriction with a decreased forced vital capacity (FVC), a decreased forced expiratory volume in the first second (FEV1), and a normal or increased FEV1/FVC ratio. Total lung capacity (TLC) and the DLCO are decreased. Note that the DLCO can sometimes be the most sensitive pulmonary function measure and may be abnormal even when lung volumes are preserved.3 Many patients with ILD demonstrate a mild resting hypoxemia with significant arterial oxygen desaturation after exercise. The resting hypoxemia is the result of both ventilation–perfusion mismatch and shunt; the worsening of the condition with exercise may reflect diffusion restrictions in addition to mismatch and shunt. In patients with normal lung volumes or spirometry results, desaturation with ambulation may be a clue to the presence of pulmonary fibrosis or comorbid pulmonary vascular disease. A 6-minute walk test with pulse oximetry is well tolerated, provides a measure of oxygen requirements, and can be a quantifiable index of disease progression.4 Pulmonary function test results reflecting airway obstruction are

sometimes seen in sarcoidosis, hypersensitivity pneumonitis, eosinophilic granuloma, granulomatosis with polyangiitis, and lymphangioleiomyomatosis (LAM).

Radiographic Findings The classic findings of ILD on a posteroanterior chest radiograph include a diffuse reticular, nodular, or reticulonodular pattern and reduced lung volume (Figure 34-3). Upper lobe predominance is seen in sarcoidosis, eosinophilic granuloma, silicosis, coal worker’s pneumoconiosis, eosinophilic pneumonia, and ILD with ankylosing spondylitis. Lower lobe predominance is found in IPF, ILD with many connective tissue diseases, and asbestosis. The presentation is usually bilateral and symmetric. The radiograph may include alveolar opacities rather than reticular abnormalities. In case of a long-standing disorder, the patient may have developed pulmonary hypertension, with suggestive changes being apparent on the chest radiograph. An array of abnormalities can be seen on the chest radiographs of patients with ILD, which sometimes assist in determining the differential diagnosis (Table 34-2).

FIGURE 34-3 Chest radiographs demonstrating predominantly rounded opacities in the upper lung fields consistent with silicosis (A). Contrast these opacities to the linear markings of asbestosis, which are most commonly observed in the lower lung fields (B).

TABLE 34-2

Radiographic Findings with Interstitial Lung Disease Finding

Associated Disease

Normal radiograph (10% of ILD cases)

Early stages of many forms of ILD

Spontaneous pneumothorax

Eosinophilic granuloma and LAM

Hilar or mediastinal lymphadenopathy

Sarcoidosis, berylliosis, and silicosis

Eggshell calcification

Silicosis

Pleural disease

Asbestos-related ILD, tuberculosis, ILD with connective tissue disease, malignancies, and LAM

Honeycombing

IPF, connective tissue disease–associated UIP, pneumoconioses, sarcoidosis

ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; LAM, lymphangioleiomyomatosis; UIP, usual interstitial pneumonitis.

High-resolution computed tomography (HRCT) is important in the diagnosis and staging of ILD. Thin sections (1.25 mm or less) are used to identify distinct patterns of disease, especially ground-glass attenuation, reticular abnormalities, and architectural distortion (traction bronchiectasis or bronchiolectasis and honeycomb change). The groundglass appearance may suggest a cellular histologic abnormality of that area of lung, especially when ground glass is seen in areas without significant reticular change. A reticular pattern is frequently associated with fibrotic parenchymal abnormality on lung biopsy. Traction bronchiectasis occurs when significant fibrotic abnormality causes traction on the airways, resulting in abnormal airway enlargement and loss of normal airway tapering toward the periphery of the lung. HRCT is significantly more sensitive and specific than a chest radiograph in the diagnosis of ILD and in assessment of both the extent and severity of the disease.5 It can identify disease before any abnormality becomes apparent on a chest radiograph. The patterns and variability of lung parenchymal involvement in ILD are more evident with HRCT and can be virtually pathognomonic for several forms of ILD, including eosinophilic granuloma, IPF, LAM, lymphangitic carcinomatosis, sarcoidosis, and hypersensitivity pneumonitis.6

The pattern of involvement observed on the CT scan of the chest also correlates strongly with the histology of UIP. In the appropriate clinical context, HRCT findings of a definite or probable pattern of UIP obviate the need for a surgical lung biopsy.7 In addition, HRCT has prognostic value in that a demonstration of honeycomb cysts indicates end-stage, irreversible fibrosis and loss of alveolar walls. Finally, HRCT can guide parenchymal biopsy sites or direct the surgeon to lymph nodes for biopsy by mediastinoscopy. Nuclear scintigraphy with gallium citrate Ga67 has been proposed as a diagnostic and staging tool in the assessment of patients with ILD, particularly sarcoidosis and IPF. Gallium uptake is nonspecific, however, and this procedure has no clinical utility either in monitoring or predicting the clinical course of patients with ILD. Similarly, technetium-99 (99mTc) radionuclide scans and positron emission tomography (PET) scans currently have no significant clinical role in either the diagnosis or staging of ILD. Respiratory Recap High-Resolution Computed Tomography ∎ High-resolution computed tomography (HRCT) can inform the ILD differential diagnosis. ∎ Characteristic findings highly suggestive of idiopathic pulmonary fibrosis, eosinophilic granuloma, LAM, sarcoidosis, and hypersensitivity pneumonitis may obviate the need for surgical lung biopsy.

Laboratory Findings Routine blood and serologic test results most often are unremarkable for patients with ILD. Many patients have a mild anemia and nonspecific elevations in the erythrocyte sedimentation rate. Serologic tests (including antinuclear antibody, rheumatoid factor, myositis antibodies, and antineutrophil cytoplasmic antibody determinations), hypersensitivity pneumonitis screening (serum precipitins), and complement fixation for fungi can be helpful in selected patients. Although nonspecific, laboratory results can support the diagnosis and narrow the differential diagnosis in ILD. Evidence of renal insufficiency or hematuria raises the possibility of renal–pulmonary

syndromes (e.g., granulomatosis with polyangiitis, anti-basement membrane syndrome, systemic lupus erythematosus, and microscopic polyangiitis), whereas abnormal results on liver function tests and high serum calcium levels favor the diagnosis of either sarcoidosis or metastatic malignancy.

Bronchoscopy A specific ILD diagnosis often cannot be established on the basis of the history, physical examination, pulmonary function test results, chest imaging, and laboratory studies. Bronchoscopy with lavage and transbronchial lung biopsy can occasionally help narrow the differential diagnosis or confirm a specific disease. Note that bronchoscopy is frequently nondiagnostic, however, and it will not significantly inform the clinical evaluation for many patients with ILD. Nevertheless, bronchoalveolar lavage may be particularly helpful in patients with hemoptysis or acute ILD (Figure 34-4).

FIGURE 34-4 Approach to the evaluation of a patient with interstitial lung disease.

Description In the United States, more than 50% of patients with ILD undergo bronchoscopy.8 In the evaluation of ILD, the clinician performs bronchoalveolar lavage to sample cells and noncellular material from the lower respiratory tract. Currently, lavage has only limited clinical application in ILD. Although this technique can occasionally be diagnostic (e.g., pulmonary alveolar proteinosis), especially when particular cytologic or immunohistologic stains are applied (e.g., eosinophilic granuloma and alveolar hemorrhage syndromes), it does not yield precise information for most ILD disorders. Lavage is most useful in excluding mimics of ILD (infection, malignancy) or infections that may complicate ILD treatment. The processing of lavage fluid should include cytologic studies and smears or cultures for acid-fast bacilli, fungi, Pneumocystis jirovecii, and nucleic acid amplification tests for viruses

when clinically indicated. The cellular profiles obtained through analysis of the lavage fluid have been associated with the underlying cause of the ILD. Lymphocytosis can be seen in patients with sarcoidosis, berylliosis, and hypersensitivity pneumonitis. CD4 (T helper) lymphocytes increase in patients with sarcoidosis, with a ratio of CD4 to CD8 cells of more than 3:5, whereas CD8 cells predominate in patients with hypersensitivity pneumonitis. A lavage sample yielding more than 25% eosinophils supports a diagnosis of chronic or acute eosinophilic pneumonia. This distinction is especially important for acute eosinophilic pneumonia, which is often characterized by a lack of eosinophils in the complete blood count. Neutrophils classically predominate in several forms of ILD, including IPF and asbestosis. Respiratory Recap Bronchoalveolar Lavage Bronchoalveolar lavage can assist in the diagnosis of lung infections, alveolar hemorrhage, pulmonary alveolar proteinosis, eosinophilic granuloma, and pneumoconiosis.

The diagnostic yield of transbronchial biopsy (TBBx) varies based on the specific form of ILD being evaluated. TBBx is helpful in the evaluation of lung malignancies (including lymphangitic carcinomatosis), infectious pneumonitis, or sarcoidosis. It sometimes facilitates the diagnosis of necrotizing vasculitis seen in granulomatosis with polyangiitis, rheumatoid lung disease, LAM, eosinophilic granuloma, silicosis, and hypersensitivity pneumonitis. By contrast, TBBx has little diagnostic utility in the evaluation of suspected IPF or ILD associated with connective tissue disease. Respiratory Recap Transbronchial Biopsy Transbronchial biopsy can aid in the diagnosis of sarcoidosis, lung infection, cancer, and hypersensitivity pneumonitis.

Many forms of ILD require a more comprehensive evaluation of the

spatial distribution of interstitial abnormalities than can be accomplished with biopsies the size of those obtained with TBBx. Transbronchial lung cryobiopsy is a form of bronchoscopic biopsy that freezes lung tissue with a bronchoscopic cryoprobe and yields large pathologic specimens; unfortunately, it has also been associated with higher risks of procedural complication. The role of transbronchial lung cryobiopsy in the evaluation of ILD has not been well evaluated.9,10

Surgical Lung Biopsy Surgical lung biopsy is conventionally regarded as the gold standard for determining a specific histologic pattern of ILD, which in turn can lead to an accurate clinical diagnosis. Histopathologic examination of tissue can allow confirmation of a specific diagnosis, inform the development of a treatment plan, predict response to therapy, and provide prognostic information.11 It can also provide insights into the pathogenesis of the ILD. Even so, a histologic pattern of ILD identified on surgical lung biopsy does not necessarily confirm a specific disease; instead, the clinician must incorporate multidisciplinary data—including clinical and radiographic findings—to establish an accurate diagnosis.1 Surgical lung biopsy is nondiagnostic in approximately 10% of cases. However, even when a specific pathologic diagnosis cannot be established, surgical lung biopsy often helps narrow the differential diagnosis.12 In the United States, fewer than 50% of patients with ILD have a lung biopsy to facilitate the diagnostic evaluation. Surgical lung biopsy is most helpful in patients younger than 50 years of age and those with constitutional symptoms, hemoptysis, or atypical radiographic features. Diagnostic yield is lower in the setting of acute respiratory failure, where specific pathologic diagnoses often do not change treatment options. Similarly, pathologic information does not meaningfully change management for many patients with well-defined systemic connective tissue disease because histopathologic patterns do not reliably predict treatment response.13 Lung biopsy via video-assisted thoracoscopic surgery (VATS) or thoracotomy is well tolerated with low morbidity and mortality rates.14 However, surgical outcomes vary based on the surgeon’s experience and the severity of the patient’s ILD preoperatively. Higher mortality rates

have been observed when patients undergo urgent surgical lung biopsy for the evaluation of acutely decompensated ILD. Relative contraindications for surgical lung biopsy include high supplemental oxygen requirements (>2 L/min), pulmonary hypertension, DLCO < 40% predicted, frailty, or multiple medical comorbidities. Biopsy specimens should be obtained from several sites, including apparently normal lung tissue adjacent to and remote from obviously involved tissue. The clinician should avoid taking samples from areas of advanced parenchymal destruction and honeycombing: The end-stage fibrotic changes of many diseases have a similar appearance, such that establishing a specific pathologic diagnosis is not possible. HRCT can help determine the optimal biopsy sites. Alveolar and subpleural tissue is required. Tissue processing requirements include samples untreated for bacteriologic and virologic studies; fixed in 10% formalin, Methacarnoys solution for immunofluorescence, glutaraldehyde for electron microscopy, and cryopreserved for immunologic and molecular studies.

Pathology Individual pathologic features are observed in many forms of ILD and are rarely pathognomonic for a specific disease.15 Alveolitis (granulomatous or nongranulomatous), interstitial infiltration with various types of inflammatory cells, or a relatively acellular interstitial infiltrate may predominate. Airways, blood vessels, and pleura may be involved. The clinician can establish a pathologic diagnosis not only by identifying a specific collection of pathologic features but also by determining the distribution of disease. For example, many types of ILDs demonstrate fibroblast foci and interstitial thickening with a relatively acellular collagenous material, but identification of these pathologic features in a temporally and spatially heterogeneous pattern with significant subpleural disease would strongly suggest a pathologic diagnosis of UIP. Different clinical entities may have similar underlying histologic patterns, and, conversely, specific diseases may manifest as ILD in several histologic patterns (Table 34-3). TABLE 34-3 Histologic Patterns with Interstitial Lung Disease Pattern

Associated Disease

Usual interstitial pneumonitis (UIP)

Idiopathic pulmonary fibrosis, CTD-ILD, asbestosis, sarcoidosis, hypersensitivity pneumonitis, radiation, drug reactions

Nonspecific interstitial pneumonitis (NSIP)

CTD-ILD, drug reactions, hypersensitivity pneumonitis

Cryptogenic organizing pneumonitis (COP)

CTD-ILD, drug reactions, radiation, infection

Desquamative interstitial pneumonitis (DIP)

Smoking-related ILD, eosinophilic granuloma, drug reactions

Lymphocytic interstitial pneumonitis (LIP)

CTD-ILD, immunodeficiency, drug reactions

Eosinophilic pneumonia

Acute respiratory distress syndrome, drug reactions, eosinophilic granulomatosis with polyangiitis, tropical eosinophilia, hypereosinophilic syndrome

Diffuse alveolar hemorrhage

Vasculitis, CTD-ILD, Goodpasture syndrome, idiopathic pulmonary hemosiderosis

Alveolar proteinosis

Pulmonary alveolar proteinosis, silicosis

Granulomas

Sarcoidosis, hypersensitivity pneumonitis, berylliosis, infections

CTD-ILD, connective tissue disease–associated interstitial lung disease; ILD, interstitial lung disease.

Prognosis The prognosis associated with ILD varies depending on the diagnosis.16 Generally, ILD associated with an underlying connective tissue disease is associated with a higher chance of treatment response and favorable prognosis. However, the prognosis is highly variable even among the subtypes of connective tissue disease–related ILD (CTD-ILD). For example, organizing pneumonia associated with rheumatoid arthritis may confer a relatively good prognosis, whereas UIP associated with rheumatoid arthritis has a poor prognosis that mirrors IPF.17 Contemporary understanding of ILD prognosis is derived from studies of IPF, for which the median survival is approximately 3.8 years from the time of diagnosis.18 Findings in the history, chest imaging, underlying histopathology of the disease, and the response to therapy can provide prognostic information. In IPF, factors predicting a better chance of survival in untreated patients include female gender, younger age at presentation or symptom onset, less dyspnea, less severe impairment of DLCO, and a more cellular histologic appearance on biopsy. Respiratory Recap Factors Indicating an Improved Prognosis in Idiopathic Pulmonary Fibrosis ∎ Female patient ∎ Younger age ∎ Less dyspnea ∎ Relatively cellular infiltrate on histopathologic specimens

Management Left untreated, many forms of ILD are progressive and may result in death secondary to progressive respiratory insufficiency and cor pulmonale. An important tenet of management is to remove the inciting or injurious agent to the lung, if possible, which begins with an exhaustive search for a causative agent. Management may include environmental modification or avoidance (chronic hypersensitivity pneumonitis) or discontinuation of an offending medication. Similarly, the clinician should determine whether the patient has an underlying connective tissue disease. Establishment of a diagnosis of CTD-ILD typically confers a more favorable prognosis and suggests a potential therapeutic role for immune suppression. Conversely, administration of immune-suppressing medications for patients with fibrotic forms of ILD who do not have an established connective tissue disease (such as IPF) may worsen outcomes.19 Few published guidelines or standards define the optimal treatment for ILD or indicate which patients should be offered pharmacologic treatment. Likewise, little evidence is available to guide decisions regarding the optimal time to initiate treatment. The natural history of many ILD subtypes is a steady progression and functional deterioration. In each case, the clinician must weigh the potential benefit of initiating therapy to halt or slow ILD progression against the risk of potential toxicity. Unfortunately, high-quality evidence to guide this decision is lacking. Important factors to consider for an individual patient’s management plan include severity of functional impairment, anticipated disease course, risk factors for treatment intolerance (frailty and medical comorbidities), and likelihood of response to the proposed therapy (largely determined by the specific ILD diagnosis). Several forms of ILD are amenable to specific treatments, but many forms of ILD lack a well-established treatment option and are often treated empirically with corticosteroids or other forms of immune suppression. Corticosteroids are rarely curative but can help either control disease activity (sarcoidosis, CTD-ILD) or accelerate recovery (hypersensitivity pneumonitis) from some types of ILDs. However, corticosteroids are associated with many adverse side effects, which

often emerge in a linear and dose-dependent fashion. Few adequately controlled trials have assessed corticosteroid benefit in ILD. Although as many as half of patients with ILD experience subjective improvement with steroids, only 15% to 20% improve by objective measures. Steroid regimens vary considerably in terms of dosage and length of therapy. Many ILD experts will employ a therapeutic trial of steroids, with a plan to objectively assess therapeutic response and minimize the dose or discontinue therapy as soon as possible. Attentive supportive care can improve the quality of life of patients with ILD. Such therapy includes vaccination against influenza and pneumococcal infection, early evaluation of acute symptomatic changes, supplemental oxygen with PaO2 less than 55 mm Hg, bronchodilators for comorbid airways disease, adjunct pharmacologic therapy for chronic cough, psychosocial therapy, and pulmonary rehabilitation. In hypoxemic patients, supplemental oxygen therapy can help relieve symptoms of dyspnea at rest and during exercise. Titration of supplemental oxygen during a 6-minute walk test can help determine the optimal oxygen prescription. Oxygen therapy may enable patients with ILD to maintain activities of daily living and increase exercise endurance, especially patients with end-stage disease. Higher oxygen flows and oxygenconserving devices may be needed as the ILD progresses and hypoxiarelated complications occur. Bronchodilators may be used selectively to increase exercise capacity for patients with comorbid airways obstruction by reducing the increased work of breathing and sensation of breathlessness. Coupled with oxygen therapy, bronchodilators may promote physiologic improvements and subsequently improve quality of life among patients with severe symptoms from ILD. Patients with chronic lung conditions such as ILD can also benefit from pulmonary rehabilitation programs. A comprehensive and individualized exercise training and education program may provide longterm health benefits to the patient and help prevent and treat exacerbations.20 Rehabilitation programs can provide psychosocial support for patients, smoking cessation programs, and good nutrition guidance. Stop and Think

You are asked to perform a 6-minute walk test for a patient with ILD. What are other ways that you, as a respiratory therapist, can help with the care of this patient?

Specific Interstitial Lung Diseases Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis (IPF) predominantly affects males in the fifth to seventh decades of life. Although genetic mutations associated with familial forms of pulmonary fibrosis have been identified, the majority of cases are considered sporadic and have not yet been linked to a specific genetic abnormality. The pathogenesis of IPF is incompletely understood but likely reflects either an aberrant host response to injury at the alveolar epithelium or a protracted and dysregulated process of wound healing.2 Most patients report a history of a gradual onset of dyspnea with exercise. Physical examination often reveals bibasilar Velcro-like crackles but is otherwise unremarkable. More than 30% of patients experience constitutional symptoms such as weight loss, malaise, and easy fatigability. With progression of the disease, dyspnea at rest, clubbing of the fingers and toes, and evidence of cor pulmonale become more prominent. The chest radiograph correlates poorly with clinical findings. In 10% of patients, the radiograph is normal, but a reticular pattern at the lung bases is most characteristic of IPF. The distribution and pattern of parenchymal abnormality on HRCT, including lower lobe–predominant, subpleural reticular abnormalities with architectural distortion (traction bronchiectasis or bronchiolectasis and honeycomb change), correlate well with histopathologic findings of UIP. Characteristic HRCT abnormalities, especially honeycomb change, may be sufficient to establish a confident diagnosis of IPF in the appropriate clinical context, obviating the need for surgical lung biopsy.7 Pulmonary function tests show reduced lung volumes and a decrease in DLCO. Laboratory values are nonspecific. Transbronchial biopsy is usually nondiagnostic because the small sample sizes are insufficient for evaluating lung architecture and establishing a reliable histopathologic diagnosis. Although once considered the standard of care, many patients with HRCT findings of a definite or probable UIP pattern of fibrosis do not need to undergo surgical lung biopsy, as the radiographic findings are highly predictive of the histopathologic results. Patients with atypical clinical features, with an abnormal radiographic

distribution of disease, or for whom there is high suspicion of an alternative diagnosis may still require surgical lung biopsy. Biopsies typically reveal a spatially and temporally heterogeneous pattern of fibrosis with fibroblast foci and a paucity of inflammatory cell infiltration. IPF is, by definition, a diagnosis of exclusion. That is, the clinician must first rule out other causes of a UIP pattern of ILD, such as connective tissue disease, drug toxicity, or environmental exposures, before making this diagnosis. Notably, no pathognomonic clinical, biochemical, or pathologic findings are unique to IPF. As the lesions progress, lung architecture becomes distorted, and respiratory failure ensues. The clinical course varies among patients with IPF, with some suffering a relatively rapid and consistent decline in lung function and others experiencing relatively little loss in lung function until they develop an exacerbation. IPF exacerbations are characterized by acute worsening of dyspnea and hypoxemia, widespread alveolar opacities on chest radiographs, and an exceedingly high mortality rate. Approximately 10% to 20% of patients with IPF will experience an exacerbation each year. An underlying cause for acute IPF exacerbations, such as pulmonary infection or environmental exposure, is identified in only a small minority of cases. The overall mortality rate for IPF patients approximates 50% at 4 years after diagnosis. The prognosis is worse for men and for patients with honeycombing and severely depressed pulmonary function. Clinical practice guidelines for the treatment of IPF were updated in 2015.19 Until recently, treatment options for IPF were lacking. Failed therapies, including various forms of immune suppression, pulmonary vasodilators, and anticoagulation, demonstrated no benefit or resulted in harm when evaluated in high-quality clinical trials.21 In 2014, the Food and Drug Administration (FDA) cleared the antifibrotic agents nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. Although these medications do not cure IPF or improve patients’ lung function, both slow the decline in FVC at 1 year by approximately 50%. Treatment with either nintedanib or pirfenidone has been associated with a reduced risk of exacerbations and with trends toward reduced mortality. Nintedanib slows lung function decline by inhibiting multiple tyrosine kinases. The most common adverse effect is diarrhea. Caution must be exercised in patients taking anticoagulants or at high risk for

atherothrombotic events, as nintedanib has been associated with both bleeding and arterial thrombotic complications. Pirfenidone slows IPF progression through inhibition of transforming growth factor beta production and fibroblast proliferation. The mechanism underlying its beneficial effect is incompletely understood. The adverse effects most commonly associated with pirfenidone include anorexia, nausea, and photosensitivity. The dose is titrated over 14 days (or longer) to maximize patient tolerance. Liver function tests must be monitored during therapy with both nintedanib and pirfenidone, as hepatotoxicity has been (rarely) reported with their use. Nintedanib and pirfenidone are considered equally effective, though no head-to-head prospective study comparing the efficacy of these agents has been completed. Preliminary studies of combination therapy with both pirfenidone and nintedanib suggest a potential benefit from this approach, albeit with higher rates of gastrointestinal side effects. The optimal time to initiate and discontinue antifibrotic therapy is unknown. For patients with advanced disease and functional impairment, lung transplantation may be a therapeutic option. The rapidly progressive and unpredictable nature of IPF requires early referral for transplant evaluation. Respiratory failure from ILD is the primary indication for lung transplantation in approximately one-half of all transplant recipients in the United States.22 Respiratory Recap Characteristics of Idiopathic Pulmonary Fibrosis ∎ IPF predominantly affects individuals in the fifth to seventh decades of life. ∎ It has an insidious onset, and progressive exertional dyspnea is common. ∎ Chest radiograph correlates poorly with clinical findings. ∎ High-resolution computed tomography findings can often help establish a diagnosis without surgical lung biopsy. ∎ Bronchoscopy and transbronchial biopsy are recommended only when there is high suspicion for an alternative diagnosis. ∎ Patients with atypical clinical findings or inconclusive HRCT may require a surgical lung biopsy to establish the diagnosis. ∎ IPF remains a diagnosis of exclusion, requiring a careful evaluation for other causes of usual interstitial pneumonitis. ∎ Its mortality rate is approximately 50% at 4 years. ∎ The antifibrotic agents nintedanib and pirfenidone reduce the rate of FVC decline by 50%

at 1 year.

Sarcoidosis Sarcoidosis is a systemic disorder characterized by noncaseating granulomatous inflammation. It is a common disorder and the most prevalent ILD of unknown cause. The estimated prevalence in North America is 10 to 20 cases per 100,000 people; the prevalence is substantially higher in Scandinavia, at approximately 80 per 100,000. The disorder is rare in Africa, South America, and Central America. Most cases occur between 20 and 45 years of age, and the disease is rare in children and the elderly. In the United States, sarcoidosis disproportionately affects African Americans. The lung is the most frequently involved organ in sarcoidosis. This high frequency of respiratory tract involvement suggests an inhaled antigen may be important in pathogenesis. A significant proportion of individuals with sarcoidosis are asymptomatic (40% to 60%), even though the chest radiograph is abnormal in more than 90%. The chest radiograph in sarcoidosis shows one of the following patterns: Lymph node enlargement, which most frequently is bilateral and hilar (stage I disease) ILD with lymph node enlargement (stage II) ILD alone (stage III) Advanced ILD with architectural distortion and cavity or cyst formation (stage IV) Patients do not necessarily progress from one stage to the next in a linear fashion. Most patients with stage II or stage III disease demonstrate a restrictive pattern on pulmonary function testing. Some individuals with sarcoidosis may also have airway obstruction. Laboratory abnormalities may include hypercalcemia and occasional abnormal liver function testing. As many as 60% of patients will have some spontaneous regression of both the adenopathy and ILD: This occurs in 80% of patients with stage I disease, 40% of patients with stage II disease, and 10% to 20% of patients with stage III sarcoidosis. At the other extreme, the interstitial

disease may progress to extensive scarring and end-stage lung disease with severe respiratory compromise. The course of the disease usually is dictated in the first 24 months, with almost all spontaneous remissions occurring during this time. Patients with sarcoidosis commonly develop extrapulmonary involvement. Eye and skin involvement is a particularly common manifestation of sarcoidosis, but the disease may also have cardiac, neuromuscular, hematologic, hepatic, endocrine, and peripheral lymph node manifestations. Mortality from sarcoidosis is most often associated with cardiac involvement. The diagnosis of sarcoidosis can be made in several ways and depends on the pretest probability. The history, physical examination, and chest radiography may strongly support the diagnosis in young African American women with bilateral hilar adenopathy. When histopathologic confirmation is warranted, endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes offers a high diagnostic yield. TBBx demonstrates noncaseating granulomas (which have a central core of histiocytes, epithelioid cells, and multinucleated giant cells) in as many as 90% of patients. The yield of TBBx is favorable because sarcoidosis is a process involving peribronchial and bronchiolar tissue. Rarely, the clinician may need to perform mediastinoscopy to sample hilar and mediastinal lymph nodes as a means to confirm the diagnosis when bronchoscopy is nondiagnostic. Biopsies of other involved tissues (skin, conjunctiva, salivary glands, or liver) can also confirm the diagnosis. Thoracoscopic or open lung biopsy is rarely required for diagnostic confirmation. The initial treatment of sarcoidosis consists of corticosteroid administration when the patient has evidence of progressive functional impairment of one or more vital organs. Pharmacologic treatment of patients with mild symptoms or nonprogressive disease is not typically required. Severe pulmonary dysfunction; hypercalcemia; myocardial, nervous system, and eye involvement; and disfiguring skin lesions necessitate corticosteroid treatment. The appropriate dose, duration, and tapering of the corticosteroid have not been defined. Although the response to the treatment becomes evident within 12 weeks, the corticosteroid regimen is typically continued for at least 12 months, with a goal of gradual reduction to the minimum effective dose. Relapses of

sarcoidosis frequently occur as the corticosteroid is tapered. Antimetabolite agents such as methotrexate and azathioprine are used for steroid-resistant disease, in steroid-sparing regimens, and for individuals who have contraindications to or adverse effects from steroids. Generally, methotrexate is favored over azathioprine because both have similar efficacy, but methotrexate is associated with a lower risk of infectious complications.23 Lung transplantation may be appropriate for irreversible end-stage lung disease from sarcoidosis. Respiratory Recap Characteristics of Sarcoidosis ∎ Sarcoidosis is an idiopathic noncaseating granulomatous systemic inflammatory disorder. ∎ It is the most common ILD of unknown origin. ∎ Patients are most commonly 20 to 45 years old at disease onset. ∎ The disease is more common in African Americans. ∎ The lung is the organ most frequently involved. ∎ Chest radiograph shows bilateral hilar lymph node enlargement (stage I), ILD with lymph node enlargement (stage II), or ILD alone (stage III). ∎ Adenopathy and ILD regress spontaneously in more than 50% of cases. ∎ Extrapulmonary involvement is common. ∎ Transbronchial needle aspiration or transbronchial biopsy demonstrates noncaseating granulomas. ∎ Thoracoscopic or open lung biopsy is rarely needed for diagnosis. ∎ Steroids are given as first-line treatment only for patients with functional impairment of one or more organs.

Interstitial Lung Disease with Connective Tissue Disease Patients with a connective tissue disease (CTD) can develop ILD. Indeed, ILD is one of the most serious complications of CTD and results in significant morbidity and mortality. Specific CTDs associated with ILD include systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (polymyositis and dermatomyositis), Sjögren syndrome, and mixed connective tissue disease.24 Although the progression of CTD-related ILD (CTD-ILD) is

sometimes slower, the presenting symptoms and examination findings may resemble those for IPF. CTD-ILD manifests in multiple histopathologic patterns including UIP, NSIP, organizing pneumonia (OP), lymphoid interstitial pneumonia (LIP), follicular bronchiolitis, and alveolar hemorrhage with or without vasculitis. Histopathologic findings suggesting CTD-ILD include pulmonary parenchymal lymphoid hyperplasia, cellular interstitial pneumonitis, airway-centered inflammatory infiltrates, and subpleural sparing. The diagnosis is assumed in patients with a known, underlying CTD and classic clinical features of ILD (crackles, dyspnea, interstitial infiltrates, and restrictive results on pulmonary function tests). For patients with a well-defined CTD, surgical lung biopsy is usually not indicated, as the results are unlikely to change initial management. A trial of immune suppression is offered for patients with progressive CTD-ILD. Although several immune-suppressing regimens have demonstrated efficacy, research has not yet established a single best approach to pharmacologic management.13,24 The optimal management for patients with clinical findings typically associated with CTD but lacking sufficient criteria to support a specific diagnosis is unknown. Idiopathic pneumonia with autoimmune features (IPAF) is not an established diagnosis but rather a term developed to facilitate further study of this poorly understood entity.25 Patients fulfilling the criteria for IPAF generally have a more favorable prognosis than those with IPF but a lower survival than patients with established CTDILD.26 A trial of immune suppression is often offered for patients with progressive ILD. The effectiveness of antifibrotic therapy for these patients has not yet been defined. Respiratory Recap Connective Tissue Disease–Related Interstitial Lung Disease (CTD-ILD) ∎ Pulmonary symptoms of CTD-ILD are similar to those of idiopathic interstitial pneumonias like IPF. ∎ CTD-ILD can manifest as ILD in multiple histopathologic patterns. ∎ CTD-ILD is assumed in patients with ILD and a well-established connective tissue disease, usually obviating the need for surgical lung biopsy ∎ Treatment involves administration of corticosteroids, immunosuppressive agents, or both.

Eosinophilic Granuloma Eosinophilic granuloma, also called Langerhans cell histiocytosis, is a rare disease that occurs almost exclusively in smokers or former smokers between the ages of 20 and 40 years. Although its cause remains unknown, eosinophilic granuloma probably involves an inflammatory response by Langerhans cells to a component of tobacco smoke. Common presenting symptoms include a nonproductive cough, chest pain, and dyspnea on exertion. Weight loss, fever, and hemoptysis occasionally occur. Extrapulmonary features, including involvement of the posterior pituitary gland with the development of diabetes insipidus and lytic bony lesions, have been described in approximately 20% of patients. The physical examination often is unremarkable, although patients may demonstrate occasional wheezing. Pulmonary function tests show a decrease in lung volumes and diffusing capacity with normal or reduced expiratory flows. Radiographic findings of nodular densities in the upper and mid-lung fields with sparing of the lung bases are characteristic, but reticular, reticulonodular, and cystic lesions are also observed. Patients rarely experience pleural effusions. Pneumothorax occurs in approximately 10% of patients. The HRCT scans are highly distinctive, revealing numerous stellate peribronchiolar nodular and upper lobe– predominant cystic lesions and relative sparing of the costophrenic angles. HRCT findings can be diagnostic, obviating the need for histopathologic confirmation with lung biopsy. As the disease progresses, the nodules are replaced by cysts that become confluent. Biopsy reveals a mixture of inflammatory, cystic, nodular, and fibrotic lesions centered at or adjacent to bronchioles. Light microscopy shows the cleft nuclei of the Langerhans cells and the stellate pattern of fibrosis in 80% of patients. Aggregates of Langerhans cells can be demonstrated by immunostaining for S-100 protein or OKT6 antigen. Electron microscopy reveals Birbeck granules (X bodies) within these large, mononuclear phagocytes. As the inflammation progresses, the alveolar architecture is destroyed and replaced by cysts and fibrosis. In patients with eosinophilic granuloma, complete cigarette smoking cessation is imperative. For patients who successfully stop smoking,

spontaneous remissions are the rule, and no therapy beyond symptomatic and supportive care is required. As many as one-fourth of patients experience progressive loss of pulmonary function, even when they stop smoking. Corticosteroids are often prescribed for severe and progressive disease, although only limited data support their efficacy. BRAF gene inhibitors, which have demonstrated efficacy in control of extrapulmonary Langerhans cell histiocytosis, are being evaluated for the treatment of progressive pulmonary disease. Respiratory Recap Characteristics of Eosinophilic Granuloma ∎ This disease is also called Langerhans cell granulomatosis/histiocytosis. ∎ Eosinophilic granuloma was first described as a bone disease but is now recognized as a predominantly pulmonary disorder. ∎ It occurs almost exclusively in smokers or former smokers who are 20 to 40 years old. ∎ Nonproductive cough, chest pain, and dyspnea on exertion are common presenting symptoms. ∎ Extrapulmonary features include diabetes insipidus and lytic bony lesions. ∎ High-resolution computed tomography scans are frequently diagnostic. ∎ Light microscopy shows cleft nuclei of the Langerhans cells and a stellate pattern of fibrosis in 80% of patients. ∎ Spontaneous remissions are common after smoking cessation. ∎ Patients must stop smoking if the disease is to resolve.

Respiratory Bronchiolitis Interstitial Lung Disease Respiratory bronchiolitis interstitial lung disease (RB-ILD) is a rare disorder that occurs exclusively in cigarette smokers. Most of these individuals are asymptomatic, but some have a mild cough, dyspnea, and sputum production. Crackles are inconsistently detected in some patients on physical examination. The chest radiograph may demonstrate reticulonodular infiltrates at the bases but may also be normal. Pathologic studies reveal intracytoplasmic, golden-brown granular pigment in alveolar macrophages in the respiratory and terminal bronchioles. Although some patients experience disease improvement or

remission after they quit smoking, more than 50% suffer persistent or progressive disease despite smoking cessation. Glucocorticoids are often prescribed for persistent disease following smoking cessation, but their efficacy is not well established.

Pulmonary Alveolar Proteinosis Pathologically, pulmonary alveolar proteinosis (PAP) is characterized by filling of alveolar spaces with a lipoproteinaceous exudate and varying degrees of interstitial fibrosis. The intra-alveolar phospholipid stains bright pink with periodic-acid Schiff (PAS) reagent. Although some patients are asymptomatic, most have dyspnea, cough, and alveolar infiltrates (seen on chest radiograph). The disease spontaneously remits in one-third of patients. While the mortality rate for PAP was high in the past, death is now rare following the introduction of whole-lung lavage of 20 to 40 L of saline as the treatment of choice. This disease generally results from impaired clearance of surfactant proteins from the alveolar space. Primary PAP occurs when autoimmune disease causes enhanced clearance of granulocyte-monocyte colonystimulating factor (GM-CSF) or genetic mutations in GM-CSF signaling pathways. Secondary forms of PAP result from impaired GM-CSF signaling and macrophage function in patients with exposure to silica and hydrocarbons or in patients with underlying myelodysplastic syndromes or hematologic malignancies. PAP is uniquely associated with several atypical pulmonary infections caused by microbes thriving in the proteinaceous fluid, such as Pneumocystis jirovecii, Nocardia species, and atypical mycobacteria.

Drug-Induced Interstitial Lung Disease Many drugs have been implicated as causes of ILD. The clinical and radiographic features of drug-induced ILD vary depending upon the implicated agent. Clinical presentations may include the syndromes of acute pneumonitis, chronic interstitial pneumonitis, acute alveolar hemorrhage, or noncardiac pulmonary edema. In some cases, a doserelated toxicity (e.g., as with antineoplastic agents) may be seen, but

often ILD develops as an idiosyncratic reaction. Agents may act synergistically with each other, with radiation, or with oxygen exposure in the pathogenesis of lung toxicity. A number of mechanisms are involved in drug-induced ILD, including cytotoxicity, hypersensitivity pneumonitis, and noncardiogenic pulmonary edema. Cytotoxic drug injury may occur with bleomycin, alkylating agents, and nitrosoureas. Previous chemotherapy or radiation therapy can amplify the risk of ILD with use of these drugs. Histopathologic features of drug-induced ILD include type II pneumocyte proliferation with cellular atypia (large nuclei, prominent nucleoli, and bizarre chromatin patterns), inflammatory cell incursion, and fibrosis. Cytotoxic lung injury has a significant mortality rate (10% to 50% of patients, depending on the causative drug). Corticosteroids are most effective as a treatment for drug-induced ILD if given early, when a cellular (rather than fibrotic) histology is present. The response to corticosteroid therapy varies significantly, however, and is often negligible with established disease. Methotrexate, nitrofurantoin, gold, and sulfasalazine are associated with hypersensitivity pneumonitis. Both acute and subacute forms of these drug-induced ILDs manifest with fever, chest pain, and interstitial or alveolar infiltrates on the radiograph. The prognosis is good when the medication is stopped. Corticosteroids may hasten resolution. Salicylates, thiazides, narcotics, and cytarabine all can induce a noncardiac pulmonary edema that generally resolves with discontinuation of the offending medication.

Acute Interstitial Lung Disease A number of interstitial lung diseases manifest as a more acute illness. Acute ILD includes acute interstitial pneumonitis (Hamman-Rich syndrome), acute organizing pneumonia (formerly called bronchiolitis obliterans with organizing pneumonia), and acute eosinophilic pneumonia. The presentation of these diseases often mimics an atypical pneumonia, with the patient reporting an nonproductive cough, dyspnea, fever, and malaise. These patients may develop acute respiratory failure requiring mechanical ventilation. Acute ILDs must be considered in the differential diagnosis for a patient presenting with acute respiratory

distress syndrome (ARDS). Acute interstitial pneumonitis is a rapidly progressive form of interstitial pneumonitis thought to either exemplify an accelerated phase of IPF or represent a distinct entity of unknown origin. It has been described as ARDS without an underlying precipitating injury. Acute interstitial pneumonitis is characterized by an epithelial cell injury that results in denudation of the epithelial lining of the alveolus and edema of the alveolar walls (i.e., diffuse alveolar damage). Intra-alveolar fibrin, edema accumulation, mild acute and chronic interstitial inflammation, and formation of intra-alveolar hyaline membranes also are frequently described. Collagen deposition by fibroblasts and honeycomb lung can follow. Many patients develop hypoxemic respiratory failure, and the mortality rate is exceedingly high. Patients are often treated with corticosteroids, although the effectiveness of this treatment strategy remains unknown. Acute OP appears to be a response of the lung to a variety of injuries that affect the smaller airways and alveoli as a unit. These injuries include infections, exposure to toxic gases, radiation therapy, drug toxicity, eosinophilic pneumonia, granulomatosis with polyangiitis, and hypersensitivity pneumonitis. Acute OP frequently manifests as an upper respiratory inflammation with a persistent cough and then dyspnea. Focal alveolar infiltrates are seen on the chest radiograph. Histologically, proliferating fibroblasts appear in the alveolar spaces, and polyps (inflammatory cells and fibrosis) project into the lumina of distal bronchioles. Extrapulmonary involvement does not occur. Treatment consists of corticosteroids, with most individuals demonstrating good response. The idiopathic form of OP is classified as cryptogenic organizing pneumonia (COP) and the secondary form as secondary organizing pneumonia (SOP). Acute eosinophilic pneumonia is distinguished by fleeting pulmonary infiltrates and pulmonary eosinophilia. Importantly, peripheral eosinophilia is often absent. Simple pulmonary eosinophilia (Löffler syndrome) most commonly results from infection with parasites such as Strongyloides, Ascaris, and Ancylostoma species but can also be caused by a drug reaction. The most common symptom is a dry cough. The infiltrates resolve within 2 weeks, and the peripheral eosinophilia, if present, is transitory. Treatment is directed at an identifiable underlying cause.

Tropical eosinophilia can manifest as an acute eosinophilic pneumonia and is believed to be part of a hypersensitivity reaction to the filarial worm. Patients typically experience cough, fever, myalgia, and dyspnea. The histologic appearance is that of a cellular interstitial pneumonia with both infiltration of the interstitium and alveolar spaces by mononuclear cells and eosinophils and areas of OP. This can lead to respiratory failure requiring mechanical ventilation. Various drugs have also been reported to produce acute eosinophilic pneumonia. In these cases, the bronchoalveolar lavage shows a predominance of eosinophils. Treatment with corticosteroids, along with removal of the offending agent, cures the disease, and recurrences rarely occur.

Key Points Interstitial lung disease comprises a heterogeneous group of disorders causing abnormal expansion of the alveolar and interstitial space with infiltrates of inflammatory cells or acellular fibrotic material. Clinical manifestations of disease are often relatively nonspecific and most commonly include exertional dyspnea and nonproductive coughing. High-resolution computed tomography helps inform the diagnostic evaluation of interstitial lung disease and may obviate the need for surgical lung biopsy when patients demonstrate highly characteristic patterns of lung disease. Identifiable causes of interstitial lung disease are often related to occupational or environmental exposure; in turn, avoidance of these exposures may significantly modify disease outcomes. Connective tissue disease–related interstitial lung disease is generally associated with a more favorable prognosis than idiopathic interstitial pneumonias and a higher likelihood of a therapeutic improvement with immune suppression. Antifibrotic agents slow the progression of idiopathic pulmonary fibrosis and may reduce the risk of exacerbations and mortality.

References 1. Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188(6):733–748. 2. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med 2018;378(19):1811– 1823. 3. Martinez FJ, Flaherty K. Pulmonary function testing in idiopathic interstitial pneumonias. Proc Am Thor Soc 2006;3(4):315–321. 4. Eaton T, Young P, Milne D, Wells AU. Six-minute walk, maximal exercise tests: reproducibility in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005;171(10):1150–1157. 5. Sung A, Swigris J, Saleh A, Raoof S. High-resolution chest tomography in idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia: utility and challenges. Curr Opin Pulm Med 2007;13(5):451–457. 6. Mueller-Mang C, Grosse C, Schmid K, Stiebellehner L, Bankier AA. What every radiologist should know about idiopathic interstitial pneumonias. Radiographics 2007;27(3):595–615. 7. Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society white paper. Lancet Respir Med 2018;6(2):138–153. 8. Nagai S, Handa T, Ito Y, Takeuchi M, Izumi T. Bronchoalveolar lavage in idiopathic interstitial lung diseases. Semin Respir Crit Care Med 2007;28(5):496–503. 9. DiBardino DM, Haas AR, Lanfranco AR, Litzky LA, Sterman D, Bessich JL. High complication rate after introduction of transbronchial cryobiopsy into clinical practice at an academic medical center. Ann Am Thorac Soc 2017;14(6):851–857. 10. Patel NM, Borczuk AC, Lederer DJ. Cryobiopsy in the diagnosis of interstitial lung disease. A step forward or back? Am J Respir Crit Care Med 2016;193(7):707–709. 11. Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Human Pathol 2008;39(9):1275– 1294. 12. Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008;63(Suppl 5):v1– v58. 13. Fischer A, Brown KK, Du Bois RM, Frankel SK, Cosgrove GP, Fernandez-Perez ER, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol 2013;40(5):640–646. 14. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med 2016;193(10):1161–1167. 15. Lai CK, Wallace WD, Fishbein MC. Histopathology of pulmonary fibrotic disorders. Semin Respir Crit Care Med 2006;27(6):613–622. 16. Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease–related subtypes. Am J Respir Crit Care Med 2007;175(7):705–171. 17. Spagnolo P, Lee JC, Sverzellati N, Rossi G, Cottin V. The lung in rheumatoid arthritis: focus on interstitial lung disease. Arthritis Rheumatol 2018;70(10)1544–1554.

18. Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001–11. Lancet Respir Med 2014;2(7):566–572. 19. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 2015;192(2):e3– e19. 20. Dowman LM, McDonald CF, Hill CJ, Lee AL, Barker K, Boote C, et al. The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial. Thorax 2017;72(7):610–619. 21. Ahluwalia N, Shea BS, Tager AM. New therapeutic targets in idiopathic pulmonary fibrosis: aiming to rein in runaway wound-healing responses. Am J Respir Crit Care Med 2014;190(8):867–878. 22. Valapour M, Lehr CJ, Skeans MA, et al. OPTN/SRTR 2016 annual data report: lung. Am J Transplant 2018;18(Suppl 1):363–433. 23. Baughman RP, Grutters JC. New treatment strategies for pulmonary sarcoidosis: antimetabolites, biological drugs, and other treatment approaches. Lancet Respir Med 2015;3(10):813–822. 24. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet 2012;380(9842):689–698. 25. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Europ Respir J 2015;46(4):976–987. 26. Dai J, Wang L, Yan X, Li H, Zhou K, He J, et al. Clinical features, risk factors, and outcomes of patients with interstitial pneumonia with autoimmune features: a population-based study. Clin Rheumatol 2018;37(8):2125–2132.

CHAPTER

35 Pulmonary Vascular Disease Talal Dahhan Charles William Hargett

© Andriy Rabchun/Shutterstock

OUTLINE Pathophysiology Epidemiology Diagnosis Management of Selected Pulmonary Vascular Diseases Case Studies

OBJECTIVES 1. Describe the physiology of the pulmonary circulation and right ventricle in normal and disease states. 2. Describe the World Health Organization’s classification of pulmonary vascular diseases and various types of clinical pulmonary hypertension. 3. Describe the signs and symptoms of pulmonary vascular diseases, including those present in pulmonary embolism (PE), cor pulmonale, and idiopathic pulmonary arterial hypertension (IPAH). 4. Define the role of ventilation-perfusion scanning, computed tomographic angiography, and pulmonary angiography in the diagnosis of PE. 5. Discuss the role of anticoagulation, vena cava filters, and thrombolytic therapy in the management of acute PE.

6. Describe the pathogenesis and treatment of cor pulmonale. 7. Discuss the role of advanced therapies in the management of IPAH.

KEY TERMS anticoagulation computed tomographic angiography (CTA) cor pulmonale deep vein thrombosis (DVT) hypoxic pulmonary vasoconstriction idiopathic pulmonary arterial hypertension (IPAH) inferior vena cava (IVC) filter prostacyclin pulmonary angiography pulmonary arterial hypertension (PAH) pulmonary artery pressure pulmonary embolism (PE) pulmonary hypertension (PH) pulmonary vascular resistance (PVR) thrombolytic therapy

Introduction Pulmonary vascular disease comprises a major category of cardiopulmonary disorders; this term describes any condition that affects the blood vessels between the heart and lungs. Disorders of the pulmonary circulation include a large and heterogeneous group of conditions that can be both severe and difficult to treat. Some pulmonary vascular diseases, such as pulmonary embolism, are common, whereas others, such as pulmonary arterial hypertension, are relatively rare. Conditions that affect the movement of blood from the right side of the heart, to the lungs, and back to the left side of the heart may lead to pulmonary hypertension, or high blood pressure in the lungs, and subsequent right-sided heart failure. These disorders are perhaps most effectively described in the framework of pulmonary hypertension, which represents a final common pathway of almost all forms of pulmonary vascular disease. This chapter first reviews the pathophysiology of pulmonary vascular disease in the context of normal cardiopulmonary physiology and function. Features common to many forms of pulmonary vascular disease are then described, in addition to issues related to the diagnosis and management of several specific disorders of the pulmonary circulation.

Pathophysiology Normal Pulmonary Vascular Physiology The principal function of the pulmonary circulation is gas exchange. Venous blood low in oxygen and rich in carbon dioxide passes through the pulmonary capillaries, where oxygen is absorbed and carbon dioxide is eliminated. Subsequently, the left ventricle (LV) sends this oxygenated blood to the rest of the body. Under normal circumstances, the pulmonary circulation is a low-pressure, high-flow system, providing little resistance to the right ventricular outflow. Mean pulmonary artery pressure and pulmonary vascular resistance (PVR) at rest are approximately onesixth that of the systemic circulation.1 Although the right ventricle (RV) is sensitive to the pulmonary vascular load, in a classic view the RV serves primarily as a capacitance chamber for blood returning from the systemic veins. As long as pulmonary vascular resistance is normal, blood flows from the right side of the heart through the lungs to the left side of the heart as a result of left heart action. The contraction of the LV and interventricular septum pulls the free wall of the RV against the septum and augments the flow of blood through the pulmonary circulation.2 The phasic changes in intrathoracic pressure that accompany breathing also direct the forward flow of blood from the RV through the pulmonary circulation. Normally, the pulmonary vascular bed is able to accommodate large increases in blood flow without much change in pressure, thereby effectively preventing RV overload. For example, cardiac output can increase substantially during exercise in normal individuals, with pulmonary blood flow increasing as much as fivefold without harm.2,3 The thin-walled RV is highly compliant and able to accommodate large volumes and filling pressures. Recruitment of vessels in the poorly perfused upper lung and distention of the compliant vessels in the dependent areas allow the pulmonary circulation to accommodate these increases in cardiac output and pulmonary blood flow.4,5

Pulmonary Vascular Pathophysiology

Although the pulmonary circulation is remarkably adept at adjusting to increases in blood flow, many pathologic conditions give rise to pulmonary hypertension (PH), or an increase in blood pressure in the lung vasculature (Box 35-1). PH is present when the mean pulmonary artery pressure exceeds 20 mm Hg and may occur as a result of intrinsic abnormalities of the pulmonary vessels, secondary to underlying cardiac or pulmonary disorders, or as a complication from obstructive embolization. BOX 35-1 Selected Causes of Pulmonary Hypertension Pulmonary Arterial Hypertension (PH Associated with Pulmonary Arterial Disease) Idiopathic and familial pulmonary arterial hypertension Connective tissue disease (e.g., scleroderma, mixed connective tissue disease) Portopulmonary hypertension (liver disease–associated pulmonary hypertension) Human immunodeficiency virus (HIV) Congenital heart disease (e.g., Eisenmenger syndrome) Drugs (e.g., anorexic agents, stimulants) Persistent pulmonary hypertension of the newborn

Pulmonary Hypertension Associated with Left Heart Disease Left-sided systolic or diastolic dysfunction Left-sided valvular heart disease

Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxemia Chronic obstructive pulmonary disease (COPD) Diffuse parenchymal lung diseases (e.g., idiopathic pulmonary fibrosis) Hypoventilation Sleep-related breathing disorders

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Pulmonary embolism

Miscellaneous or Multifactorial Sarcoidosis Hemolytic anemias (e.g., sickle cell disease) End-stage kidney disease–associated pulmonary hypertension Compression of pulmonary vessels (e.g., mediastinal lymphadenopathy)

PH was originally classified as secondary in the presence of a known

cause and primary when no underlying etiology or risk factor could be identified.6 Advances in our understanding have led to the current classification, in which pulmonary hypertensive diseases are grouped into five categories according to cause and therapeutic strategy, with each category subdivided to reflect the diverse underlying etiologies and sites of injury involved.7 Although the underlying pulmonary vascular disease may differ for the various types of clinical PH, this phenotypic categorization remains useful for understanding and managing these conditions. Destruction or obliteration of the pulmonary vascular bed is likely to play a role in patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD).8 Hypoxemia causes pulmonary vasoconstriction.9 In contrast, pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling in the precapillary segments of the pulmonary vasculature due to an imbalance between endothelial mediators such as prostacyclin, thromboxane, and endothelin;10,11 the histopathology may include plexogenic arteriopathy, thrombotic lesions, and smooth muscle hypertrophy with intimal fibrosis. Unexplained PAH, also called idiopathic pulmonary arterial hypertension (IPAH), is the most well-studied form of PAH. Unresolved pulmonary emboli (or clots) may lead to further increases in pulmonary pressures, causing chronic thromboembolic pulmonary hypertension. Once PH develops, independent of the inciting event, pulmonary vascular remodeling occurs, leading to medial hypertrophy and intimal fibrosis, which further reduces the pulmonary vascular cross-sectional area and exacerbates PH. Figure 35-1 illustrates the vascular changes observed in a patient with PH. As right ventricular afterload increases with worsening PH, right ventricular hypertrophy, dilation, or failure can occur. When right heart failure is caused by a primary disorder of the respiratory system, it is classically named cor pulmonale, or pulmonary heart failure. COPD and idiopathic pulmonary fibrosis (IPF) are both commonly associated with the development of cor pulmonale.

FIGURE 35-1 The arrow shows pulmonary arteriolar smooth muscle cell hypertrophy, with prominent thickening of the medial layer.

Pathophysiology of Acute Pulmonary Embolism Venous thromboemboli that cause pulmonary embolism (PE) usually arise from deep vein thrombosis (DVT) in the lower extremities. When emboli acutely obstruct a significant portion of the pulmonary arterial bed, profound hemodynamic alterations occur. Hypoxemia occurs as a result of regions with low ventilation-perfusion ( ) and shunting that occurs secondary to perfusion of atelectatic areas. The impact of the embolic event depends on the extent of reduction of the cross-sectional area of the pulmonary vasculature and on the presence or absence of underlying cardiovascular disease.12 With massive emboli, cardiac output is diminished but may be sustained to a certain point. Increased pulmonary vascular resistance impedes right

ventricular outflow and reduces left ventricular preload. More than 50% obstruction of the pulmonary arterial bed is usually present before substantial elevation of mean pulmonary artery pressure develops. When the extent of obstruction of the pulmonary circulation approaches 75%, a normal individual cannot generate the right ventricular systolic pressures in excess of 50 mm Hg, which is required to preserve pulmonary perfusion; in such a case, cardiac failure and death will occur.13

Epidemiology Disorders of the pulmonary circulation include a diverse group of clinical conditions that result in substantial morbidity and mortality. Pulmonary embolism, for example, is recognized as the third most common cause of cardiovascular disease in the United States, after ischemic heart disease and stroke.13 Autopsy studies suggest that more than 600,000 patients in the United States develop DVT or PE or both each year, with more than half of these cases not being recognized before the patient’s death.14 PE probably causes or contributes to the death of at least 100,000 individuals each year.12 Cor pulmonale contributes substantially to mortality in patients with pulmonary parenchymal disease. The exact incidence and prevalence of cor pulmonale in COPD are unknown, but recent estimates suggest that 10% to 40% of patients with COPD have evidence of right ventricular hypertrophy.8 Cor pulmonale increases in prevalence with increased severity of lung disease and may occur in more than 70% of COPD patients with a forced expiratory volume in the first second of expiration (FEV1) of less than 0.6 L.15 The development of cor pulmonale in these patients portends a significantly worse prognosis than in patients with normal right ventricular pressures. In patients with COPD, overt right heart failure is associated with a five-year survival of only 30%.8,16 Similarly, in patients with fibrotic lung diseases such as IPF, PH is an important predictor of survival.17,18 Pulmonary arterial hypertension is an uncommon disorder of the pulmonary vessels associated with severe elevation in pulmonary vascular resistance. The incidence of PAH is unknown but is estimated at 5 cases per 1 million people in the general population.11,19 This condition is most commonly found among younger patients (ages 20 to 40 years) and occurs at least three times as frequently in women as in men. PAH is a devastating disease that has traditionally been associated with poor prognosis, with a 5-year survival of only 34%.20 Poor survival has been associated with worse functional class (III or IV) and reduced right ventricular hemodynamic function (specifically, elevated mean right atrial pressure and decreased cardiac index).

Pulmonary vascular disease clinically and pathologically indistinguishable from IPAH can occur in association with a number of systemic illnesses, such as scleroderma and human immunodeficiency virus (HIV) infection, or in association with the use of certain drugs, including appetite suppressants.21–23 The appetite suppressants fenfluramine and dexfenfluramine significantly increase the risk of pulmonary hypertension (odds ratio of greater than 20 with more than 3 months of use).23 Despite clearance by the Food and Drug Administration (FDA) of nine PAH drugs in four different classes over the past 20 years, PAH remains a severe condition, often leading to significant debility and death, and generally requires advanced medical therapy and possibly procedural or surgical interventions.

Diagnosis Acute Pulmonary Embolism The history, physical examination, arterial blood gas analysis, electrocardiogram (ECG), and chest radiograph often are useful in suggesting the presence or absence of pulmonary embolism. The clinical evaluation alone, however, is not a reliable guide to the diagnosis of PE, as is underscored by the high incidence of unsuspected PE in autopsy series.24 PE should be considered whenever unexplained dyspnea occurs, as well as when a patient with another potential explanation for dyspnea, such as underlying cardiopulmonary disease, develops new or worsening symptoms. Box 35-2 lists common risk factors for PE; the presence of one or more risk factors should increase the clinical suspicion. Unexplained dyspnea in association with pleuritic chest pain or hemoptysis is suggestive of PE, and PE must also be considered in the setting of unexplained syncope or sudden hypotension. BOX 35-2 Important Risk Factors for Pulmonary Embolism Recent surgery Acute medical illness Malignancy Pregnancy or postpartum Immobilization Prior history of deep vein thrombosis or pulmonary embolism Hypercoagulable states such as: Factor V Leiden mutation Prothrombin gene mutation Protein C or S deficiency Antithrombin III deficiency Dysfibrinogenemia Antiphospholipid syndrome Heparin-induced thrombocytopenia

The physical examination may be unrevealing in patients with acute PE. Because patients with lower-extremity DVT often do not exhibit pain, warmth, erythema, or swelling, the physical exam may not provide clues to the presence of an underlying DVT. An increased pulmonic component

of the second heart sound has been reported in massive PE, but the nonspecific findings of tachypnea and tachycardia remain the most common physical examination abnormalities described in PE. Hypoxemia is common in acute PE but not universally present. Young patients without underlying lung disease may have a normal PaO2. In a retrospective analysis of hospitalized patients with proven PE, the PaO2 was more than 80 mm Hg in 29% of patients younger than 40 years, compared with 3% in the older group.25 The alveolar–arterial difference was abnormal in all patients, however. Thus, the diagnosis of acute PE cannot be excluded based on a normal PaO2. Laboratory tests that may be useful include testing for D-dimer, a breakdown product of cross-linked fibrin found in conjunction with acute DVT and PE. Unfortunately, D-dimer may also be present in patients with infections, cancer, and other inflammatory disorders, rendering it nonspecific for acute venous thromboembolism. If the clinical suspicion of acute DVT or PE is low, however, a negative quantitative D-dimer test is generally considered sensitive enough to rule out venous thromboembolism (VTE). Electrocardiographic findings in acute PE are generally nonspecific and include T wave changes, ST segment abnormalities, and left or right axis deviation. Manifestations of acute right heart failure, including the S1Q3T3 pattern, right bundle branch block, P-wave pulmonale, or right axis deviation, were present in patients with massive PE in the Urokinase Pulmonary Embolism Trial (UPET).26 The majority of patients with PE have nonspecific abnormalities on chest radiographs, with common findings including atelectasis, pleural effusion, pulmonary infiltrates, and elevation of a hemidiaphragm.27 Classic radiographic findings of pulmonary infarction such as wedgeshaped pleural density (Hampton’s hump) or decreased vascularity (Westermark sign) are suggestive but occur only infrequently. A normal chest radiograph in the setting of severe dyspnea and hypoxemia without evidence of bronchospasm or cardiac shunt strongly suggests PE. In general, however, the clinician cannot use the chest radiograph to conclusively diagnose or exclude PE. Ventilation-perfusion ( ) scanning may be performed when PE is suspected. When abnormal, scans are conventionally read as showing

low, intermediate, or high probability for PE. Normal and high-probability scans are considered diagnostic. Figure 35-2 illustrates a highprobability scan in a patient with PE. In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study,28 patients with PE had scans that were high, intermediate, or low probability—but so did most patients without PE. Although the specificity of high-probability scans was 97%, the sensitivity was only 41%. Of interest, 33% of patients with intermediate-probability scans and 12% of patients with low-probability scans were diagnosed definitively with PE by pulmonary arteriography. When the clinical suspicion of PE was considered high, PE was found to be present in 96% of patients with high-probability scans, 66% of patients with intermediate-probability scans, and 40% of patients with lowprobability scans. Given these results, the clinician must pursue additional diagnostic tests when the scan is of low or intermediate probability if the clinical scenario suggests the patient has PE.

FIGURE 35-2 This perfusion scan (posterior view) reveals extensive pulmonary embolism with essentially absent flow to the left lung and perfusion defects in the right lung. The ventilation scan was normal.

scan use has decreased in favor of contrast-enhanced computed tomographic angiography (CTA) of the chest, which may reveal emboli

in the main, lobar, or segmental pulmonary arteries. The reported sensitivity and specificity of single-slice helical CTA has ranged from 53% to 100% and from 81% to 100%, respectively, but visualization of segmental and subsegmental pulmonary arteries is substantially better with newer multidetector scanners, as evidenced in the PIOPED II study, where the specificity of chest CTA was 95% and the sensitivity 83%.29,30 These technologies are helpful to identify right ventricular enlargement through calculation of the right ventricular to left ventricular ratio.31 Figure 35-3 illustrates chest CTA identification of a proximal pulmonary artery clot in a patient with PE. Box 35-3 summarizes the advantages and disadvantages of chest CTA in the diagnosis of PE.

FIGURE 35-3 Computed tomographic angiogram in a patient with bilateral, proximal, acute pulmonary emboli (arrows).

BOX 35-3 Utility of Computed Tomographic Angiography of the Chest in the Diagnosis of Pulmonary Embolism

Advantages Excellent visualization of pulmonary arteries Objective assessment of the right ventricle Noninvasive Relative rapidity of procedure Diagnosis of other (nonvascular) abnormalities

Disadvantages Experienced radiologist required to interpret the results Adverse reactions to contrast (e.g., anaphylaxis, nephrotoxicity) Radiation exposure

Figure 35-4 depicts a pulmonary angiogram diagnostic of PE. Although serious complications of pulmonary angiography occur infrequently (less than 0.5% incidence), respiratory failure, renal failure, significant bleeding, and death have all been reported.32 Angiography requires the presence of experienced physicians to perform the test and interpret the results. This test is rarely needed, however, because CTA is very accurate and offers the potential for additional diagnoses. In selected stable patients with suspected acute PE and nondiagnostic lung scans, serial noninvasive lower-extremity testing to rule out DVT may be a reasonable alternative approach because a positive lower-extremity study requires treatment without further testing.33

FIGURE 35-4 Pulmonary angiogram demonstrating acute pulmonary embolism. There is a large filling defect in the right pulmonary artery (arrow) and marked hypoperfusion to the right upper and middle lobes.

Although not sensitive for the diagnosis of PE, echocardiography may nonetheless play an important role in the evaluation of PE. Transthoracic echocardiographic signs of acute PE include dilation and hypokinesis of the RV, paradoxical motion of the interventricular septum, and lack of collapse of the inferior vena cava during inspiration.34 The McConnell sign (free-wall RV hypokinesis with moving apex) may be a more specific finding; rarely, direct visualization of a thrombus may guarantee the diagnosis.35 The speed and portability of echocardiography make it particularly useful in patients who are suspected of having PE and are too unstable for further evaluation with CTA or scan. Additionally, echocardiography helps stratify risk in patients with proven PE, and serial exams may demonstrate interval change in cardiac function.36,37 Echocardiography may also be useful in identifying other causes of

shock, such as aortic dissection (if performed transesophageally) and cardiac tamponade. Stop and Think A patient with DVT has an increasing oxygen requirement. She is tachypneic and mildly hypotensive. What would you suggest?

Respiratory Recap Diagnosis of Pulmonary Embolism ∎ The physical examination may be unremarkable. ∎ Hypoxemia is common but not universally present. ∎ Electrocardiographic findings often are nonspecific. ∎ The chest radiograph is often unremarkable; a normal chest radiograph with dyspnea and hypoxemia (and without significant wheezing or bronchospasm) is suggestive of PE. ∎ In patients with a low pretest probability for PE, a negative quantitative D-dimer assay result can be used to exclude PE. ∎ High-probability / scans are diagnostic when acute PE is clinically likely. ∎ Chest computed tomographic angiography is the test most commonly employed to detect PE; it is both sensitive and specific for this condition. ∎ Pulmonary angiography is the most accurate diagnostic test for PE but is invasive. ∎ Echocardiography is insensitive for the diagnosis of PE but plays an important role in clinical evaluation and risk stratification.

Chronic Pulmonary Hypertension and Right Heart Failure The manifestations of PH are generally nonspecific, so careful attention to the clinical history and physical examination can provide important clues to the presence of disease. In all patients, a careful history of current and prior medication use and concomitant medical conditions is essential. Dyspnea is a common feature of PH, and chest pain or heaviness may also occur. These symptoms may often be attributed to common conditions such as asthma, deconditioning, weight gain, panic attacks, coronary artery disease, or gastroesophageal reflux disease. This

misattribution may significantly delay the diagnosis. Patients in the PAH registry had symptoms from 2 to 5 years prior to a formal diagnosis.37 The Raynaud phenomenon may occur in patients with IPAH but is much more common with PAH associated with connective tissue disease. Exertional presyncope and syncope may be due to the patient’s inability to increase cardiac output in response to the increased demand and suggests advanced PH with right heart failure. Orthopnea is relatively common in patients with severe COPD, albeit not necessarily accompanied by worsening cardiac function. Orthopnea in these patients is related to hyperinflation of the lungs and the subsequent effects on ventricular function or reduction in venous return, or both. In patients with cor pulmonale and other forms of PH, increased venous and hepatic congestion can occur in advanced disease and lead to the development of early satiety, increasing lower-extremity edema, and fluid overload. A loud pulmonic valve closure sound is a common finding in patients with PH, independent of the cause. It may be accompanied by a parasternal or epigastric lift resulting from a hypertrophied RV. Tricuspid valvular regurgitation also develops because of dilation of the RV, which causes a prominent jugular V wave. Progressive signs of chronic right ventricular dilation and failure include pulmonic valve insufficiency, a right ventricular third heart sound, jugular venous distention, hepatojugular reflux, hepatomegaly, lower-extremity edema, ascites, and eventually anasarca. Patients with cor pulmonale and PH resulting from COPD also invariably have findings associated with their obstructive lung disease, including decreased breath sounds and hyperinflation. Individuals with cor pulmonale secondary to interstitial lung disease often exhibit dry crackles at the lung bases. Auscultation of the lungs in IPAH is generally unremarkable. Clubbing is common in patients with pulmonary fibrosis but not in patients with PH alone. Patients with significant PH and cor pulmonale are often hypoxemic, whereas those with PAH may have normal arterial oxygenation until late in the disease. Pulmonary function tests may sometimes identify the etiology of pulmonary vascular disease. The presence of significant PH and cor pulmonale with mild abnormalities in pulmonary function tests should suggest a diagnosis of primary pulmonary vascular disease.

In contrast to acute PE, in which nonspecific ECG changes are commonly observed, right heart strain—including P pulmonale, right axis deviation, and right ventricular hypertrophy—is typically present in patients with advanced pulmonary hypertension or cor pulmonale. Approximately 80% of patients with IPAH show evidence of right heart strain.38 Patients with longstanding PH or cor pulmonale have markedly abnormal radiographs that suggest the presence of their disease. Enlarged pulmonary arteries with or without an enlarged RV are often evident. Figure 35-5 illustrates severe bilateral pulmonary artery and RV enlargement in a patient with IPAH.

FIGURE 35-5 Chest radiograph in a patient with primary pulmonary hypertension. Enlarged right and left pulmonary arteries are evident (arrows).

Echocardiography is quite useful in the diagnosis of PH.39 The echocardiogram also helps establish secondary causes for PH, such as left ventricular dysfunction, mitral valve abnormalities, or congenital heart disease. Although echocardiography is not foolproof in the detection of mild to moderate PH, it is sensitive to severe elevations in pulmonary artery pressure. The majority of such patients have tricuspid regurgitation, thereby allowing a reasonably accurate estimate of pulmonary artery systolic pressure. Because echocardiography is

noninvasive, it is generally used early in the patient’s evaluation to determine the presence and severity of PH in the presence or absence of cor pulmonale. It is also useful for serial monitoring of patients with established PH after therapeutic interventions. For evaluation of a patient with PH, scanning is important in excluding chronic thromboembolic disease as a secondary cause of PH.39 The gold standard for the diagnosis of PH remains right heart catheterization, which should always be performed prior to instituting therapy. This technique utilizes a thermodilution balloon catheter to measure right ventricular, pulmonary artery, and pulmonary capillary wedge pressures.7,40 Patients with PAH have wedge pressures less than 15 mm Hg. The presence of a higher capillary wedge pressure suggests a left-sided cause of PH. In addition, right heart catheterization allows the clinician to compare the oxygen saturation in the patient’s central veins, right atrium, right ventricle, and pulmonary artery, thereby determining whether left-to-right or right-to-left shunting is present. Right heart catheterization supplements the echocardiographic data in the diagnosis and evaluation of congenital heart disease. In many centers, exposure to a pulmonary vasodilator is done during cardiac catheterization to assess vascular reactivity. In summary, in patients in whom PH is suspected based on the clinical history or physical exam, a reasonable diagnostic approach may begin with a chest radiograph and echocardiogram. A scan should be performed to exclude PE in patients with evidence of PH. If PH is a high probability, then CTA, pulmonary arteriography, or both should be performed. Respiratory Recap Diagnosis of Pulmonary Hypertension ∎ Dyspnea is common but not specific. ∎ Chest tightness or heaviness may occur but generally emerges with more advanced PH. ∎ Exertional presyncope or syncope, or both, may occur with advanced PH. ∎ A loud second heart sound (pulmonic valve closure) is common in severe PH. ∎ Hypoxemia is often present in patients with advanced PH. ∎ Electrocardiographic findings consistent with right heart strain are commonly observed. ∎ Enlarged pulmonary arteries may be seen on the chest radiograph. ∎ Echocardiography may help determine the underlying cause of PH.

∎ Echocardiography is also useful in determining and following RV size and function. ∎ The gold standard for the diagnosis of pulmonary hypertension is right heart catheterization.

Stop and Think Your patient with severe COPD has noted increasing lower-extremity edema for the past month and now has been admitted to the hospital with an exacerbation. What do you suggest for further evaluation and management?

Management of Selected Pulmonary Vascular Diseases Acute Pulmonary Embolism Anticoagulation has been proven to reduce mortality in acute PE, and it should be immediately instituted unless contraindications are present. Although anticoagulants do not directly dissolve preexisting clots, they prevent thrombus extension and indirectly decrease clot burden by allowing the natural fibrinolytic system to proceed unopposed.41 In case of a high clinical suspicion for PE, anticoagulation is appropriate while diagnostic testing is under way unless the risk of therapy is deemed excessive. Standard therapy consists of parenteral anticoagulants (fulldose unfractionated heparin, low-molecular-weight heparin, or fondaparinux) followed by oral vitamin K antagonists (warfarin) or new direct oral anticoagulants (NOACs). Unfractionated heparin (UFH) is usually delivered by continuous IV infusion, with therapy being monitored via measurement of the activated partial thromboplastin time (aPTT). Traditional physician-directed dosing of heparin often leads to subtherapeutic aPTT. Use of validated dosing nomograms can reduce the time to achieve therapeutic anticoagulation and decrease the risk of recurrent thromboembolic events.42–44 A heparin regimen consisting of a bolus of 80 units/kg followed by 18 units/kg/h has been recommended; following the institution of intravenous UFH, the clinician should follow the aPTT at 6-hour intervals until it is consistently in the therapeutic range of 1.5 to 2.0 times control values.45 Hospital protocols determine how to further adjust the heparin dose. Low-molecular-weight heparin (LMWH) is at least as safe and effective as UFH for the treatment of acute VTE and is favored for most hemodynamically stable patients45,46 with acute DVT or PE, except when the much shorter-acting heparin is deemed more appropriate. LMWH preparations offer several advantages over UFH, including greater bioavailability, longer half-life, lack of need for an intravenous infusion, more predictable anticoagulant response to weight-based dosing, and a decreased risk of heparin-induced thrombocytopenia (HIT). These preparations can be administered once or twice per day subcutaneously

and do not require monitoring of aPTT. Monitoring of factor Xa levels is reasonable in certain settings such as morbid obesity, very small patients (100 mg/L) may be seen in severe pneumococcal or Legionella pneumonia.23,24 CRP is not routinely used to aid in the diagnosis of CAP. Unlike CRP, procalcitonin, a hormone, is elevated in acute bacterial infections but not in viral infection or other inflammatory conditions.25 Serum procalcitonin levels are elevated in the acute phase of bacterial infection and decrease during recovery.26 As such, procalcitonin is increasingly used to diagnose and manage bacterial infections. However, a negative test for procalcitonin should not prompt withholding antibiotics in a patient in whom the clinical suspicion for bacterial CAP is strong, and a high initial procalcitonin level does not predict mortality.27 Rather, the utility of procalcitonin in CAP is to guide antibiotic discontinuation. Following the drop in procalcitonin levels over the course of recovery can aid clinicians in deciding when to stop antibiotics, and meta-analyses show that procalcitonin-guided antibiotic management in acute respiratory infections leads to shorter duration of antibiotic therapy and decreased mortality.28

Choosing Diagnostic Methods Choosing the right diagnostic tests for a given patient requires consideration of patient-specific (risk versus benefit, severity of illness) and hospital-specific (availability, expertise, cost-effectiveness) factors. In a patient with mild pneumonia who does not require hospitalization, sputum Gram stain and culture may be the only tests necessary. In contrast, critically ill patients with severe pneumonia may require more extensive and invasive testing. Respiratory Recap Diagnostic Methods ∎ Sputum Gram stain and culture ∎ Blood culture ∎ Serology and PCR ∎ Thoracentesis ∎ Bronchoscopy The choice of diagnostic method is patient-specific and depends on risks, benefits,

availability, expertise, severity of illness, and cost-effectiveness.

Risk Stratification The World Health Organization (WHO) reports that lower respiratory tract infections are the third leading cause of death worldwide. In the United States and Canada, CAP has a mortality of approximately 7% in hospitalized patients29 and 12% among hospitalized patients older than age 65.30 Risk factors for mortality from CAP include advanced age, systolic blood pressure < 90 mm Hg, respiratory rate > 30 breaths/min, acidemia, blood urea nitrogen > 11 mmol/L, and need for mechanical ventilation.30 Several scoring systems have been developed to help healthcare providers stratify patients’ risk related to CAP, including CURB-65 and the Pneumonia Severity Index (PSI) score. The PSI predicts mortality based on a scoring system accounting for demographics and clinical findings (Box 36-2), with higher risk classes predicting a higher risk of mortality (Table 36-3).31 Based on the associated mortality risks, patients in risk classes I and II are usually treated as outpatients, those in risk class III usually require observation or hospitalization, and those in risk class IV or higher require hospitalization, frequently including care in the intensive care unit (ICU).18, 31 TABLE 36-3 Risk of Mortality in Patients with CAP According to the Pneumonia Severity Index Score

Description * Patients without any risk factors are included in risk class I. Information from Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336(4):243–250.

BOX 36-2 The Pneumonia Severity Index (PSI) Criteria Demographic Factors Age Female sex Nursing home residence

+1 point per year −10 points +10 points

Presence of Coexisting Illnesses Neoplastic disease +30 points Congestive heart failure +10 points Cerebrovascular disease +10 points Renal disease +10 points Liver disease +20 points Physical Examination Findings

Altered mental status Pulse ≥ 125/min Respiratory rate ≥ 30/min Systolic blood pressure < 90 mm Hg Temperature < 35° C or ≥ 40° C

+20 points +10 points +10 points +20 points +15 points

Laboratory or Radiographic Findings Blood urea nitrogen ≥ 30 mg/dL +20 points Glucose ≥ 250 mg/dL +10 points Hematocrit < 30% +10 points Sodium < 130 mmol/L +20 points PaO2 < 60 mm Hg +10 points Arterial pH < 7.35 +30 points Presence of pleural effusion +10 points Information from Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002;165(7):867–903.

The CURB-65 score is simpler and calculated from five risk factors (1 point each) associated with increased mortality in patients with CAP (Box 36-3).32 In patients with a score of 0, the 30-day mortality is 0.7%. By comparison, scores of 1, 2, 3, 4, and 5 are associated with mortality rates of 3.2%, 3%, 17%, 41.5%, and 57%, respectively. Thus, patients with a CURB-65 score of 0 to 1 can likely be treated as outpatients, whereas a score of 2 likely requires hospitalization, and a score of 3 or greater requires hospitalization and possibly ICU-level care.32 BOX 36-3 The CURB-65 Criteria Confusion Blood urea nitrogen (BUN) ≥ 20 mg/dL Respiratory rate ≥ 30 breaths/min Systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg Age ≥ 65 years Information from Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58(5):377–382.

While these scoring systems have improved the ability of healthcare providers to risk stratify patients with CAP, they have several limitations. The PSI can be burdensome to calculate, and the necessary variables may not always be available. Conversely, the CURB-65 score consists of only five variables that are readily available but may incorrectly classify high-risk patients as low risk.33 No scoring system is perfect, of course, so healthcare providers must incorporate all available clinical data when determining an individual patient’s prognosis. The Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) have published guidelines on risk-stratifying patients for admission to the ICU. ICU admission is recommended for patients meeting one major criterion or three minor criteria for severe CAP (Box 36-4).18 Additionally, PaCO2 < 35 mm Hg or > 45 mm Hg within 24 hours of hospital admission predicts a higher risk of transfer to the ICU and a higher 30-day mortality.34 BOX 36-4 IDSA/ATS Criteria for Severe Community-Acquired Pneumonia Major Invasive mechanical ventilation Septic shock

Minor Respiratory rate ≥ 30 breaths/min PaO2/FIO2 ≤ 250 mm Hg Multilobar infiltrates Confusion/disorientation Uremia with blood urea nitrogen ≥ 20 mg/dL Leukopenia < 4000 cells/mm3 Thrombocytopenia < 100,000 cells/mm3 Hypothermia < 36° C Hypotension requiring aggressive fluid resuscitation Information from Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2): S27–S72.

Therapy Antibiotics The mainstay of CAP treatment is appropriate antimicrobial therapy. The initial (empiric) antimicrobial drugs are directed toward the pathogens for which the patient is most likely at risk. Not only does this require identification of a patient’s risk factors for certain pathogens, but it also requires knowledge of local antibiotic-susceptibility patterns for specific bacteria.18 Clinicians should administer antibiotics as soon as possible and within 1 hour in patients with sepsis. In patients hospitalized with CAP, delay in antibiotic administration by more than 4 hours is associated with higher mortality.35 Empiric treatment for CAP depends on treatment location (e.g., outpatient versus inpatient), severity of illness, and patient risk factors.18 For previously healthy nonhospitalized patients without risk factors for drug-resistant S pneumoniae (DRSP), macrolides (e.g., azithromycin, clarithromycin) are first-line therapy for treatment of CAP, although doxycycline may be adequate. Risk factors for DRSP include age ≤2 years or ≥65 years; antibiotic therapy within the past 3 months; chronic medical comorbidities such as heart, lung, liver, or kidney disease; diabetes mellitus; malignancy; immunosuppressed state; alcoholism; asplenia; and exposure to a child in day care. For patients with DRSP risk factors, first-line therapy includes (1) a respiratory fluoroquinolone (e.g., moxifloxacin, levofloxacin) or (2) a beta-lactam (high-dose amoxicillin or amoxicillin-clavulanate) with a macrolide (doxycycline could be substituted for a macrolide if indicated). In regions where macrolideresistant S pneumoniae is highly prevalent, patients should receive one of these alternatives.18 For patients hospitalized on the medical ward, first-line therapy for CAP includes a respiratory fluoroquinolone, or a beta-lactam (ceftriaxone, cefotaxime, or ampicillin is preferred; ertapenem is reasonable in selected patients) with a macrolide (or doxycycline). For patients admitted to the ICU, a beta-lactam (cefotaxime, ceftriaxone, or ampicillinsulbactam) plus either azithromycin or a respiratory fluoroquinolone is recommended. Penicillin-allergic patients should be treated with a respiratory fluoroquinolone and aztreonam.18 Some patients with severe CAP who require ICU admission have risk

factors for multidrug-resistant organisms (e.g., MRSA, Pseudomonas), such as structural lung disease (e.g., COPD, bronchiectasis) or frequent antibiotic use. If Pseudomonas infection is a concern, patients should receive a beta-lactam active against Pseudomonas (piperacillin/tazobactam, cefepime, imipenem, or meropenem) plus an antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin), or a beta-lactam as mentioned earlier plus an aminoglycoside plus either azithromycin, moxifloxacin, or levofloxacin. In patients with a penicillin allergy, aztreonam should be substituted for the beta-lactam.18 If MRSA is a concern, the antibiotic regimen should include vancomycin or linezolid,18 although a retrospective study of patients with CAP due to MSSA and MRSA found that treatment with a toxin-inhibiting drug such as linezolid or clindamycin was associated with improved survival.14 Once healthcare providers have identified the etiology of CAP in hospitalized patients, they can narrow the antibiotic regimen based on the pathogen. De-escalating the number and potency of antibiotics reduces the likelihood of antibiotic resistance and the risk of antibioticassociated complications such as Clostridium difficile colitis. Patients should be switched from intravenous to oral therapy when they are clinically stable or improving (e.g., afebrile, normotensive, no longer tachycardic or tachypneic, not requiring supplemental oxygen, exhibiting normal mentation, and tolerating oral intake).36 The same criteria may be used to identify patients who are candidates for discharge from the hospital.18 Approximately 48 to 72 hours prior to discontinuation of antibiotics, patients should be afebrile, have discontinued supplemental oxygen, and have normal vital signs. By following this general guidance, antibiotic duration will be approximately 5 to 7 days, which is in accordance with IDSA/ATS guidelines.18 Exceptions arise with virulent pathogens or when pneumonia becomes complicated by respiratory failure, septic shock, empyema, pulmonary abscess, or extrapulmonary dissemination. Nonmetastatic MRSA pneumonia requires 7 to 21 days of antibiotics depending on the extent of infection.37 Based on extrapolation of VAP data, uncomplicated Pseudomonas pneumonia can be treated for 7 to 10 days,38 though courses may last 14 days in patients who are slow to recover, are neutropenic, or have concurrent bacteremia.

Adjunctive Corticosteroids The rationale for using glucocorticoids in pneumonia is to decrease unregulated inflammation that leads to complications and higher morbidity and mortality. However, its practical role remains controversial, as studies show conflicting results from this therapy. Some metaanalyses have demonstrated a small mortality benefit, reduction in rate of ARDS, and reduced length of stay in patients hospitalized with CAP,39–41 whereas others show no mortality benefit and an increased rate of complications.42 The most commonly reported complication with glucocorticoids is hyperglycemia, although hospital readmission has also been observed.39,42 Based on these studies, the population thought to benefit most from glucocorticoids comprises immunocompetent patients with severe CAP and hypoxemia requiring ICU admission, but currently no consensus exists on these agents’ use. Stop and Think A 65-year-old male is admitted to the hospital for pneumonia. This is his second admission in two months. He has a history of diabetes mellitus and bronchiectasis. For which pathogens is the patient most at risk? Which antibiotic(s) should this patient receive?

Complications of Community-Acquired Pneumonia Normal time to resolution of CAP depends on the infecting organism and the patient’s risk factors. While the general teaching holds that pneumonia resolves in 3 to 4 days, risk factors such as advanced age, COPD, diabetes, cancer, and alcoholism may prolong recovery times. Failure to respond to initial antibiotics within the expected time frame should prompt the clinician to evaluate the type of organism, the appropriateness of antimicrobials, and the presence of complications of CAP. Treatment failure increases the morbidity and mortality linked to CAP.18,43 Complicated parapneumonic effusion and empyema occur in approximately 7% of patients hospitalized with CAP.44 These pleural effusions range from severe inflammatory reactions (parapneumonic effusion) to purulent infections of the pleural space (empyema).

Empyema is uncommon, representing 0.5% to 1.5% of cases of CAP.44,45 Treatment requires fluid drainage via tube thoracostomy, a prolonged antibiotic course, and in refractory cases, surgical debridement. Given the high morbidity associated with complicated parapneumonic effusion and empyema, pneumonia-associated pleural fluid should be sampled if feasible and if the quantity is sufficient to safely perform the procedure. Necrotizing pneumonia is another complication of CAP. Characterized by either multiple pulmonary cavities or a single lung abscess, necrotizing pneumonia is frequently the result of infection with S aureus,46 Klebsiella, or anaerobic organisms. Although there is no specified duration of antibiotics to treat this condition, antibiotics are usually required for at least 3 weeks to resolve the abscess or cavities. Surgery may be required in cases refractory to antibiotics, such as with large abscesses (>6 cm), obstructing tumors, or hemorrhage.

Prevention Once the most common cause of death worldwide, CAP has now become a preventable disease due to the revolutionary development of vaccines. Vaccines currently exist for the most common causes of CAP: S pneumoniae and the influenza virus. Many studies have reported that immunization against S pneumoniae reduces the likelihood of hospitalization and improves survival.47–50 In the United States, the Food and Drug Administration (FDA) has cleared two pneumococcal vaccines for use in adults: the pneumococcal conjugate vaccine (PCV13), which covers 13 serotypes, and the pneumococcal polysaccharide vaccine (PPSV23), which covers 23 serotypes. Given certain populations’ increased risk of developing invasive pneumococcal disease, PPSV23 is recommended in adults between ages 19 and 65 with ongoing cigarette use, chronic lung disease, chronic heart disease, alcoholism, chronic liver disease, and diabetes.51 Both PCV13 and PPSV23 are recommended in adults ≥65 years and in adults ≥19 years with immunosuppressed conditions (e.g., HIV infection, systemic corticosteroids, radiation therapy, chronic renal failure or nephrotic syndrome, solid-organ transplant, malignancy, congenital immunodeficiency), functional or anatomic asplenia, cerebrospinal fluid (CSF) leaks, or cochlear implants.52 Whenever possible, PCV13 should

be administered first, followed by PPSV23 1 year later. If PPSV23 is given first, PCV13 should be administered at least 1 year later. However, the efficacy of pneumococcal vaccines has been known to decline over time,53 and a PPSV23 booster is recommended after 5 years for all patients who received their first dose prior to 65 years of age or once they turn 65 years of age, whichever comes first. During influenza season, influenza vaccination reduces the severity of both primary viral pneumonia and secondary bacterial pneumonia.54 Furthermore, it reduces the risk of hospitalization from influenzaassociated pneumonia.55 Although some studies show a significant decrease in mortality among patients hospitalized with pneumonia,56 the true mortality benefit remains controversial due to confounding factors in prior studies.57 Nevertheless, the benefits of the vaccine outweigh the risks, and all major medical organizations continue to recommend yearly vaccination against influenza for all adults.

Aspiration and Anaerobic Pneumonia Aspiration into the lower airway can cause a number of respiratory complications, including pneumonia, lung injury, and airway obstruction.58 The aspiration of sterile, acidic gastric secretions can cause a chemical lung injury called aspiration pneumonitis, which typically presents soon after the aspiration event and resolves by 48 hours.59 In contrast, aspiration pneumonia is caused by inhalation of bacteria-rich oropharyngeal or gastric secretions, which leads to an indolent lung infection. Distinguishing between pneumonia and pneumonitis, however, can be difficult.58,59 Predisposing risk factors for aspiration include decreased level of consciousness, cardiac arrest, general anesthesia, neurologic disorders, immobility, poor dental hygiene, gastroesophageal reflux, bowel obstruction or vomiting, esophageal disorders, laryngeal injury (trauma, radiation, or surgery), recent or prolonged orotracheal intubation, and oropharyngeal dysphasia. Respiratory Recap Management of Pneumonia ∎ Differentiate between community-acquired and nosocomial pneumonia. ∎ Identify the organisms for which the patient is most at risk. ∎ Promptly administer appropriate, empiric antibiotics. ∎ Provide supportive care. ∎ Administer pneumococcal and influenza vaccinations to at-risk patients.

In community-dwelling, healthy patients, oropharyngeal flora is normally composed of viridans streptococci, H influenzae, and anaerobic bacteria.60 The anaerobes most commonly implicated in aspiration pneumonia include Bacteroides melaninogenicus, Fusobacterium nucleatum, and Peptostreptococcus species. These and other anaerobes seldom cause infections by themselves; instead, they act synergistically with other pathogens to cause polymicrobial infections. Respiratory samples from patients with anaerobic infections are frequently foul smelling due to the microbial production of volatile short-chain fatty

acids.61 In contrast to community-dwelling patients, the oropharyngeal flora of hospitalized patients typically shifts after approximately 48 hours from anaerobes to gram-negative rods. Aspiration pneumonia is a clinical diagnosis that is supported by patient-specific risk factors, microbiology, and chest imaging. Respiratory secretions may grow a specific organism or oropharyngeal flora. The chest radiograph most commonly shows involvement in the lungs’ dependent areas. When the patient assumes the supine position, these are the posterior segments of the upper lobes and the superior segments of the lower lobes. In the sitting or standing position, they more commonly comprise the lower lobes.61 When aspiration pneumonia is suspected, providers should promptly initiate antimicrobial treatment. Reasonable antibiotics for suspected anaerobic aspiration pneumonia include clindamycin, beta-lactams with beta-lactamase inhibitors (e.g., amoxicillin-clavulanate, ampicillinsulbactam), carbapenems, or moxifloxacin. Metronidazole has poor activity against Streptococcus species, so it is only adequate in combination with a beta-lactam.61 If the anaerobic lung infection remains untreated, it may eventually (after 7 to 14 days) cause necrosis, lung abscess, bronchopleural fistula, and empyema. For patients hospitalized more than 48 hours with aspiration pneumonia, empiric treatment with antibiotics with coverage against multidrug-resistant gram-negative rods and MRSA is appropriate.

Actinomycosis Actinomyces species are anaerobic, gram-positive rods that normally inhabit the human oropharynx, gastrointestinal tract, and female genital tract. Most commonly, these anaerobes gain access to the lungs via aspiration, although infection can also follow penetrating trauma. Patients with structural lung disease or alcohol abuse are at increased risk for such infections. Pulmonary actinomycosis is an indolent disease. The initial presentation can resemble tuberculosis (TB) or lung cancer, with signs and symptoms including cough, fever, hemoptysis, chest pain, weight loss, and malaise. A chest radiograph may reveal mass-like consolidation with cavitation or chest wall involvement. In fact, one of the hallmarks of

pulmonary actinomycosis is the direct invasion of surrounding structures such as adjacent lung tissue, pleura, bone, and soft tissue. Ultimately, this can lead to formation of a bronchocutaneous fistula. Diagnosis of pulmonary actinomycosis can be difficult to establish and requires the integration of available clinical, radiographic, microbiological, and histopathologic data. Classic histopathologic findings include granulomatous inflammation and sulfur granules.62 First-line treatment for pulmonary actinomycosis consists of high-dose intravenous penicillin for 2 to 6 weeks, followed by oral penicillin for 6 to 12 months. Patients who do not respond to antibiotic therapy alone may require surgical debridement.62,63

Nosocomial Pneumonia Pneumonia in hospitalized patients is called nosocomial pneumonia. Nosocomial pneumonia differs significantly from CAP in regard to risk factors (e.g., mechanical ventilation) and microbiology (i.e., more commonly caused by multidrug-resistant [MDR] organisms). MDR pathogens (or potentially MDR pathogens) are notable because they (can) rapidly acquire resistance to antibiotics, which complicates diagnosis, treatment, and prognosis. Nosocomial pneumonia encompasses two major subtypes: hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). In 2005, a third type, healthcare-associated pneumonia (HCAP), was introduced, but it was subsequently removed from the IDSA/ATS consensus statement in 2016.4 HCAP referred broadly to pneumonia in nonhospitalized patients with current or recent (within 90 days) exposure to healthcare systems, such as use of hemodialysis, wound care, infusion therapy, hospitalization, or skilled nursing or long-term care facilities.64 While no longer technically included under the nosocomial pneumonia definition, some patients with chronic healthcare use may develop pneumonia due to resistant pathogens such as MRSA or MDR gram-negative rods that differs from classic CAP. Risk factors for nosocomial MDR infections (HAP/VAP) include prior use of intravenous antibiotics within the past 90 days, 5 or more days of hospitalization prior to VAP onset, development of ARDS or need for acute renal replacement therapy (i.e., dialysis) prior to VAP onset, septic shock at the time of VAP onset, patient history of infection with an MDR pathogen, and high institutional prevalence of MDR infections among mechanically ventilated patients.4 The last risk factor specifically should reflect an institution’s local antibiogram, which should drive decisions on empiric antibiotic selections.4

Hospital-Acquired Pneumonia Hospital-acquired pneumonia (HAP) occurs in non-mechanically ventilated patients who are hospitalized for more than 48 hours and who

are not incubating the infection at the time of their admission.4 HAP is one of the most common nosocomial infections, occurring in 1% to 2% of hospitalized patients.65 This type of pneumonia increases mean hospital stay by 7 to 9 days and healthcare costs by more than $40,000 per patient.64 A number of risk factors for HAP have been identified, including malnutrition (albumin < 2 mg/dL), chronic kidney disease, anemia (hemoglobin < 10 g/dL), altered consciousness, Charlson comorbidity index ≥ 3, previous hospitalization, and thoracic surgery.66 Additionally, the use of proton-pump inhibitors (PPIs) has been associated with 30% increased odds of HAP.67 HAP should be diagnosed noninvasively, when feasible, including by chest radiograph and noninvasive blood and respiratory sample collection (e.g., sputum induction or nasotracheal suctioning).4 Treatment of HAP is similar to treatment of VAP and requires attention to risk factors for MDR pathogens (MRSA, MDR gram-negative organisms) and risk of death (septic shock, need for mechanical ventilation). For patients with MRSA risk factors, those hospitalized in a unit with more than 20% prevalence of MRSA, and those at high risk of death, empiric treatment should include vancomycin or linezolid.4 Similar principles apply for patients at risk of infection with MDR gram-negative pathogens. High-risk patients should receive two antipseudomonal antibiotics (a beta-lactam and either a fluoroquinolone or aminoglycoside). Patients at low risk for MDR gram-negative infections may receive monotherapy with either an antipseudomonal beta-lactam or fluoroquinolone, but not an aminoglycoside.4 Complications of HAP occur quite frequently—perhaps in more than 50% of patients. In one study, HAP-associated complications included respiratory failure (52.9%), septic shock (10.1%), acute kidney injury (7.6%), pleural effusion or empyema (9.2%), transfer to the ICU (9.2%), and initiation of mechanical ventilation (5.8%). The mean length of stay was approximately 26 days, and only one-third of patients were discharged home. The other two-thirds were either discharged to a skilled nursing facility (33%) or did not survive the hospitalization (33%).66

Ventilator-Associated Pneumonia Ventilator-associated pneumonia (VAP) is pneumonia occurring in patients receiving mechanical ventilation after 48 hours of endotracheal intubation.4 VAP occurs in approximately 15% to 26% of intubated patients,68,69 with an incidence of 7 to 28 episodes per 1000 ventilatordays.70,71 VAP increases the cost of hospitalization, duration of mechanical ventilation, ICU stay, and hospital stay.72 Mortality attributable to VAP is greater in surgical patients and in the elderly but might not be as high as was assumed in the past.73–75

Pathogenesis of VAP The pathogenesis of VAP relies on four major factors: the patient, healthcare devices, the hospital environment, and bacterial colonization. Bacterial colonization by aerobic gram-negative and gram-positive microbes (including MRSA) occurs universally in mechanically ventilated patients. The most heavily colonized sites are the oropharynx, sinuses, and stomach. These are also common sites for indwelling healthcare devices (e.g., nasogastric or orogastric tubes), which allow for biofilm formation. Biofilms also form on the endotracheal tube, allowing pathogens direct entry into the lower respiratory tract via leakage around the tube (despite the inflated cuff) or through the lumen of the tube. The endotracheal tube also circumvents the patient’s host defenses by impairing the cough reflex, damaging the tracheal epithelial barrier, and impeding mucociliary clearance.60 Other healthcare devices that can deposit bacteria into the lower airways include fiberoptic bronchoscopes and suction catheters.76 Patient factors known to increase the risk of VAP include cigarette smoking, postsurgery status, reintubation, supine position, malnutrition, enteral feeding, use of sedatives/paralytics, use of proton-pump inhibitors, transport out of the ICU, and bacterial sinusitis.60,76 VAP can also arise from a contaminated hospital environment. For example, Legionella has been isolated from hospital water supplies and is a reported cause of epidemic VAP.60

Diagnosis of VAP The diagnosis of VAP is traditionally based on a combination of clinical signs and symptoms of respiratory infection, chest imaging (new or worsening lung infiltrates), and microbiology data (positive qualitative or quantitative respiratory specimen cultures). Signs and symptoms of VAP can include fever, leukocytosis, altered mental status, purulent tracheobronchial secretions, and/or hypoxemia.77 However, these criteria lack sensitivity and specificity for VAP when compared with autopsy findings.78,79 A widely used tool to diagnose VAP is the Clinical Pulmonary Infection Score (CPIS). The CPIS was developed in a cohort of 28 patients and uses the patient’s temperature, WBC count, tracheobronchial secretions, PaO2, chest radiographic findings, and respiratory culture data to predict the likelihood of VAP.80 Although the CPIS initially appeared promising, subsequent studies revealed it to be imprecise and neither sensitive nor specific; thus, its use is no longer recommended.4 Biomarkers have been proposed to assist in diagnosing HAP and VAP, including procalcitonin, soluble triggering receptor expressed on myeloid cells (sTREM-1), and C-reactive protein (CRP), However, the use of these biomarkers alone or in conjunction with clinical findings is not currently recommended.4 The failure of CPIS and biomarkers to improve VAP diagnosis is in part due to the lack of an objective, universally accepted VAP definition.

Ventilator-Associated Events Many questions need to be answered before a definition of VAP gains widespread acceptance. Is pneumonia within the first 24 hours of mechanical ventilation the same as pneumonia after 5 days? How can pneumonia be distinguished from edema or atelectasis on chest radiograph? What constitutes infection versus microbial colonization? In an attempt to answer these and other questions, in 2011 a multidisciplinary panel of experts from pulmonary, critical care, infectious disease, respiratory care, epidemiologic, and governmental organizations convened to develop an algorithm to define ventilator-associated events (VAE).81 This algorithm was published in 2013 and has since been

updated and simplified. The definition is not intended to support clinical diagnosis but rather to facilitate epidemiologic surveillance. Thus, it is designed to detect a broad range of events, including ventilatorassociated conditions (VAC), infection-related ventilator-associated complications (IVAC), and possible ventilator-associated pneumonia (PVAP). For VAE to be present, a patient on a ventilator needs to be stable or improving for a minimum of 2 days, followed by a period of 2 days during which the patient has worsening hypoxemia (increase in positive endexpiratory pressure [PEEP] ≥ 3 cm H2O or FIO2 ≥ 0.2). This deterioration is called a VAC. If the patient has signs of an infection (e.g., abnormal body temperature or WBC count) and antibiotics are initiated, the condition is called an IVAC. A PVAP is identified when the patient meets the criteria for IVAC and also has a positive respiratory culture above the semiquantitative or quantitative threshold, or has purulent respiratory secretions and a positive respiratory culture below the threshold, or has a positive pleural fluid culture, evidence of pneumonia on lung biopsy (histopathology), a positive Legionella test, or a positive respiratory viral test. By definition, a patient will not meet criteria for PVAP until at least ventilator day 4.82 Notably absent from the VAE definition is the requirement for specific findings on a chest radiograph. This omission largely reflects the high variability in radiographic image quality, interpretation, and accuracy. Chest radiographs are not sensitive for diagnosing VAP, missing as many as 25% of lung infiltrates.74 In a study comparing chest radiograph and autopsy findings (the gold standard for VAP diagnosis), radiographic infiltrates did not correlate well with lung histopathology.83 Many conditions may cause infiltrates in ventilated patients that could be mistaken for pneumonia, such as atelectasis, chemical pneumonitis (aspiration), pulmonary edema (heart failure), pulmonary embolism (lung infarction), alveolar hemorrhage, and ARDS.84

Microbiology The microbiology of nosocomial pneumonia differs from that of CAP. Nosocomial pneumonia is more commonly caused by MDR or potentially

MDR pathogens. This is especially true for late-onset nosocomial pneumonia, which is defined as occurring more than four to five days after hospitalization or intubation. Conversely, early-onset nosocomial pneumonia occurs within four days of hospitalization or intubation, is more frequently caused by antibiotic-sensitive bacteria, and usually carries a better prognosis (Table 36-4).64,74,85 TABLE 36-4 Most Likely Etiologies of Ventilator-Associated Pneumonia Early Onset and No Risk for MDR Pathogens Streptococcus pneumoniae Haemophilus influenzae Methicillin-sensitive S aureus Escherichia coli Klebsiella pneumoniae Enterobacter spp. Proteus spp. Serratia spp.

Late Onset or at Risk for MDR Pathogens Methicillin-resistant Staphylococcus aureus Multidrug-resistant enteric and non-enteric gram-negative rods (e.g., Acinetobacter, Pseudomonas, Stenotrophomonas) ESBL- or KPC-producing organisms Early-onset pathogens

ESBL, extended-spectrum beta-lactamase; KPC, K pneumoniae carbapenemase; MDR, multidrug resistant.

The most common (potentially) MDR pathogens causing nosocomial pneumonia include (1) the gram-positive coccus S aureus, (2) the enteric gram-negative rods (e.g., Escherichia coli, Proteus, Serratia, Enterobacter, Citrobacter, and Klebsiella species), and (3) the nonenteric gram-negative rods (e.g., Pseudomonas, Stenotrophomonas, and Acinetobacter species). Of these, the predominant pathogens are S aureus (26%), Pseudomonas (23%), and Acinetobacter (19%).77 A risk factor for MDR VAP is tracheobronchial colonization with Candida species, a relatively common phenomenon in intubated patients.86 Of particular concern are the emerging K pneumoniae carbapenemase (KPC)-producing organisms (named for their initial discovery in Klebsiella) that are resistant to all beta-lactams, cephalosporins, monobactams, and carbapenems; these organisms have also been identified in a number of other enteric and non-enteric bacteria. Carbapenems are among the most broad spectrum antibiotics

manufactured to date, so infection with KPC-producing bacteria significantly complicates treatment and is associated with an increased mortality.87 Determining whether pathogens isolated from the lower respiratory tract are the source of the infection (as opposed to colonizers) can be difficult and requires clinical correlation of the results. The first step is collecting respiratory secretions that can be cultured. Current guidelines recommend noninvasive sampling (e.g., endotracheal aspirate) over invasive sampling (e.g., BAL or protected specimen brush [PSB]).4 Guidelines also recommend semiquantitative techniques (e.g., heavy or 4+) rather than quantitative methods (e.g., >104 CFU/mL) to measure bacterial growth.4 For patients who do undergo invasive respiratory sampling with quantitative bacterial culture reporting, standardized cutoffs exist for the microbiologic diagnosis of VAP by BAL or PSB (Box 36-5).74 Bacterial counts that fall below these cutoffs may suggest the absence of respiratory infection or may be due to prior antibiotic exposure, poor sampling, or laboratory error and should still be interpreted in the context of the patient’s clinical condition.4 BOX 36-5 Thresholds for the Diagnosis of Ventilator-Associated Pneumonia Endotracheal aspirates Bronchoalveolar lavage Protected specimen brush

≥105–106 CFU/mL ≥104 CFU/mL ≥103 CFU/mL

CFU, colony-forming unit.

Treatment According to the 2016 IDSA/ATS recommendations, patients with suspected or confirmed nosocomial pneumonia, especially those at risk for MDR pathogens, should receive early, empiric, combination antibiotic therapy. Such therapy increases the likelihood that MDR pathogens are treated with a drug to which they are susceptible and should be informed by local susceptibility patterns.4

Specifically, patients at risk for MRSA and/or MDR gram-negative pathogens or patients at high risk of death (e.g., with septic shock or need for mechanical ventilation) should be given one antibiotic from each of the following three antibiotic categories: (1) an antipseudomonal cephalosporin (e.g., cefepime, ceftazidime), carbapenem (e.g., imipenem, meropenem), or penicillin/beta-lactamase inhibitor (e.g., piperacillin/tazobactam); (2) an antipseudomonal fluoroquinolone (e.g., ciprofloxacin, levofloxacin) or aminoglycoside (e.g., gentamicin, tobramycin, amikacin); and (3) an anti-MRSA antibiotic (vancomycin or linezolid) (Box 36-6). BOX 36-6 Empiric Antibiotic Treatments for Ventilator-Associated Pneumonia Early Onset and No Risk for MDR Ceftriaxone or Levofloxacin or moxifloxacin or ciprofloxacin or Ampicillin/sulbactam or Ertapenem

Late Onset or High Risk for MDR Antipseudomonal cephalosporin (cefepime or ceftazidime) or antipseudomonal carbapenem (imipenem or meropenem) or beta-lactam/beta-lactamase inhibitor (piperacillin– tazobactam) and Antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin) or aminoglycoside (amikacin, gentamicin, or tobramycin) and Anti-MRSA antibiotics (e.g., linezolid, vancomycin) MDR, multidrug resistance; MRSA, methicillin-resistant S aureus.

Patients with early-onset VAP who do not have identifiable risk factors for MDR pathogens can be given a more limited-spectrum antibiotic regimen (e.g., monotherapy with levofloxacin, cefepime, piperacillintazobactam, imipenem, or meropenem). At institutions where 10% or less of gram-negative isolates are resistant to the single antibiotic being considered, double coverage is not necessary, unless the patient is high risk for gram-negative infections, as in the case of structural lung disease such as cystic fibrosis. The same principle applies in units with less than 10% to 20% prevalence of MRSA.4 In all cases, the choice of antibiotics

for a given patient should be guided by the patient’s previous antibiotic exposure, allergies/sensitivities, historical culture data, and local patterns of pathogen prevalence and antibiotic susceptibility.64 Knowledge of the local resistance patterns and pathogen prevalence is especially critical, as studies have found a significantly higher mortality in patients who receive inappropriate initial antibiotics.88 In patients with suspected or confirmed MRSA nosocomial pneumonia, emerging data can inform the choice of antibiotics. In one study, patients with MRSA pneumonia treated with linezolid experienced higher clinical cure rates (57% versus 46%) and lower incidence of renal failure (8% versus 18%), but similar 60-day mortality compared to patients treated with vancomycin.89 In a prospective, nonblinded study of patients with MRSA VAP, trends were found for improved clinical cure rate, duration of ventilation, hospital and ICU length of stay, and survival in patients treated with linezolid compared to vancomycin.90 Several new antibiotics with activity against MRSA have now received FDA approval. The glycopeptide televancin is FDA-cleared for nosocomial pneumonia, and the fifth-generation cephalosporin ceftaroline is FDA-cleared for CAP. Other FDA-approved anti-MRSA antibiotics may also be useful for pneumonia, including tedizolid91 and dalbavancin,92 although further studies are needed to confirm their effectiveness. Ceftobiprole, another fifth-generation cephalosporin that is approved in Europe but not in the United States, may be effective in HAP but has not been shown to perform as well in VAP compared to currently approved antibiotics.93 Omadacycline is a semisynthetic derivative of tetracycline that has activity against MRSA and is currently undergoing FDA evaluation. Daptomycin, another anti-MRSA antibiotic, is not appropriate for treating MRSA lung infections because it is inactivated by pulmonary surfactant phospholipids. Patients with nosocomial pneumonia due to Pseudomonas who are at high risk of death (>25% risk) should be treated with combination antipseudomonal antibiotic therapy (double coverage) until the antibiotic susceptibilities are known, and perhaps even until acuity of illness subsides (e.g., septic shock resolves). Monotherapy is recommended for stable patients with Pseudomonas HAP/VAP and for patients with known antibiotic susceptibilities.4 Acinetobacter pneumonia should be treated with either carbapenems or ampicillin-sulbactam, if susceptible; if not

susceptible, the treatment is intravenous polymixins (colistin or polymixin B). Pneumonia due to extended-spectrum beta-lactamase (ESBL) producing gram-negative rods is generally treated with carbapenems. However, carbapenems are hydrolyzed and inactivated by KPCproducing organisms, necessitating the use of systemic aminoglycosides and/or polymixins with or without adjuvant inhaled colistin. Until recently, polymixins (e.g., colistin, polymixin B) were rarely used due to their higher rates of nephrotoxicity and neurotoxicity. With the increasing prevalence of KPC, however, the use of polymixins is on the rise.87 Novel antibiotics with extended gram-negative coverage but less toxicity as the polymixins have recently been developed. Ceftolozane-tazobactam and ceftazidime-avibactam are cephalosporins paired with beta-lactamase inhibitors that recover activity against ESBL-producing organisms. Ceftazadine-avibactam is specifically approved for nosocomial pneumonia. An emerging concept for treating patients with VAP, particularly those with MDR organisms, is the use of nebulized antibiotics. Experimental pneumonia models indicate that nebulized antibiotics are deposited in high concentrations in the lung. Given the increasing use of systemic, toxic antibiotics (e.g., colistin), nebulized antibiotics represent a very attractive option that can treat pneumonia but avoid systemic toxicity. A number of studies have investigated the use of adjunctive inhaled antibiotics for VAP but have yielded mixed results—finding either significant improvement in rates of clinical cure, microbial eradication, and even mortality94–96 or little to no improvement in these outcomes.97–100 Most of these studies found that the addition of inhaled antibiotics was safe, with one exception: A study of nebulized ceftazidime noted that the nebulized drug caused obstruction of the ventilator’s expiratory filter in three patients, one of whom suffered a cardiopulmonary arrest as a direct result.98 Another study found a trend for increased bronchospasm (7.8% versus 2%).97 Nevertheless, in patients with extensively resistant VAP at high risk of death, the addition of inhaled antibiotics to a systemic antibiotic regimen may provide patients with an increased chance for clinical cure, and its use is generally considered safe. For these reasons, the 2016 IDSA/ATS recommended the use of aerosolized colistin for VAP, especially MDR VAP with few therapeutic options.4

De-escalation and Duration of Antibiotic Treatment Once the susceptibilities of the isolated pathogens are known, the antibiotic regimen should be de-escalated to the most narrow-spectrum drug(s) possible. This strategy is intended to reduce the development of antibiotic resistance and complications such as Clostridium difficile colitis. Moreover, in patients who have not had any changes to their antibiotic regimen for more than 72 hours, a negative respiratory specimen culture supports the de-escalation of combination antibiotics to monotherapy in an otherwise stable patient, provided the patient receives ongoing coverage for organisms based on the local antibiogram.4 In addition to narrowing the antibiotic regimen, evidence supports shortening the duration of antibiotic exposure. For the treatment of VAP, two prospective, randomized clinical trials found no difference between a short (8 days) and long (15 days) antibiotic course in regard to clinical cure rate or mortality, though longer durations may be indicated for clinical scenarios such as immunocompromised patients or unrelieved post-obstructive pneumonia.64,85,101 The 2016 IDSA/ATS guidelines therefore recommend a 7-day regimen for VAP and a regimen of 7 days or less for HAP. Stop and Think You are caring for a 71-year-old male undergoing mechanical ventilation for an exacerbation of COPD. On ventilator day 6, he is requiring more oxygen and has a new fever. What is the differential diagnosis? What test should be ordered to help determine the diagnosis?

Reasons for Deterioration or Nonresolution Even with the initiation of appropriate antibiotics for suspected VAP, patients may not clinically improve until day 3. Given this reality, the antibiotic regimen should generally not be changed before this time unless the patient experiences significant clinical deterioration or new respiratory culture data become available. Patients with nosocomial pneumonia who do not improve or who worsen by day 3 of antibiotics are considered to have failed therapy. In one study, as many as 31.8% of patients with VAP failed to improve by day 3. Independent predictors of clinical failure were lack of improvement in PaO2/FIO2 and persistent fever

by day 3.102 Clinical failure may occur for several reasons. First, assuming the diagnosis and the antibiotic choice(s) are correct, the antibiotic dose or dosing frequency could be incorrect, a drug–drug interaction could cause rapid metabolism or poor absorption of the antibiotic, or the antibiotic may poorly penetrate the site of infection. Second, the diagnosis may be correct, but the pathogen may be resistant to the antibiotic(s). Third, the diagnosis may be incorrect; that is, instead of VAP, the patient might have another cause of lung infiltrates, such as atelectasis, ARDS, pulmonary hemorrhage, congestive heart failure, pulmonary embolus with infarction, lung contusion, or chemical pneumonitis. Fourth, host factors, such as immunosuppression, may delay clinical improvement. Fifth, there could be other undrained pulmonary sites of infection, such as empyema, postobstructive pneumonia, or lung abscess, or coexisting nonpulmonary sites of infection, such as sinusitis, central venous catheter–related infections, C difficile pseudomembranous colitis, or urinary tract infections, that delay clinical improvement.64

Prevention of VAP Ventilator-Care Bundles A number of practices have been identified that improve outcomes in mechanically ventilated patients. These ventilator bundles focus on reducing exposure to mechanical ventilation (e.g., use of noninvasive positive pressure ventilation), reducing the duration of mechanical ventilation (e.g., accelerated weaning protocols, daily sedation vacations, daily spontaneous breathing trials), reducing aspiration of contaminated secretions (e.g., oral care with chlorhexidine, endotracheal cuff pressure 20–30 cm H2O, continuous aspiration of subglottic secretions, elevation of the head of the bed up to 45 degrees—especially during enteral feeding), and reducing nonventilator complications (e.g., prophylaxis with unfractionated or low-molecular-weight heparin to prevent deep venous thromboses, and prophylaxis with H2 blockers to prevent gastric stress ulcers and gastrointestinal bleeding). H2 blockers may be preferable to proton-pump inhibitors, which one observational cohort study found may increase the risk of VAP and C difficile infection.103 Ultimately, ICUs

should also incorporate staff education, infection control, and microbiologic surveillance into their individualized VAP prevention policies (Box 36-7).104 BOX 36-7 Ventilator-Care Bundle Elevation of the head of the bed to 30–45 degrees Daily awakening trial and assessment of readiness for extubation Deep vein thrombosis prophylaxis Peptic ulcer disease prophylaxis (controversial) Continuous aspiration of subglottic secretions (controversial) Oral care with chlorhexidine (no longer recommended)

Some VAP prevention strategies have been called into question. For example, subglottic secretion drainage is associated with lower VAP rates but does not decrease duration of mechanical ventilation, length of stay, ventilator-associated events, mortality, or antibiotic usage.105 Headof-bed elevation, sedative infusion interruptions, spontaneous breathing trials, and thromboembolism prophylaxis appear beneficial, whereas daily oral care with chlorhexidine and stress ulcer prophylaxis may prove harmful in some patients.106

Early Versus Late Tracheostomy One suggested strategy to reduce the frequency of VAP in orotracheally intubated patients is to perform tracheostomies early (within 2 to 4 days) rather than after 10 to 16 days (the usual practice). Rumbak et al. found that patients randomized to early tracheostomies had significantly decreased mortality, VAP, duration of mechanical ventilation and time in the ICU, and damage to mouth and larynx, compared with patients who received late tracheostomies.107 Subsequent randomized controlled trials found no reduction in mortality or VAP from this practice.108,109 Terragni et al. found early tracheostomy increased successful ventilator liberation and ICU discharge.109 These studies employed slightly different inclusion criteria, making generalizability difficult, although a meta-analysis found similar findings to those obtained by Terragni et al.110 It seems likely that early tracheostomy benefits some patients and not others, but criteria for selecting patients who will benefit remain unclear.

Respiratory Recap Nosocomial Pneumonia ∎ Nosocomial pneumonia is very common and increases morbidity, mortality, and healthcare costs. ∎ Nosocomial pneumonia is more likely to be caused by multidrug-resistant organisms. ∎ The number one risk factor for nosocomial pneumonia is an endotracheal tube. ∎ Guidelines for the management of nosocomial pneumonia emphasize appropriate empiric antibiotic therapy, de-escalation of initial antibiotic therapy, and shortening the duration of antibiotic therapy to the minimum effective period. ∎ VAP prevention should focus on avoiding mechanical ventilation, reducing duration of ventilation, and minimizing aspiration of contaminated secretions.

Viral Pneumonia Respiratory viruses cause the vast majority of upper respiratory tract infections (URIs). A growing body of evidence suggests these viruses also account for a significant number of pneumonia cases. In fact, among patients admitted to the ICU with pneumonia, as many as one-third of cases may be due to viruses.111 The viruses most commonly associated with pneumonia are influenza, parainfluenza, human metapneumovirus, adenovirus, rhinovirus, and respiratory syncytial virus (RSV). Other viruses that can cause pneumonia in immunocompromised hosts are cytomegalovirus (CMV), varicella zoster virus (VZV), and herpes simplex virus (HSV). Rare but often fatal causes of viral pneumonia include hantavirus, measles, and the emerging Middle East respiratory syndrome coronavirus (MERS-CoA).

Influenza Virus Seasonal influenza infection causes nearly 1 million hospitalizations annually,112 with its incidence traditionally peaking in the winter months. Individuals particularly susceptible include young children, the elderly, and patients with chronic medical conditions. Influenza infection is frequently complicated by secondary bacterial pneumonia, usually due to S aureus or S pneumoniae, and portends a worse prognosis.113 The diagnosis of influenza is based on clinical symptoms (e.g., high fevers, chills, pharyngitis, malaise, myalgias) and viral testing. Rapid influenza detection assays are nearly 100% specific but only 40% to 50% sensitive in adults; their sensitivity is only slightly higher in children.114 Viral culture and PCR have near perfect performance characteristics in making the diagnosis but are more expensive, are not universally available, and can take several days to complete.115 Influenza is spread via aerosolized respiratory droplets, so once this disease is suspected or confirmed, patients should be isolated to avoid infecting others. Healthcare practitioners can reduce their risk of exposure by wearing a surgical mask. Standard treatment of influenza infection includes antiviral therapy (i.e., neuraminidase inhibitors—

oseltamivir and zanamivir) and supportive care.116 Oseltamivir given within 48 hours of symptom onset can accelerate symptom resolution, decrease risk of post-influenza bacterial pneumonia, and decrease the risk of hospitalization.117 Approximately 60% of influenza infections are prevented annually by the influenza vaccine.118 Although their efficacy varies from year to year depending on the degree of antigenic match between vaccine strain and circulating strain,119 vaccines have consistently reduced the risk of hospitalization and severe illness,55,120 even in the face of antigenically drifted strains.121 Currently the Centers for Disease Control and Prevention recommends influenza vaccination for everyone older than 6 months of age.122 In the past, the influenza vaccine was contraindicated in patients with chicken egg allergies, but this recommendation has since been revised for patients with non-anaphylactic reactions. Reactions are also less likely with the attenuated vaccine compared with the live vaccine.123 In contrast to the seasonal influenza virus, zoonotic influenza viruses arise after human strains combine with avian or porcine strains. Their unpredictability makes vaccine development a yearly challenge for the World Health Organization.119,124 Highly pathogenic pandemics include bird flu H5N1 from 2003 to 2006 and swine flu H1N1 during 2009 and 2013. The most recent pandemic, caused by bird flu H7N9, was responsible for more than 1330 cases and 365 deaths from 2014 to early 2018 in China.124,125 Unlike seasonal influenza, these outbreaks target both chronically ill patients and previously healthy young adults,126 with mortality rates as high as 60%.127 Obesity and pregnancy (or postpartum status) are unique risk factors for severe H1N1 infection, as these patients have higher rates of H1N1-associated complications and mortality.128 Interestingly, elderly populations were relatively protected from the H1N1 pandemic, perhaps because of antigenic similarities to prior influenza strains.129 Stop and Think You are caring for an elderly woman hospitalized for influenza pneumonia. Which precautions should be taken to protect yourself and others?

Age-Specific Angle RSV infection is frequent in children, particularly in the winter months.

Viral Pneumonias in Children RSV is the most common cause of lower respiratory tract infections in children younger than 1 year of age and an infrequent cause of pneumonia in adults.127 The incidence of this infection peaks in the winter months like influenza; unlike influenza, however, RSV causes significantly more wheezing and acute bronchiolitis. Treatment is primarily supportive. Other common respiratory viruses include parainfluenza, adenovirus, and rhinovirus. These viruses are frequent causes of conjunctivitis and URIs127 and have emerged as concerning causes of pneumonia in children.130 The majority of these viral pneumonias are self-limited, but some do progress to severe acute respiratory failure. No specific treatments are available for these diseases other than supportive care. Human metapneumovirus (hMPV) is an emerging pathogen in children prior to age 3 years.131 Much like influenza and parainfluenza, hMPV causes one childhood hospitalization per thousand in the United States. Of those hospitalized with hMPV infections, 50% are diagnosed with pneumonia.

Viral Pneumonias in Immunosuppressed Individuals Patients with impaired immune function are at risk for pneumonia caused by varicella virus (VZV), herpes simplex virus (HSV), and cytomegalovirus (CMV). These viruses—all members of the Herpesviridae family—are commonly acquired during childhood or adolescence. CMV can also be contracted from blood products or tissues from a CMV-positive donor. After the self-limited infection resolves, these viruses remain dormant in the body forever and can reactivate if the immune system is weakened. While CMV reactivation is often the product of immunosuppression, the virus itself also increases the risk of bacterial coinfection132 and Pneumocystis pneumonia133 in transplant patients. Herpesviruses have also been isolated in the blood and

bronchoalveolar fluid of non-immunocompromised, critically ill patients on mechanical ventilation.134–136 It is still unclear whether reactivation during critical illness is pathogenic or a symptom of severe illness. The presence of CMV is associated with longer time on mechanical ventilation, increased nosocomial infections, longer ICU stay, and mortality.134,137 By contrast, HSV viremia and pneumonitis do not appear to be associated with ICU mortality.135,136 Signs and symptoms of pneumonia due to a Herpesviridae virus may be nonspecific and include fever, dry cough, tachypnea, and hypoxemia. Chest imaging commonly shows diffuse nodular or interstitial infiltrates. Diagnosis generally requires microbiologic and histopathologic confirmation of infection. Treatment includes antiviral medications and supportive care. CMV pneumonitis is treated with ganciclovir or foscarnet, whereas varicella and herpes simplex pneumonias are treated with acyclovir, vidarabine, or foscarnet. The best treatment of course is prevention. Varicella vaccination is now recommended during childhood. While no vaccine for CMV is available, prophylactic ganciclovir or valganciclovir can be administered to immunocompromised patients at risk of reactivation.

Other Viral Pneumonias Once thought to be nearly eradicated in the United States due to the measles–mumps–rubella (MMR) vaccine, measles has resurged in the 21st century as a consequence of the false claim that MMR vaccines lead to autism138 and the subsequent social movement against childhood vaccinations. States permitting philosophy- or religion-based nonmedical exemptions for vaccines have lower rates of vaccination and are at higher risk for disease outbreaks.139 In 2014, 383 cases of measles occurred among unvaccinated Amish communities in Ohio. Between December 2014 and February 2015, 125 cases of measles were reported among tourists visiting the California Disney theme parks. Of the vaccineeligible patients involved in this outbreak, 67% were found to be intentionally unvaccinated.140 Pulmonary complications are the leading cause of mortality in measles due to the high rate of bacterial and viral coinfection.141 Signs and symptoms of measles pneumonia generally include the classic

measles rash, followed by prolonged fever, cough, and progressive respiratory failure requiring mechanical ventilation. Intravenous ribavirin has been used to treat measles, but most cases resolve with supportive care alone. Hantavirus is transmitted by aerosolized droppings of the deer mouse, which is native to the southwestern United States.142 Infection causes an influenza-like illness with fever and myalgia, followed by dyspnea, hypoxemia, pulmonary edema, hemorrhage, and shock. There is no specific therapy for this virus, and it is often fatal. In the 21st century, two coronavirus strains emerged that cause severe pneumonia: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERSCoV).143 These viruses are hypothesized to have migrated from animals to humans, although the precise animal reservoir remains controversial. Unlike other zoonotic infections, these viruses can also be transmitted between humans.143,144 The SARS-CoV epidemic was responsible for nearly 800 deaths between 2002 and 2004.127 MERS-CoV infection has been less widespread to date, but pandemic potential still exists. Both infections cause an influenza-like illness progressing to profound respiratory failure. There is no known antiviral therapy, and reported mortality is 50%.143

Mycobacterial Pneumonia Tuberculosis Tuberculosis (TB) is caused by Mycobacterium tuberculosis complex (MTB) and is a major cause of morbidity and mortality worldwide. In fact, one-third of the world’s population has been infected with MTB.145 In 2012, 1.3 million TB-related deaths were documented. One-third of these occurred in India and South Africa, largely due to their burden of HIV infection. With the institution of an aggressive public health campaign, the global burden of disease is declining by approximately 2% per year. Even so, adequate MTB control has not yet been realized, and MTB continues to represent a major public health threat.146

Initial Infection Tuberculosis is transmitted by cough-induced dispersal of infected droplets. These droplets are then inhaled by exposed persons into the small airways, where infection becomes established. The initial TB infection, also known as primary TB, is usually asymptomatic, although some patients may experience fever, malaise, or other respiratory symptoms. In most cases, primary TB is contained by the host immune responses via granuloma formation, scarring, and calcification. Such a calcified area of the lung on a chest radiograph is called a Ghon focus; when present with a calcified ipsilateral, hilar lymph node, it is called a Ranke complex. Patients able to contain their initial TB infections are said to have latent TB. When MTB avoids initial containment, it causes active primary TB. Patients with active primary TB may present with middle or lower lobe pneumonia and pleural effusion or hematogenous dissemination due to miliary TB. Miliary TB is characterized by innumerable small pulmonary nodules and can be seen in patients with severe immune compromise, such as in end-stage HIV.

Latent TB Patients with TB infection who do not have signs or symptoms of active

disease (including by chest radiography) are said to have latent TB. Latent TB is diagnosed by an immunologic test such as a tuberculin skin test (TST) or interferon gamma (IFN-γ) release assays (IGRA). A TST will be positive in as many as 30% of patients exposed to MTB. Latent TB represents a state of equilibrium between the host defenses and MTB. The infection is merely contained, but not eradicated. Thus, if the host becomes weakened, MTB can progress to active disease.147 Because of this risk, patients with latent TB are generally treated for 6 to 12 months with isoniazid (INH) and/or a rifamycin (e.g., rifampin, rifabutin, rifapentine). This prophylactic treatment can reduce the subsequent risk of developing reactivation TB by as much as 90%.148

Post-Primary TB Patients who do develop reactivation of latent TB are said to have postprimary TB. This condition is characterized by upper lobe cavity formation with a productive cough or hemoptysis and B symptoms such as malaise, anorexia, fever, night sweats, and weight loss (Figure 36-3). Rarely, post-primary TB can develop in patients with repeated primary MTB infection. Post-primary TB occurs only when the host immune defenses are weakened, such as with HIV/AIDS (CD4 count > 300 cells/mm3), organ transplantation,149 severe malnutrition,150 use of 151 152 immunosuppressive drugs, or malignancy. Post-primary TB develops in 5% to 10% of TB-exposed patients and usually occurs within 2 years of initial infection. Its diagnosis requires microbiological confirmation, usually accomplished by isolation of MTB from cultured sputum. Occasionally, confirmation of the diagnosis requires bronchoscopy.

FIGURE 36-3 Posteroanterior chest radiograph of a patient with active tuberculosis pneumonia showing right upper lobe consolidation and volume loss.

Treatment of TB Treatment of TB consists of 6 or more months of INH and rifampin (RIF),

plus 2 months of ethambutol (EMB) and pyrazinamide (PZA). Longer treatment courses are given to patients with certain high-risk features, including persistently positive sputum cultures after 2 months, presence of a lung cavity, or omission of PZA during the initial phase of therapy.148 The increasing prevalence of TB resistance to INH and RIF (MDR TB) poses a public health threat. MDR TB occurs in 3.5% of incident TB cases and 20% of patients with previously treated TB. Approximately 9% of patients with MDR TB are believed to have extensively drug-resistant TB (XDR TB), defined as MDR TB that is also resistant to a fluoroquinolone and an injectable anti-TB drug. Rates of cure for MDR TB vary and were only 52% in one cohort study.153 Mortality rates for patients with MDR TB are as high as 15%. Anti-TB agents for the treatment of MDR TB include levofloxacin, IV amikacin, clofazimine, and ethionamide. WHO recommends a five-drug regimen lasting 9 to 12 months.154 In 2012, the FDA cleared bedaquiline, the first anti-TB drug with a novel mechanism of action since 1971.155 Bedaquiline is approved as part of combination therapy for patients with MDR TB. When used in combination with the background regimen for MDR TB, bedaquiline decreases the time to sputum conversion (83 days versus 125 days) and increases the rate of cure at 120 weeks (58% versus 32%) compared to placebo.156,157 Although additional studies support its safety when used with other MDR drugs and antiretrovirals, it cannot be used as monotherapy for MDR TB.153

Infection Control Exposure to TB can occur in a variety of settings, including household contacts of infected individuals, endemic areas, correctional facilities, homeless shelters, and healthcare facilities. Healthcare exposures can occur during routine patient examination or during invasive procedures such as bronchoscopy.158 Patients suspected of having TB should be isolated in a negative pressure room. Additionally, the rate of TB transmission can be reduced by as much as 56% by placing surgical masks on patients suspected of having the infection.159

Nontuberculous Mycobacteria

Nontuberculous mycobacteria (NTM) are found worldwide in both soil and water. This diverse group of mycobacteria comprises more than 100 species with varying spectrums of pathogenicity, ranging from transient colonization to pulmonary cavitations, depending on the species and the host.160 The most common NTM in the United States is Mycobacterium avium complex (MAC), which is composed of two frequently indistinguishable species: M avium and M intracellulare. The two major risk factors for NTM infection are impaired immunity and structural lung disease such as cystic fibrosis, COPD, previous TB, pneumoconiosis (especially silicosis), alveolar proteinosis, and bronchiectasis.161 Bronchiectasis, in particular, appears to have a bidirectional relationship with NTM: It is both a risk factor for, and a consequence of, NTM infection. Pulmonary MAC manifests in two forms, though other NTM infections have similar findings. Nodular bronchiectasis is frequently seen in older, thin, female never-smokers who experience an asymptomatic or indolent disease. In contrast, fibrocavitary disease is frequently seen in middleaged smoking males with a history of alcohol abuse and/or COPD.162 Fibrocavitary MAC is associated with quicker progression and more complications such as hemoptysis and secondary infections. Symptoms of NTM infection are nonspecific and include low-grade fevers, night sweats, weight loss, and cough. Chest imaging shows upper lobe–predominant micronodules, bronchiectasis, or cavitary lesions. The diagnosis of NTM infection is made based on clinical, radiologic, and microbiological findings (Box 36-8). BOX 36-8 American Thoracic Society Diagnostic Criteria for Pulmonary Disease Caused by Nontuberculous Mycobacteria Clinical (both required) 1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a highresolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules and 2. Appropriate exclusion of other diagnoses

Microbiologic 1. Positive culture results from at least two separate expectorated sputum samples. If the results from (1) are nondiagnostic, consider repeat sputum AFB smears and cultures

or 2. Positive culture result from at least one bronchial wash or lavage or 3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM 4. Expert consultation should be obtained when NTM are recovered that are infrequently encountered or that usually represent environmental contamination. 5. Patients who are suspected of having NTM lung disease but who do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded. 6. Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients. AFB, acid-fast bacilli; NTM, nontuberculous mycobacteria. Reproduced with permission of the American Thoracic Society. Copyright © American Thoracic Society. From Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367–416.

As NTM is difficult to eradicate, treatment of all pulmonary NTM requires a multidrug regimen lasting more than a year. The most common treatment regimen for MAC consists of a macrolide, rifampin, and ethambutol. Other NTM infections may require a combination of fluoroquinolones, aminoglycosides, imipenem, sulfonamides, cefoxitin, clarithromycin, and/or linezolid. Amikacin liposome inhalation suspension is FDA-cleared for the treatment of MAC lung disease as part of a combination antibacterial drug regimen for adult patients who have limited or no alternative treatment options.163 If the treatment regimen fails or is stopped prematurely due to medication intolerance, and disease is isolated to a single cavitary lesion, surgical resection can be considered.162

Fungal Pneumonia Aspergillosis Aspergillus species are ubiquitous, spore-forming molds. Inhalation of Aspergillus spores by susceptible hosts (i.e., immunocompromised patients) can cause a necrotizing, hemorrhagic respiratory infection called invasive pulmonary aspergillosis (IPA). The most common cause of IPA is A fumigatus. The predominant risk factor for IPA is impaired host immunity, most commonly from neutropenic conditions including post-chemotherapy status, post solid-organ transplant or hematopoietic stem cell transplant (HSCT), and hematologic malignancy. Among patients with HSCT or hematologic malignancies, the reported IPA prevalence ranges from 0.8% to 8%.164,165 Signs and symptoms of pulmonary IPA include fever, pleuritic chest pain, dyspnea, cough, and hemoptysis. The diagnosis is largely based on clinical findings. Healthcare providers must incorporate the patient’s signs and symptoms with radiologic, microbiologic, and histopathologic data. Patients should have compatible signs and symptoms, chest imaging, and a positive diagnostic test for IPA, such as detection of indirect laboratory markers (e.g., galactomannan), isolation of Aspergillus from culture, and/or identification of Aspergillus on a biopsy specimen.166 Patients suspected of having IPA should be treated promptly. First-line therapy consists of combination voriconazole with or without an echinocandin for 6 to 12 weeks.167 In patients who fail or are intolerant of voriconazole, salvage antifungal therapy may include amphotericin B, posaconazole, itraconazole, caspofungin, or micafungin. The newest antifungal agent, isavuconazole, was cleared by the FDA in 2015 as an alternative or for those patients who have not responded to first-line therapy.168 Isavuconazole has a much better side-effect profile than amphotericin and traditional azoles in terms of its renal and hepatic toxicities. If IPA invades the chest wall, great vessels, or other critical structures, surgical resection may be necessary. Treatment may also be rendered more effective by reducing the patient’s regimen of concurrent immunosuppressive drugs.166

Zygomycosis Mucor is an order of fungi that includes the Mucor, Rhizopus, Rhizomucor, and Cunninghamella species. These molds are found in soil and decaying organic matter. Mucor can cause a severe, necrotizing, angioinvasive pneumonia called zygomycosis (or mucormycosis) when inhaled by immunocompromised hosts. Patients at risk for Mucor infection are the same as those at risk for Aspergillus infection. Interestingly, Mucor sinus disease has a strong association with diabetes.169 Voriconazole, which is often taken by immunocompromised patients for fungal prophylaxis, is inactive against Mucor species; as a result of this positive selective pressure, the incidence of Mucor infections is rising. Zygomycosis requires aggressive surgical debridement, early initiation of antifungal therapy, and minimization of immune suppression.170 The first-line antifungal is amphotericin B, and step-down or salvage therapy can consist of posazonale or the new isavuconazole, which has demonstrated activity against mucormycosis with similar efficacy to amphotericin.171 Unfortunately, even with optimal therapy, the mortality of zygomycosis is very high. In one study of HSCT patients with zygomycosis, only 50% were alive at 1 month and 30% were alive at 3 months.172

Histoplasmosis Histoplasma capsulatum is a dimorphic fungus endemic to the Ohio and Mississippi river valleys. Exposure occurs by the inhalation of H capsulatum spores found in soil and bird or bat droppings. Certain activities are more frequently associated with H capsulatum exposure, such as construction, chopping contaminated wood, and spelunking. Most individuals exposed to H capsulatum are asymptomatic. However, immunocompromised hosts or individuals exposed to a large inoculum may develop a range of pulmonary disease, from self-limited flu-like symptoms to respiratory failure to chronic pulmonary histoplasmosis. Acute pulmonary histoplasmosis can range from a mild influenza-like illness occurring several weeks to months after exposure to severe acute respiratory failure and extrapulmonary dissemination.

Chronic pulmonary histoplasmosis typically occurs in patients with structural lung disease, such as emphysema, and leads to cavitary lung disease. Rare complications include broncholithiasis and fibrosing mediastinitis. The diagnosis of pulmonary histoplasmosis is made by detection of H capsulatum antigen in urine, blood, or BAL fluid; isolation of fungus on culture; or visualization of yeast on biopsy. Treatment depends on the duration of symptoms, host immune function, and severity of disease. Most infections are self-limited and require no therapy. However, in patients with large inoculum exposure, respiratory failure, or immunocompromised state, the use of azoles or amphotericin B is indicated. Itraconazole is indicated for mild to moderate disease lasting more than 1 month. Amphotericin B is indicated for severe respiratory failure or dissemination. Methylprednisolone may also be used as an adjunctive therapy.170

Blastomycosis Blastomyces dermatitidis is a dimorphic fungus endemic to the southern and midwestern United States. Growth of B dermatitidis in soil is favored by decaying organic debris and high humidity. Blastomycosis is acquired via inhalation of spores and can be transmitted sexually. Due to its ability to disseminate to the skin, joints, genitourinary system, and central nervous system, blastomycosis can mimic other diseases. However, the lungs are most commonly affected. Similar to histoplasmosis, symptoms of pulmonary blastomycosis range from flulike illness to, rarely, respiratory failure. Chronic blastomycosis presents with similar symptoms as well as weight loss and hemoptysis and can involve the skin, bones, joints, and central nervous system. The diagnosis is made by identification on fungal stains and/or cultures from sputum, bronchial lavage, pleural fluid, skin lesions, cerebrospinal fluid, or urine. Unlike histoplasmosis, which often resolves without treatment, blastomycosis requires treatment with itraconazole or, in severe disseminated cases, amphotericin B.170

Cryptococcosis Cryptococcus neoformans is a yeast found worldwide in soil contaminated with bird (especially pigeon) droppings. C neoformans is the most common pathogen in human cryptococcal disease, although C gattii is an emerging pathogen in the U.S. Pacific Northwest and Canada. Cryptococcus spores can become aerosolized and inhaled, leading to infection. Although most infections are asymptomatic, disease can occur in immunocompromised or normal hosts. Normal hosts usually develop a self-limited pneumonia without extrapulmonary manifestations. Symptoms of pulmonary cryptococcosis include dry cough, dyspnea, and chest pain. Immunocompromised hosts more frequently experience disseminated disease, most commonly to the meninges, but virtually any other organ can be involved. The diagnosis of pulmonary cryptococcosis requires microbiological confirmation. Cryptococcus can be cultured from sputum, BAL fluid, or tissue or can be directly observed on histopathology stains. The cryptococcal antigen test is a noninvasive blood test that is useful in immunocompromised patients with pulmonary infection, though it is much less sensitive in immunocompetent hosts. Fluconazole for 6 to 12 months is first-line therapy for mild to moderate pulmonary cryptococcosis in the absence of disseminated disease.173 Other azoles, including the new antifungal isavuconazole, are alternatives.174 Disseminated and CNS cryptococcosis requires treatment with amphotericin B plus flucytosine.170

Coccidioidomycosis Coccidioides immitis lives in soil and is endemic in areas with arid climates such as the southwestern United States, Mexico, and areas of South and Central America. Infection occurs following inhalation of Coccidioides spores. For unclear reasons, the incidence of pulmonary coccidioidomycosis increased nearly eightfold from 1998 to 2011. This trend might be due to higher temperatures, drought, or disruption of soil due to construction.175 Signs and symptoms of pulmonary coccidioidomycosis include fever, malaise, anorexia, myalgia, cough, hemoptysis, rash, and chest pain, although infection is asymptomatic or self-limited in the majority of cases.

The chest radiograph may demonstrate patchy alveolar infiltrates, nodules, cavitation, or a miliary pattern consistent with dissemination. Hematogenous dissemination is more common in African Americans and Filipinos. A minority of patients may develop chronic, progressive, pulmonary coccidioidomycosis characterized by apical fibronodular infiltrates. The diagnosis of pulmonary coccidioidomycosis requires isolation of the organism from cultures of sputum, BAL fluid, or lung tissue. In a patient with a compatible clinical presentation, the diagnosis is supported by a positive complement fixation test and positive serologies. Pulmonary coccidioidomycosis in immunocompetent hosts is usually a self-limited infection that does not require antifungal therapy.176 However, therapy is indicated in those patients whose symptoms extend beyond a month, who are unable to work, or who experience extensive pulmonary involvement. Treatment may also be indicated in patients with risk factors for disseminated disease, including structural lung disease, chronic kidney disease, congestive heart failure, diabetes mellitus, pregnancy, HIV infection, and use of tumor necrosis factor alpha (TNF-α) inhibitors.176 First-line antifungals are fluconazole or itraconazole for 3 to 6 months for mild to moderate disease or amphotericin B for severe respiratory failure or pregnant women during the first trimester due to the teratogenicity of azoles.177

Candidiasis Candida species are yeasts and part of normal human flora. These organisms colonize the skin, the gastrointestinal and female genital tracts, and the oropharynx. As a result, invasive candidiasis, predominantly due to candidemia, is a common nosocomial infection in the United States.170 Pulmonary candidiasis is uncommon and usually occurs secondary to hematogenous dissemination. Primary infection is very rare. Although Candida is frequently isolated from lower respiratory tract specimens of intubated patients, it rarely causes pneumonia. One autopsy study of 135 patients who died with pneumonia in the ICU (30% of whom were immunocompromised) did not find a single case of pulmonary candidiasis—despite isolating Candida from premortem

respiratory specimens in 57% of the patients.178 In another autopsy study of 351 immunocompromised patients with proven pulmonary candidiasis, 9% of the cases were due to primary pneumonia, whereas 91% were due to secondary pneumonia. In this study, the overall prevalence of primary pulmonary candidiasis among 7725 autopsies performed over 20 years was 0.4%.179 Because of the high frequency with which patients become colonized with Candida relative to the low frequency of primary pulmonary candidiasis, the diagnosis requires histopathologic confirmation. When present, primary pulmonary candidiasis causes a hemorrhagic, necrotizing pneumonia. Treatment is based on local epidemiologic data, the patient’s clinical status, the likelihood of drug toxicity, and prior exposure to antifungal drugs. Antifungal therapy can include amphotericin B, an echinocandin (e.g., micafungin), fluconazole, or voriconazole.170 Oral candidiasis occurs in fewer than 5% of patients using inhaled corticosteroids. This infection can be largely avoided by using a spacer or valve holding chamber or, most important, rinsing the oropharynx after treatment.180

Pneumonia in Immunocompromised Patients Immunocompromised patients are at risk for both infectious and noninfectious causes of lung disease. Impaired immune function predisposes individuals to infection from both typical pathogens (e.g., pneumococcus) and opportunistic pathogens (e.g., CMV). Moreover, these patients commonly have other comorbidities and frequently use high-risk medications, which increases their risk for noninfectious pulmonary complications such as diffuse alveolar hemorrhage, pneumonitis due to drug toxicity, pulmonary edema, and progression of their underlying disease. As a result, immunocompromised patients with suspected pneumonia require a thorough (and at times, invasive) workup to differentiate between infectious and noninfectious diseases and to identify the causative pathogen when infection is present.

Clinical Considerations In immunocompromised patients with pneumonia, the presenting history can provide clues regarding the causative pathogen. Two relevant components of the history are the timing of illness and the acuity of symptom onset. The timing of the illness refers to when the symptoms started in relation to other events such as recent chemotherapy administration, diagnostic procedures, or organ transplantation. For example, within 30 days of HSCT, pneumonia is more frequently due to nosocomial bacteria, Candida, and HSV, whereas at 100 days postHSCT, pneumonia is more frequently due to Nocardia, Listeria, encapsulated bacteria, Pneumocystis, endemic fungi, CMV, VZV, and Epstein-Barr virus. Pathogens that overlap these periods include Aspergillus, molds, and respiratory viruses.181 Acuity of symptom onset refers to the rapidity with which the symptoms develop and peak. For example, pneumococcal pneumonia causes abrupt symptom onset and peaks within 1 to 2 days, whereas symptoms of Pneumocystis pneumonia (PCP) in an immunocompromised patient may develop and peak over 6 weeks. In contrast, symptoms due to post-primary TB develop and peak over months.

Once signs and symptoms of pneumonia do develop, they may differ between immunocompromised and immunocompetent patients. For example, dry cough may be the only presenting symptom in an immunocompromised patient with pulmonary aspergillosis, whereas immunocompetent patients may develop a productive cough, fever, dyspnea, and chest pain. This difference largely occurs because signs and symptoms are produced by inflammation—a process that is impaired in immunosuppressed states. Immunocompromised patients are also more likely to present with disseminated disease. Furthermore, the pattern of organ system involvement may provide clues as to the causative pathogen. For example, patients with pulmonary blastomycosis may present with a rash, whereas patients with pulmonary cryptococcosis may develop meningitis. A third relevant component of the patient’s history is the type of immune defect present. Different defects in immune function cause varying degrees of immunosuppression and confer risks to different opportunistic pathogens. For example, asplenic patients are at increased risk for infections caused by encapsulated bacteria (e.g., S pneumoniae, Klebsiella, and Neisseria meningitidis), whereas neutropenic patients are at increased risk for invasive fungal infections.

Radiologic Considerations The clinical differential diagnosis in immunocompromised patients with pneumonia is usually quite broad but can be narrowed with the appropriate use of thoracic imaging. Radiographic findings for one type of infection may differ quite dramatically from findings for another type. For example, in a study of HIV-negative immunocompromised patients, PCP more frequently caused homogeneous and sharply demarcated groundglass opacities (GGO) in the upper lung zones, whereas CMV pneumonia more frequently caused poorly demarcated GGO with centrilobular nodules and consolidation.182

Diagnostic Considerations Essential to the management of pneumonia in an immunocompromised

patient is diagnosis of the cause of the infection. Once the causative pathogen is known, a more focused antimicrobial regimen can be instituted to reduce the patient’s exposure to toxic antimicrobial drugs. Because many of the microbes can be identified only by culture and/or histopathology, immunocompromised patients must frequently undergo invasive procedures such as bronchoscopy. Numerous studies have evaluated the role of bronchoscopy in this clinical setting and have found mixed results. However, early bronchoscopy (within 48 to 72 hours of presentation) is generally recommended over empiric therapy. When bronchoscopy is performed, the combination of BAL, PSB sampling, and transbronchial biopsy increases the diagnostic yield from 38% (BAL alone) to 86%.183 This may be due to the inadequate diagnostic power of BAL for viral and fungal pneumonia, because these pneumonias often require further histopathologic confirmation of tissue invasion. This concept was underscored by Brownback et al., who found that reticular or nodular patterns on chest CT, which are more commonly due to viral and fungal infections, were associated with a lower diagnostic yield from BAL compared to consolidation, ground-glass, or tree-and-bud patterns of infiltrate.184 Respiratory Recap Immunocompromised Patients with Pneumonia ∎ Different immune defects predispose patients to different types of pneumonias. ∎ Early, invasive diagnostic procedures are indicated for most immunocompromised patients with pneumonia. ∎ Approximately 25% of lung infiltrates are due to noninfectious diseases.

Treatment Considerations Antimicrobial therapy in immunocompromised patients with pneumonia must be started promptly, broadly, and concurrently with an early invasive diagnostic workup. Delayed or inadequate antibiotic therapy has been associated with increased mortality in numerous studies.

Pneumonia and HIV/AIDS In 2012, an estimated 35.3 million people worldwide were HIV-positive. Populations in developing regions such as sub-Saharan Africa continue to be disproportionally affected by this disease, accounting for 70% of new infections. Incident HIV infections are also rising in Eastern Europe, Central Asia, the Middle East, and North Africa. Because these resourcepoor areas carry much of the disease burden, only one-third of those eligible for antiviral therapy actually receive it.185 In the United States, there are more than 1 million HIV-infected persons, and nearly 1 in 5 is undiagnosed.186 As a result, the prevalence of untreated HIV and endstage AIDS will continue to rise, as will the infectious complications associated with HIV/AIDS. The most common infection among HIV-infected persons is pneumonia. The etiology of pneumonia is largely influenced by the degree of immune suppression as measured by the CD4 count. For example, CD4 counts of less than 200 cells/mm3 (and even 200–499 cells/mm3) confer a significantly increased risk of bacterial pneumonia and PCP.187,188 Other factors influencing pneumonia etiology include geographic location, use of anti-Pneumocystis prophylaxis, history of prior infections, route of HIV exposure, virulence of the infecting microorganism, and use of highly active antiretroviral therapy (HAART).187,189 Prior to the development of HAART, the most common cause of pneumonia among HIV-infected patients in the United States was the fungus Pneumocystis jirovecii. Since the introduction of HAART along with anti-Pneumocystis prophylaxis, however, rates of PCP in the United States have declined. The top three pulmonary infections among HIV-infected persons in the United States (in descending order) are now bacterial pneumonia, PCP, and TB.

Bacterial Pneumonia HIV infection is associated with a more than 10-fold increased risk of bacterial pneumonia.189 The most common cause of bacterial pneumonia in patients with HIV/AIDS is S pneumoniae, followed by H influenzae, P

aeruginosa, and S aureus.188,189 Risk factors for bacterial pneumonia in HIV-infected persons include cigarette smoking, intravenous drug use, detectable HIV viral load, prior episodes of bacterial pneumonia, and poor adherence to HAART.189 Less common causes of bacterial pneumonia include Rhodococcus and Nocardia. These pathogens cause indolent pneumonia, which can mimic lung cancer, and are characterized by alveolar infiltrates or nodules with necrosis or cavitation, pleural effusions, and mediastinal/hilar lymphadenopathy.190

Pneumocystis Pneumonia While the incidence of Pneumocystis pneumonia is declining, it remains the second leading cause of pneumonia in HIV-infected persons in developed countries.189,191 PCP is caused by the yeast-like fungus P jirovecii. Infection is likely acquired via inhalation, although the exact mechanism and source of exposure remain unknown. When inhaled by a susceptible host, Pneumocystis causes a subacute pneumonia. Patients typically report gradually worsening dyspnea over 4 to 8 weeks, along with fever, chills, malaise, and a dry cough. In the early phase of illness, the chest radiograph can be normal. More commonly, however, the chest radiograph shows perihilar or diffuse, bilateral interstitial opacities (Figure 36-4). These can rapidly progress to diffuse, bilateral alveolar opacities and ARDS. Additional radiographic findings can include pneumothorax due to ruptured cysts. Notable laboratory findings generally include significant arterial hypoxemia with an elevated alveolar–arterial oxygen tension gradient as well as elevated serum lactate dehydrogenase.191

FIGURE 36-4 Portable anteroposterior chest radiograph of a patient with AIDS and Pneumocystis pneumonia showing bilateral diffuse infiltrates.

Diagnosis of PCP requires confirmation of the pathogenic organism. Because P jirovecii cannot be cultured in vitro, the organism must be directly visualized in sputum, BAL fluid, or lung tissue. Identification of P jirovecii can be aided by using special stains such as methenamine silver. Respiratory specimens can also be sent for Pneumocystis DNA PCR. Because the diagnostic yield of induced sputum varies, the gold standard for obtaining respiratory specimens to diagnose PCP is bronchoscopy.191 The mainstay of PCP treatment is trimethoprim-sulfamethoxazole. For patients with moderate to severe hypoxemia, prednisone has also been shown to reduce the risk of respiratory failure and death.192 In patients who do not improve after 5 to 7 days, switching from standard treatment to salvage therapy (clindamycin and primaquine) may be appropriate.191

Primary PCP prophylaxis should be given to all HIV-infected persons with the following risk factors: previous history of PCP, history of any opportunistic infection, CD4 count less than 200 cells/mm3, oral candidiasis, or unexplained constitutional symptoms. The most effective prophylactic regimen consists of one double-strength trimethoprimsulfamethoxazole tablet taken orally three times weekly, although alternative drugs are available.191

MTB and HIV Infection Tuberculosis is the third leading cause of pneumonia among HIV-infected persons in the United States, but globally it is the number one cause. Worldwide, nearly half of the documented TB cases in 2012 occurred in HIV-positive individuals. While the risk of developing active TB among immunocompetent hosts is 10% over a lifetime, among HIV-infected persons it is 10% per year. The signs and symptoms of TB in HIV-infected persons can vary. Some patients may have few or no TB symptoms. In one cohort study, 8.5% of HIV-infected patients were found to have active but asymptomatic TB.193 Coinfected patients are also more likely to present with extrapulmonary TB, typically involving the lymphatic and pleural spaces. Other frequently involved sites include the thoracic spine, joints, psoas muscle, central nervous system, and pericardium.194 The radiographic appearance of TB among HIV-infected persons depends on their level of immune suppression. HIV-infected persons with a CD4 count greater than 350 to 400 cells/mm3 generally present with post-primary TB and have upper lobe cavitary lung disease. By contrast, patients with a CD4 count less than 200 cells/mm3 more commonly present with primary TB and have middle or lower lung zone infiltrates, a pleural effusion, and mediastinal/hilar lymphadenopathy.189 The diagnosis of TB in HIV-positive individuals requires microbiological confirmation, similar to the case for HIV-negative persons. This can be difficult, however: As many as 75% of HIV-infected persons with active TB are acid-fast bacilli (AFB) smear–negative, leading to delays in diagnosis.193 Treatment of TB in HIV-infected persons includes the same anti-TB four-drug regimen as in HIV-negative persons, albeit with some special considerations. First, WHO recommends that all HIV-TB–coinfected

patients receive HAART, which has been shown to improve survival.146 Unfortunately, concurrent therapy has associated risks, such as a large daily pill burden, potential for overlapping drug toxicity or drug–drug interactions, and risk of immune reconstitution syndrome.194 Therefore, this regimen may not be possible in all patients. Second, WHO recommends starting trimethoprim-sulfamethoxazole 1 month after initiation of anti-TB drugs, which also may reduce the risk of death.146 Finally, patients with CD4 counts less than 100 cells/mm3 are at high risk of TB recurrence and require a longer duration of therapy.

AIDS-Defining Pneumonias An HIV-infected person is said to have AIDS when one of the following conditions is present: CD4 count of less than 200 cells/mm3, CD4 cells represent less than 14% of total T cells, or the presence of an AIDSdefining illness. Many of the AIDS-defining illnesses are pneumonias, such as recurrent bacterial pneumonias, PCP, and TB. As previously mentioned, TB and recurrent bacterial pneumonias can occur at virtually any CD4 count, whereas PCP generally occurs at CD4 counts < 200 cells/mm3. Several other pneumonias qualify as AIDS-defining illnesses and generally occur at CD4 counts < 50 cells/mm3, including pulmonary candidiasis, HSV pneumonia, and CMV pneumonia.190 Fungal pneumonias such as coccidioidomycosis, histoplasmosis, and cryptococcosis are considered AIDS-defining illnesses only when they are extrapulmonary. Cryptococcosis—one of the most common fungal infections in HIV-infected persons—generally disseminates when the CD4 count is less than 100 cells/mm3. Dissemination usually involves the meninges, causing meningitis. The diagnosis of disseminated disease can be made with a high cryptococcal serum antigen.190 Extrapulmonary NTM infections are also considered AIDS-defining illnesses. MAC is the most common cause, and dissemination generally occurs at CD4 counts less than 100 cells/mm3. Common sites of dissemination include the liver, spleen, and bone marrow. Symptoms can include fever, weight loss, night sweats, malaise, and diarrhea.190 NTM can be cultured from blood or bone marrow, confirming the diagnosis. MAC prophylaxis with a macrolide antibiotic is recommended for patients with CD4 counts less than 50 cells/mm3.

Respiratory Recap Pneumonia in HIV-Infected Patients ∎ HIV-infected patients with pneumonia require aggressive workup similar to other immunosuppressed patients. ∎ S pneumoniae is a leading cause of pneumonia in HIV-infected persons. ∎ Pneumocystis pneumonia can cause severe ARDS. ∎ HIV infection is the most significant risk factor for TB. ∎ HIV-infected persons with TB may present with primary TB rather than post-primary TB.

Case Studies Case 1. Community-Acquired Pneumonia A 44-year-old male presents to the local emergency department for a productive cough. He was in his usual state of health until 3 days ago, when he developed a cough productive of yellow sputum. One day ago, he developed subjective fevers and chills. He also noticed dyspnea with minimal exertion and right-sided chest pain with deep inspiration. He denies weight loss, night sweats, and exposure to tuberculosis. He has a history of alcohol abuse and has smoked a pack of cigarettes every day for the past 15 years. The nurse records the following vital signs: temperature, 102.1° F (38.9° C); respiratory rate, 34 breaths/min; blood pressure, 125/79 mm Hg; heart rate, 125 beats/min; and oxygen saturation, 93% when breathing room air. On physical examination, the patient is in mild respiratory distress. Auscultation of the chest demonstrates rales over the right lower lung field with associated dullness to percussion and increased tactile fremitus. Laboratory studies show the WBC count is 16,000 cells/mm3; the differential is 20% band neutrophils, 70% neutrophils, and 10% lymphocytes. Serum protein is 7 g/dL, and lactate dehydrogenase (LDH) is 210 units/L. Serum electrolytes, creatinine, liver function panel, hemoglobin, and platelet count are unremarkable. A chest radiograph demonstrates consolidation involving the right middle and right lower lobes with a right-sided pleural effusion. Blood and sputum samples are collected and sent to the microbiology lab for Gram stain and culture. The patient is given intravenous azithromycin and ceftriaxone and admitted to the general medicine service. A diagnostic thoracentesis is performed, and pleural fluid analysis demonstrates the following: pH, 7.37; WBC count, 1000 cells/mm3 (95% neutrophils); total protein, 5 g/dL; and LDH, 198 units/L. Pleural fluid Gram stain is negative, but sputum Gram stain reveals 3+ gram-positive, lancet-shaped diplococci. On the second hospital day, the patient’s cough and dyspnea are slightly improved. He is given a nicotine patch to help with cigarette cravings and is counseled about the importance of alcohol and tobacco

cessation. On the third hospital day, the sputum and blood cultures collected in the emergency department grow S pneumoniae sensitive to amoxicillin. The antibiotic regimen is switched from intravenous ceftriaxone and azithromycin to intravenous ampicillin. On the fourth hospital day, the patient continues to improve, and the intravenous ampicillin is changed to oral amoxicillin. On the fifth hospital day, he is discharged home with oral amoxicillin to complete an 8-day antibiotic course. Prior to discharge, he receives an influenza vaccine and a pneumococcal (PPSV23) vaccine. The patient is given an appointment to follow up at an outpatient clinic in 1 week. The patient will need a followup chest radiograph in 4 to 8 weeks to ensure complete resolution of the radiographic abnormalities.

Case 2. Pneumonia in an Immunocompromised Host A 26-year-old female is hospitalized for dyspnea. She reports significant weight loss (approximately 15 kg over a 3-month period) and cough for 5 weeks. The cough was initially dry but became productive of brown sputum approximately 1 week ago. Over the past week, the patient also has noticed worsening dyspnea, subjective fever, and chills. She denies exposure to TB. She has no past medical history, but does report highrisk sexual encounters. The nurse records the following vital signs: temperature, 101.2° F (38.4° C); respiratory rate, 39 breaths/min; blood pressure, 90/55 mm Hg; heart rate, 145 beats/min; and SpO2, 82% breathing room air and 94% on 6 L/min O2 via nasal cannula. On physical examination, the patient is in moderate respiratory distress. Diffuse rales are noted on chest auscultation. The serum electrolyte values are normal. The hematocrit is 23%, the platelet count is 85,000 cells/mm3, the WBC count is 5000 cells/mm3, and the differential is 10% bands, 80% neutrophils, and 10% lymphocytes. Serum protein is 8 g/dL, albumin is 1.5 g/dL, and LDH is 900 units/L. A chest radiograph shows diffuse interstitial opacities with focal consolidation in the right upper lobe. Blood cultures are collected. Sputum is induced with 3% saline and sent for the following microbiological tests: Gram stain, bacterial culture, KOH preparation and

fungal culture, AFB stain and mycobacterial culture, and silver stain to evaluate for P jirovecii. The patient is given intravenous azithromycin, ceftriaxone, and vancomycin for severe CAP. There is also concern for Pneumocystis pneumonia, so intravenous trimethoprim-sulfamethoxazole and oral prednisone are initiated. On the second hospital day, the patient’s condition worsens, and she is transferred to the medical ICU for severe hypoxemic respiratory failure. Her PaO2 is 65 mm Hg (breathing 100% O2) and she undergoes endotracheal intubation and initiation of mechanical ventilation. Bronchoscopy is performed, and BAL fluid is sent for the following tests: Gram stain and culture, KOH preparation and fungal culture, AFB stain, MTB PCR, mycobacterial culture, cytology, WBC count and differential, and Pneumocystis PCR. On the third hospital day, the Pneumocystis PCR returns positive. The BAL fluid AFB smear and MTB PCR tests are also positive. TB treatment is initiated with INH, rifampin, pyrazinamide, and ethambutol. On the fourth hospital day, the HIV enzyme-linked immunosorbent assay (ELISA) and Western blot return positive. The patient’s CD4 count is 10 cells/mm3, and she is initiated on HAART. Over the next 3 weeks, the patient’s condition gradually deteriorates. She has multiple complications including MRSA bacteremia, an upper gastrointestinal hemorrhage, and acute kidney injury requiring dialysis. On the 35th hospital day, she dies of multiple organ failure.

Key Points Pneumonia is the inflammation and consolidation of lung tissue caused by an infection. The most common cause of pneumonia worldwide is Streptococcus pneumoniae. Community-acquired pneumonia (CAP) occurs outside the hospital. Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are acquired in the hospital. Pneumonia diagnosis involves both noninvasive and invasive procedures. Organisms causing pneumonia include Gram-positive, Gramnegative, atypical, and anaerobic bacteria; viruses; mycobacteria; and fungi. Prognosis and treatment location for CAP can be determined from the patient’s pneumonia severity score. Pneumonia is the second most common nosocomial infection. Multidrug-resistant organisms are common causes of nosocomial pneumonia. VAP is associated with increased morbidity and mortality. Guidelines for the management of HAP and VAP emphasize early combination antibiotic therapy, de-escalation of initial antibiotic therapy, and shortening the duration of therapy to the minimum effective period. The endotracheal tube is the main risk factor for VAP. Prevention should focus on avoiding intubation, rapidly weaning patients from ventilation, and minimizing aspiration of contaminated secretions. Pulmonary infections are common in immunocompromised patients, and bronchoalveolar lavage is often required for diagnosis. PCP and TB are common causes of mortality in patients with HIV. Children usually recover fully from pneumonia, and no pathogen is identified in about half of all cases. Delayed initiation of appropriate antibiotics for pneumonia increases mortality.

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CHAPTER

37 Cystic Fibrosis Teresa A. Volsko Catherine A. O’Malley Bruce K. Rubin

© Andriy Rabchun/Shutterstock

OUTLINE History Pathogenesis Diagnosis Extrapulmonary Manifestations Respiratory Manifestations Major Respiratory Complications Standard Therapy of Lung Disease

OBJECTIVES 1. 2. 3. 4. 5. 6.

Describe the inheritance pattern of cystic fibrosis. Describe the pathogenesis of cystic fibrosis. List the diagnostic criteria for cystic fibrosis. Describe the numerous extrapulmonary manifestations of cystic fibrosis. Describe the typical respiratory manifestations of cystic fibrosis. Discuss the approach to managing life-threatening respiratory complications of cystic

fibrosis. 7. Describe the principles of preventive care for cystic fibrosis. 8. Outline an approach to managing exacerbations of cystic fibrosis. 9. Describe the role that lung transplantation plays in the management of cystic fibrosis.

KEY TERMS bronchial artery embolization (BAE) cepacia syndrome cystic fibrosis (CF) cystic fibrosis–related diabetes (CFRD) cystic fibrosis transmembrane conductance regulator (CFTR) distal intestinal obstruction syndrome (DIOS) lung transplantation meconium ileus steatorrhea sweat test

Introduction Cystic fibrosis (CF) is an autosomal recessive genetic disorder, passed from parents to their children. Each parent must be a carrier of the CF transmembrane conductance regulator (CFTR) gene defect if their children are to be affected; in such a case, each child has a 25% chance of inheriting CF. Two-thirds of the children who do not inherit the disease are expected to be carriers, and one-third will have two normal copies of the CFTR gene.

History Independently, Dorothy H. Andersen and Guido Fanconi were the first to describe CF in the late 1930s. Fanconi described the connection among bronchiectasis, malabsorption, and pancreatic changes associated with CF.1 Dorothy Andersen described cystic fibrosis of the pancreas as a distinct disease entity in 1938.2 She conducted a pathology study, describing affected infants who presented with intestinal obstruction or malnutrition as a consequence of malabsorption.3 In those days, the diagnosis was based on the patient’s clinical presentation, and effective treatment was unavailable. Children with CF usually died in the first year of life. Postmortem studies revealed obstruction of pancreatic ducts and the gut with abnormally tenacious mucus, prompting use of the term mucoviscidosis to describe this condition.3 In the 1950s, di Sant’Agnese and colleagues investigated cases of severe dehydration in children with CF during a summer heat wave in New York City and recognized that excessive salt loss occurred through sweat.4 This observation led to the development of the use of pilocarpine iontophoresis to stimulate the sweat glands and induce localized sweating in an effort to measure the concentration of salt in the sweat.5 A salt concentration of 60 milliequivalents per liter (mEq/L) or higher is an abnormal test result for children; it usually indicates CF, although other causes of a high sweat test are also possible, including malnutrition. The pilocarpine iontophoresis sweat test, described by Gibson and Cooke in 1959, remains a standard diagnostic test for CF. In 1989, the gene responsible for CF was discovered and cloned, and its protein product was named cystic fibrosis transmembrane conductance regulator (CFTR) or ABC-C7.6 Today, CF is recognized as the most common life-shortening genetic disease in the Caucasian population. In North America, 1 in 29 Caucasians carries a mutant CFTR allele, and one in 3300 live births is affected with CF. Other ethnic populations have lower mutation carrier rates and, therefore, lower incidences of CF disease. Survival now commonly extends into adulthood, with a median life expectancy of 46.2 years.7 Approximately 33,000 patients with CF have been identified in the United States; more than half (53.5%) are older than 18 years.

This chapter describes the pathogenesis, diagnosis, and clinical manifestations of CF. Although CF is a multisystem disease, the discussion here emphasizes the management of acute and chronic respiratory complications.

Pathogenesis Genetics of Cystic Fibrosis CF is a monogenetic classic mendelian disorder that is inherited in an autosomal recessive pattern. Persons who carry a single mutated CFTR gene along with a normal CFTR allele are termed carriers and have few or no symptoms attributable to CF. In keeping with mendelian genetics, each offspring conceived from two CF carriers has a one in four chance of being affected with CF and a two in four chance of being a CF carrier. The CFTR gene belongs to a family of membrane adenosine triphosphate (ATP)-binding cassette (ABC-C7) proteins that serve as molecular pumps. CFTR is a cAMP-regulated chloride channel in epithelial tissues. Since the discovery of the CFTR gene in 1989, more than 2300 individual mutations have been identified.8 The most common mutation, c.1521_1523delCTT (legacy F508del), accounts for 66% of CF alleles reported worldwide, with approximately half of all persons with CF being homozygous for this mutation.9 The exact prevalence of individual mutations also varies according to the ethnic group being studied, with the c.1521_1523delCTT mutation being less common among nonwhite populations. Mutations in the CFTR gene have been categorized into six groups reflecting the mechanism for decreased or loss of CFTR function (Figure 37-1 and Table 37-1). Class I mutations result in the loss of protein production and, therefore, absence of full-length CFTR. Abnormal protein processing between the cell nucleus and plasma membrane occur with class II mutations. This class of mutations includes the most common c.1521_1523delCTT mutation, with which improper protein glycosylation and folding prevent normal transport to the apical cell membrane with subsequent degradation in the endoplasmic reticulum. Class III mutations in the CFTR gene affect the regulation or activation of the CFTR chloride channel: Although the protein often reaches the plasma membrane, the channel does not open fully to chloride transport. These mutations tend to produce milder disease. Class IV mutations also allows the protein to reach the plasma membrane but affect the conductance of chloride through the channel pore. Class V CFTR mutations decrease the

abundance of mature CFTR messenger RNA (mRNA) and protein levels and may include mutations in gene promoters or regions that influence mRNA splicing. Class IV is the result of a dysfunctional ATP-binding site 2 in the nucleotide binding domains, which causes a gating defect. Class I VI mutations may permit the production of adequate CFTR levels to confer a less severe disease phenotype.10

FIGURE 37-1 An illustration of the CTFR mutations by class. Reproduced from Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993;73(7):1251-4 and Claustres M. Molecular pathology of the CFTR locus in male infertility. Reproductive BioMedicine Online 2005; 10(1):14-41.

Description TABLE 37-1 Consequences of CFTR Gene Mutations by Class

Description ATP, adenosine triphosphate; mRNA, messenger RNA.

Predicting an individual patient’s clinical phenotype is not possible based on the specific CFTR mutations present. Some genotype– phenotype correlation has been noted, principally among a group of mutations associated with pancreatic exocrine sufficiency, milder lung disease, and borderline or even normal sweat chloride values.11 In addition, some mild mutations have been found in men who present solely with infertility resulting from the congenital bilateral absence of the vas deferens (CBAVD), often without other symptoms of CF disease.12 The manifestations of CF in an individual depend on other genetic factors (i.e., modifier genes), social and adherence factors, and environmental factors. Current research in CF is investigating specific CFTR defects and determining ways to treat them. A successful outcome of this research is ivacaftor (Kalydeco), the first CFTR modulator therapy drug that targets the underlying cause of CF. Ivacaftor, an oral medication, was cleared for use in 2012 for people with CF 6 years of age and older with the CFTR gating mutation rs75527207 (legacy G551D), which is a class III mutation.13 This medication is classified as a potentiator because it improves (potentiates) the function of the CFTR protein on the cell surface by allowing it to open to chloride transport.13 Patients on this medication show marked improvement in lung function and weight gain, which are strong predictors of life expectancy in CF. Only 4% of people with CF have the rs75527207 mutation.14

Since ivacaftor first became available to treat the rs75527207 mutation, more mutations have been identified that respond to treatment with this medication: 9 additional mutations in 2014 and 28 additional mutations in 2017. In addition to treating more mutations, the indication for ivacaftor has been extended for people 2 years and older, which means that ivacaftor therapy may potentially be used to treat 13% of people with CF. In 2015, a combination oral medication consisting of ivacaftor and lumacaftor (Orkambi) was cleared for people ages 12 years and older with CF who have two copies of the most common CFTR gene mutation in CF, F508del, which is a class II mutation. In 2016, the Food and Drug Administration (FDA) extended its indication to include people 6 years of age and older. Lumacaftor is classified as a corrector because it corrects the CFTR protein (i.e., prevents degradation), allowing it to move to the cell surface, whereas ivacaftor increases the ability of the CFTR protein to remain open. Patients receiving lumacaftor showed a modest improvement in FEV1% predicted (ranging from 2.6% to 4%), had fewer hospitalizations, and had less frequent need for intravenous antibiotics. Approximately 46% of people with CF in the United States have two copies of F508del. Therefore, CFTR modulator therapy is available to more people with CF, and this medication is being studied in children 2 to 5 years of age.15 In 2018, the FDA cleared an additional CFTR modulator therapy, tezacaftor/ivacaftor (Symdeko), for people with CF ages 12 years and older who have two copies of the F508del mutation. This therapy is an option for people who did not tolerate lumacaftor—primarily those who had increasing respiratory symptoms. Symdeko is also approved for people with CF ages 12 years and older who have a copy of one of 26 specified mutations. Further CFTR modulators in clinical trials include a triple combination therapy to help people with one copy of F508del. This medication would cover an additional 30% of people with CF, thereby bringing effective modulator therapy to nearly 90% of people with CF. Respiratory Recap Genetics of Cystic Fibrosis

∎ CF is inherited in an autosomal recessive pattern. ∎ CFTR is the gene responsible for CF. ∎ One cannot reliably predict phenotype from CFTR mutation because of modifier genes and gene–environment interactions. ∎ CFTR modifier therapy is a precision medicine: It targets specific genetic defects.

CFTR Functions and Host Defense CFTR is an ion channel expressed in the apical membrane of epithelial cells lining the lung, pancreas, gut, sweat duct, and reproductive tract (also the kidney, liver, submucosal gland, and other glands). As its name implies, however, CFTR regulates several ion conductance pathways,16 including the epithelial sodium channels (ENaC),17 chloride channels as well as CFTR,18 potassium channels, and, importantly, bicarbonate transport.19 The loss of a normally functioning CFTR can have a profound impact on epithelial ion transport. In the lung, the absence of CFTR causes decreased bicarbonate sections and lower airway surface pH, increases sodium absorption from the airway lumen,20 and reduces the capacity to secrete chloride ions via CFTR. This combination alters the local milieu so that defensive mechanisms against invading microbes are lost. One hypothesis for the mechanism underlying this defect is based on data showing that increased isotonic volume absorption from the airway lumen (driven by sodium hyperabsorption) depletes the periciliary liquid layer, leading to increased gel viscosity. CF secretions also have a pH that is slightly lower than the pH of normal mucus. Alterations in the pH are attributed to inflammation as well as impaired bicarbonate secretion.21 The changes to the airway impair both ciliary and cough clearance of airway secretions. In turn, the reduced airway clearance and retention of mucus cause airway obstruction and allow the establishment of bacterial infections. Mucociliary clearance is preserved in the nose of persons with CF, however. The middle ear and eustachian tube are also cleared by mucociliary clearance, but persons with CF do not usually develop chronic or persistent otitis media. Furthermore, persons with primary ciliary dyskinesia (PCD) have congenital absence of mucociliary transport but much milder lung disease than persons with CF. Despite the lack of ciliary function, cough clearance is not compromised in patients with

PCD.22 A second hypothesis proposes that NaCl concentrations in airway surface liquid (ASL) are normally low (100 mM) because of the inability to absorb chloride through CFTR. Elevated NaCl concentrations in ASL may inhibit the antimicrobial effects of defensins, the small, salt-sensitive peptides produced by airway epithelia.23 Challenges to this hypothesis are the scarcity of defensins in ASL relative to other salt-insensitive antimicrobial molecules (e.g., lactoferrin, lysozyme)24 and the absence of a physiologic mechanism for the generation of hypotonic fluids across the water-permeable airway epithelium. Because CFTR expression in the lung is greatest in the submucosal glands lining proximal conducting airways,25 perhaps an alteration in glandular secretion resulting from absent CFTR causes the altered airway defense seen in CF. Indeed, CFTR is involved the submucosal glands’ production of ASL in the proximal airways.26 Thus, a third hypothesis relating CFTR function and host defenses emphasizes that deficient secretion of fluid containing sodium chloride or sodium bicarbonate from submucosal glands or serous cells lining small airways may lead to a volume-depleted ASL layer, an ASL layer with an altered composition, or both. Other hypotheses relate to the pathogenesis of CF lung disease. It has been proposed that the diminished availability of intact mucin (mucus) in the CF airway leaves the airway more vulnerable to chronic bacterial infection and to the development of bacterial biofilms by organisms in the airway.27 In addition to hypotheses describing differences in airway mucins,28 some hypotheses point to the CF immune response as the culprit.29 These conceptualizations do not tightly link CFTR function with the resulting disease process, however, and in some cases they rely on observations that may occur secondary to infection. Most therapies for CF focus on airway clearance and fighting chronic bacterial infection and on modulating the hyperimmune and inflammatory response in the airway. Stop and Think A patient has a sweat chloride of 80 mmol/L. What would you include in the differential diagnosis?

Diagnosis The diagnosis of CF is based on the combination of one or more typical phenotypic features and evidence of CFTR malfunction (Box 37-1).30 Knowledge of the broad range of clinical features that may be present in CF and appropriate access to specialized diagnostic testing are necessary for an accurate diagnosis. Among the clinical features assessed are the following: BOX 37-1 Diagnostic Criteria for Cystic Fibrosis Phenotypic Features Chronic sinopulmonary disease Persistent infection with typical CF pathogens (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, atypical Mycobacteria) Chronic cough with sputum expectoration Persistent chest radiographic abnormality (e.g., bronchiectasis, hyperinflation, atelectasis) Airway obstruction pattern on pulmonary function testing Nasal polyps and chronic sinus (but not middle ear) involvement Digital clubbing Gastrointestinal or nutritional abnormalities Intestinal: meconium ileus, rectal prolapse, distal intestinal obstruction syndrome Pancreatic: pancreatic insufficiency, recurrent pancreatitis (in older children and adults) Hepatic: focal biliary cirrhosis Nutritional: malnutrition, hypoproteinemia, fat-soluble vitamin deficiency Salt loss syndrome Acute salt depletion, especially with water loss, such as during exercise in heat Chronic metabolic alkalosis Male urogenital abnormality Obstructive azoospermia resulting from congenital bilateral absence of the vas deferens (CBAVD)

CFTR Abnormalities Sweat chloride test More than 60 mmol/L on two occasions (minimum 75 mg of sweat collected during 30 minutes) without other causes for high sweat chloride (e.g., anorexia nervosa, atopic dermatitis) CFTR mutational analysis Two identified mutant CFTR alleles Nasal potential difference (PD) testing

Higher basal PD Greater amiloride-sensitive PD Absent or minimal change in PD after isoproterenol in chloride-free perfusion solution The combination of one or more phenotypic abnormalities (or CF in a sibling or a positive newborn screening test) with a CFTR abnormality constitutes a CF diagnosis. CFTR, cystic fibrosis transmembrane conductance regulator.

Presence of obstructive lung disease leading to bronchiectasis and infection with typical pathogens Chronic sinus disease with or without nasal polyposis Exocrine pancreatic insufficiency or recurrent pancreatitis in older patients Intestinal obstruction either at birth (meconium ileus) or later in life (distal intestinal obstruction syndrome, formerly called meconium ileus equivalent) Rectal prolapse Chronic liver disease Nutritional deficiencies including protein/caloric malnutrition and complications of fat-soluble vitamin deficiency Electrolyte abnormalities such as acute salt depletion or chronic metabolic alkalosis Absence of the vas deferens resulting in obstructive azoospermia in males Digital clubbing A family history of CF should also be sought in support of a clinical CF diagnosis. Early diagnosis of CF through newborn screening (NBS) has been adopted throughout the United States and Canada, Europe, and Australia. Research demonstrates that early diagnosis and treatment preserve the rate of decline in lung function; enhance growth, nutritional status, and survival with less intensive therapy; and reduce the cost of care.31 Essential components of care include well-baby and CF clinic visits as well as parental education on the symptoms of exacerbations and the importance of adhering to immunization guidelines.

Immunoreactive Trypsinogen Testing In the United States, every state’s specified NBS program now includes screening for CF. The immunoreactive trypsinogen (IRT) test is most often used for this purpose: It analyzes a drop of blood taken from the baby’s heel within the first few days of life.32 Some states directly test for common genetic abnormalities. Other states use IRT screening and, if the result is positive, go directly to genetic screening. If the IRT level is high, then the test is repeated. If it remains high, then sweat testing is performed to confirm a diagnosis of CF. Some infants demonstrate an elevated IRT on NBS with genetic abnormalities in CFTR but do not meet the diagnostic criteria for CF. The United States CF Foundation uses the term cystic fibrosis transmembrane conductance regulator–related metabolic syndrome (CRMS) to describe the infants who have evidence of CFTR dysfunction but do not meet the CF diagnostic criteria.33 Ren and colleagues reported that patients with CRMS were more likely to have sufficient pancreatic function as assessed by fecal elastase measurement and to be in a normal weight-for-age percentile at birth. Such patients were less likely to receive oral antibiotics and be hospitalized for pulmonary symptoms.34

Sweat Testing Evidence of CFTR dysfunction is typically provided by a sweat test, with a chloride concentration of more than 60 mmol/L on two or more occasions in children older than 6 months of age.30 Values greater than 40 mmol/L are considered borderline and are more suggestive of CF in infants. Values between 60 and 80 mmol/L can also be seen in individuals with diseases other than CF. Laboratory errors are common with this technique, and even a small amount of water vapor loss from the collected sweat can concentrate ions and cause a false-positive test result. All positive and borderline tests thus should be repeated at a Cystic Fibrosis Foundation–accredited center.

CFTR Mutational Analysis

A complementary approach to sweat testing is the use of CFTR mutational analysis to identify CF alleles. The identification of two disease-causing CFTR mutations is specific for the diagnosis of CF, although this approach lacks sensitivity. CFTR mutational analysis usually screens for 32 to 70 common mutations and detects as many as 95% of CF alleles. The use of mutation panels customized for a given ethnic group or clinical situation (e.g., African American, pancreatic sufficient) may increase the likelihood of identifying CF alleles. No commercially available screening panel can rule out the diagnosis of CF, however, because no test for all of the known mutations capable of causing CF currently exists. Also, many mutations may have no known functional consequences.

Nasal Epithelial Potential Difference When sweat testing and CFTR mutational analysis are inconclusive, the measurement of nasal epithelial potential difference (NPD) in response to various pharmacologic agents can be useful.35 This test is available at only a few specialized research centers, however. Respiratory Recap Diagnosis of Cystic Fibrosis ∎ Abnormal newborn screening result ∎ CMRS versus CF ∎ Clinical features consistent with the disease ∎ Family history ∎ Sweat testing ∎ Mutational analysis to identify CF alleles ∎ Nasal epithelial potential difference measurements in response to specific pharmacologic agents

Extrapulmonary Manifestations Upper Respiratory Tract Nearly all patients with CF have radiographic opacification of the paranasal sinuses,36 and a large fraction report symptoms attributable to either nasal obstruction or chronic sinusitis.37 Symptomatic nasal polyps are particularly common toward the end of the first decade and during the second decade of life but occur in fewer than half of all patients with CF.38 Manifestations include severe nasal airflow obstruction, rhinorrhea, and, occasionally, widening of the bridge of the nose. Severity of lung disease is reportedly less among children with CF presenting with recurrent nasal polyps and has been attributed to a proliferative airway repair mechanism.39 Despite the universal presence of radiographic abnormalities, very few children and adults have symptoms attributable to sinusitis. The kinds of bacteria isolated in CF sinus disease vary with age and may be similar to those cultured from the lower respiratory tract. Staphylococcus aureus and Haemophilus influenzae are commonly found in younger children, whereas Pseudomonas aeruginosa appears more frequently at a later age. Unfortunately, recurrence of polyps and sinus symptoms is extremely common after surgical interventions. Consequently, patients must be carefully selected when a surgical intervention for nasal or sinus disease is considered.

Exocrine and Endocrine Pancreas Exocrine pancreatic insufficiency is present from birth in most patients with CF.40 Enzyme deficiency results in fat and protein maldigestion, producing steatorrhea. Uncorrected malabsorption results in failure to gain weight and ultimately a failure of linear growth. To manage exocrine pancreatic insufficiency and malnutrition, patients must take oral pancreatic enzyme supplementation and dietary supplements. Impaired absorption of fat-soluble vitamins (A, D, E, and K) occasionally produces symptoms of vitamin deficiency, which can be prevented with adequate supplementation.

Age-Specific Angle Exocrine pancreatic insufficiency is present from birth in most patients with CF. Approximately 18% of newborns with CF have meconium ileus; these babies uniformly have pancreatic insufficiency.

Symptoms of pancreatitis are limited to those patients who have retained some exocrine pancreatic function. Recurrent non-ethanolinduced pancreatitis has been associated with mutations in the CFTR gene, however, and may be the presenting symptom in adolescents or adults with CF. Although the exocrine pancreas is frequently affected from birth, the gradual loss of insulin production from the endocrine pancreas occurs slowly in patients with CF. The prevalence of cystic fibrosis–related diabetes (CFRD) or glucose intolerance requiring insulin therapy has increased and is attributed to increased screening frequency and improved life expectancy of those individuals with CF. Because CFRD has an insidious onset, screening with 2-hour plasma glucose values obtained during an oral glucose tolerance test is suggested for individuals aged 10 years and older. Measurement of hemoglobin A1c is not an accurate test for CFRD due to the more rapid red blood cell turnover in patients with chronic inflammation, including those with CF. Manifestations of CFRD may include failure to gain or maintain weight despite nutritional intervention, poor growth, or an unexplained chronic decline in pulmonary function.41 Insulin is the preferred hypoglycemic agent in CFRD, because most patients have only a limited islet cell reserve. Other facets of CFRD management, however, differ substantially from management of either type 1 or 2 diabetes mellitus. Because all CF patients require a highenergy intake and generally poorly absorb fat even with appropriate pancreatic enzyme supplementation, a high-calorie diet consisting of 40% fat is recommended. Caloric restriction should not be used to manage blood glucose in CF except in the rare pancreatic-sufficient and obese patient with both CF and chronic type 2 diabetes. Instead, insulin dosage is matched to the patient’s calorie and carbohydrate intake, with the presence of infection being factored in as needed. 42 Because CF patients are also at risk for the usual microvascular complications of

diabetes,42 the glucose targets are similar to those for patients with type 1 and type 2 diabetes mellitus. Equally important, however, is the maintenance of optimal nutrition and growth, the avoidance of severe hypoglycemia, and the need to fit this additional treatment burden within the patient’s CF regimen. Respiratory Recap Extrapulmonary Manifestations of Cystic Fibrosis ∎ Upper airway ∎ Exocrine and endocrine pancreas ∎ Gastrointestinal tract ∎ Hepatobiliary system ∎ Reproductive tract ∎ Sweat glands

Gastrointestinal Tract Meconium ileus occurs in approximately 18% of newborns with CF. True meconium ileus (as opposed to the meconium plugs commonly seen in very premature infants) is nearly diagnostic for CF.43 A barium enema usually demonstrates a small colon, and the clinician may identify a site of ileal obstruction. Intestinal obstruction can also be diagnosed by fetal ultrasound toward the end of pregnancy. Later in life, intestinal obstruction may be caused by distal intestinal obstruction syndrome (DIOS), formerly referred to as meconium ileus equivalent. This syndrome usually presents with constipation, right lower quadrant abdominal pain, anorexia, nausea, vomiting, and sometimes fever. As with meconium ileus, obstruction usually occurs in the terminal ileum and is associated with copious, incompletely digested intestinal contents. DIOS has been associated with poor adherence to taking pancreatic enzyme therapy and with dietary indiscretions. Other causes of abdominal pain include simple constipation, intussusception, intestinal adhesions from previous abdominal surgery (including for meconium ileus), and chronic appendicitis that has been partially suppressed by antibiotic therapy. Although rectal prolapse

sometimes occurs, it is an infrequent event in adults with CF. Excessive pancreatic enzyme dosages have been associated with the development of fibrosing colonopathy, especially in those patients taking 6000 units or more of lipase per kilogram per meal.44 Pancreatic enzyme dosages of 2500 units or less of lipase per kilogram per meal are recommended to avoid this complication. Gastroesophageal reflux disease (GERD) is common in patients with CF. Identification and treatment of GERD are important because this process may exacerbate lung disease, just as lung disease and chronic cough can worsen gastroesophageal reflux.45

Hepatobiliary System Liver disease is a relatively frequent and an early complication of CF. Its multifactorial pathogenesis is influenced by environmental and genetic factors. Hepatic abnormalities can present as hepatosplenomegaly or as a persistent elevation of hepatic enzymes (particularly alkaline phosphatase). Rarely, patients may present with esophageal varices and hemorrhage resulting from portal hypertension. Fatty liver is also common but may improve with adequate nutrition. Individuals with CF may also present with a dysfunctional gallbladder or gallstones. Early detection and treatment are important and impact quality of life and survival.

Reproductive Tract More than 98% of male patients with CF have azoospermia (low or no sperm in ejaculate) resulting from obstruction of the vas deferens.46 In fact, the absence of a palpable vas deferens is a useful clue to the diagnosis of CF during the evaluation of a male patient with otherwise unexplained lung disease or other manifestation of CF. Semen analysis may be required to identify the very rare man with CF who is fertile. The volume of ejaculate is usually one-third to one-half of normal and void of spermatozoa; in addition, the seminal fluid has a number of chemical abnormalities that reflect the absence of secretions from the seminal vesicles.46 Because spermatozoa develop in the testis of patients with

CF, despite being absent in the ejaculate, epididymal sperm microaspiration coupled with intracytoplasmic oocyte injection may allow successful conception.46 Although male infertility is nearly universal, the rate of infertility for females with CF is only approximately 20%.46 Some women with CF are anovulatory because of chronic lung disease and malnutrition. In addition, mucus in the cervical os has abnormal electrolyte concentration and can present an obstacle to conception by impeding normal sperm migration.46 Nevertheless, hundreds of pregnancies in women with CF have been reported. A longitudinal study of 325 pregnant women with CF reported 258 live births (79%) and 67 therapeutic abortions. Pregnancy in women with CF did not have a negative effect on pulmonary status or mortality over 2 years.46 It is important for women with CF to consider their own health and expected life span in the context of family planning.

Sweat Glands Most CF patients demonstrate elevated levels of sweat chloride, owing to reduced NaCl reabsorption in the sweat ducts.47 This abnormality forms the basis for the diagnostic sweat chloride test and may predispose patients to salt depletion. Young children are most at risk for episodes of salt loss, especially in hot, arid climates and in the setting of concomitant salt/volume loss resulting from vomiting, diarrhea, or exercise. Affected children usually present with lethargy, anorexia, and hypochloremic alkalosis. By comparison, older children and adults rarely present with hypochloremic alkalosis.47 Salt restriction is not indicated in CF; indeed, salt intake should be encouraged when environmental or clinical circumstances place a patient at increased risk for salt depletion. Age-Specific Angle Young children with CF are most at risk for episodes of salt loss, especially in hot, arid climates and in the setting of concomitant salt/volume loss.

Respiratory Manifestations Symptoms Newborns with CF appear to have normal lung function, although studies in the CF pig model suggest that abnormal intrauterine airway development may occur. Clinical symptoms or evidence of increased airways resistance and gas trapping often develop very early in life, although they may not become apparent until adulthood in some patients. Respiratory symptoms typically include a cough that becomes persistent and productive of purulent sputum. Periods of clinical stability are inevitably interrupted by exacerbations, characterized by increased cough, sputum, fatigue, anorexia, weight loss, and decreased lung function. These exacerbations require more intensive therapy, with the goal of alleviating symptoms and restoring lost lung function through the use of antibiotics and airway clearance maneuvers. Over time, such exacerbations become more frequent, respond less well to interventions, and eventually result in respiratory failure. Respiratory Recap Respiratory Manifestations of Cystic Fibrosis ∎ Clinical symptoms: Cough, sputum, fatigue, anorexia, and weight loss, but not usually fever, are characteristic of an exacerbation of lung disease. ∎ Chest radiograph: Hyperinflation, progressing to bronchiectasis that is often more prominent in the upper lobes. ∎ Pulmonary function: Airflow obstruction. ∎ Respiratory microbiology: Airways become persistently infected with gram-negative pathogens such as P aeruginosa and resistant S aureus.

Stop and Think A patient presents to the CF clinic for a routine evaluation. She has experienced increased dyspnea, cough, and sputum production with a decreased appetite over the past 5 days. What diagnostic testing would you recommend?

Chest Radiography Chest radiographs in patients with CF often appear normal early in the course of disease. Hyperinflation may be the first radiographic finding in children, followed by increased interstitial markings. These increased interstitial markings progress to the typical findings of bronchiectasis, which is usually most pronounced in the upper lobes. The right upper lobe is more frequently and severely affected than the left lobe, for reasons that remain unclear. Despite high densities of bacteria in airways, findings of an alveolar filling process typical of bacterial pneumonia are not generally seen even during periods of acute illness. Segmental or subsegmental atelectasis and lobar collapse are common radiographic findings related to airway obstruction and retained secretions. Although the chest radiograph demonstrates the chronic progression of lung destruction and is useful for the detection of important complications such as lobar collapse and pneumothorax, it may not correlate closely with acute clinical changes later in the course of disease, and routine chest radiographs are not recommended for the diagnosis or therapy of a pulmonary exacerbation. High-resolution computed tomography (CT) scans of the chest may be useful to detect bronchiectasis and other early pathologic changes that are not visible on routine chest radiographs, especially during the evaluation of a patient with chronic cough and sputum production who is not otherwise known to have bronchiectasis.48 Likewise, chest CT may prove useful in the CF patient with persistent atypical or nontuberculous mycobacteria (NTM) infection, because the presence of multiple, small parenchymal nodules (so-called tree-in-bud nodules) predominating in the middle and lower lobes and patchy airspace disease represents evidence of true NTM infection.49

Pulmonary Function Pulmonary function testing is a reliable method for evaluating the severity of CF lung disease and is an objective means to determine when a patient’s clinical status has deteriorated and requires more intensive therapy. The first abnormality detected is obstruction of the small airways, as indicated by reduced flow at low lung volumes (e.g., FEF25–75%) and

gas trapping with an increase in the ratio of residual volume to total lung capacity (RV/TLC).50 Later in the course of disease, pulmonary function tests demonstrate progressive reduction in FEV1, followed by decreased functional vital capacity (FVC). FEV1 is the accepted indicator of disability and is somewhat predictive of length of survival.51 An FEV1 of approximately 30% of predicted often signals a need to initiate lung transplant evaluation, although other factors should be taken into consideration.52 Well before spirometric abnormalities appear, bronchiectatic changes and airway obstruction may be evident on CT scans, although chest Xrays may appear normal in younger children. Tests for gas trapping, such as the lung clearance index (LCI), are more sensitive in the early stages of CF and are easier for younger patients to perform. LCI is measured by performing an inert gas washout using a low concentration of an inert gas. In the future, this technique may become a standard means for evaluating the severity of early CF lung disease. As airway obstruction worsens, hypoxemia develops due to ventilation-perfusion mismatching. Even when the patient has adequate oxygenation at rest, hypoxemia may occur during sleep or with exercise in the setting of moderate to severe lung disease; the clinician should assess for this condition with exercise and sleep oximetry.53 Although significant hypoxemia tends to occur in patients with more advanced lung disease, pulmonary function test results can be a poor predictor of the need for oxygen therapy. Supplemental oxygen may improve exercise performance in patients found to desaturate during exercise54 and is generally effective in delaying the progression of pulmonary hypertension and cor pulmonale.55 Severe airway disease causes carbon dioxide retention due to an increased ratio of dead space to tidal volume, which in turn may worsen hypoxemia. Carbon dioxide retention usually does not occur until the patient has severe airway obstruction. Along with resting hypoxemia, this phenomenon is a predictor of end-stage lung disease and decreased survival.56

Respiratory Microbiology

The respiratory tract of newborns often becomes infected with typical CF pathogens early in life.57 Once chronic infection is established, it is rarely eradicated. Staphylococcus aureus and Haemophilus influenzae are often the first organisms detected, although H influenzae rarely persists beyond childhood.58 S aureus may not persist after its initial isolation during childhood or may be isolated for the first time during the adult years. The prevalence of S aureus is nearly 60% in children younger than 2 years of age, peaks at approximately 80% in children aged 6 to 10 years, and then gradually decreases after the age of 17. S aureus resistant to available β-lactam antibiotics is referred to as multiply or methicillin-resistant S aureus (MRSA). Notably, MRSA strains are becoming more prevalent in persons with CF. The mean MRSA infection rate at CF centers was reported to be 25.2% in 2018, a small increase from the 22.6% rate seen in 2012.7 Infection with MRSA is associated with more rapid decline in pulmonary function, more frequent exacerbations than infection with Pseudomonas,59 and decreased survival.60 Age-Specific Angle The respiratory tract of a child with CF often becomes infected with bacteria early in life.

For unclear reasons, the airways of CF patients have a propensity to become persistently infected with otherwise uncommon gram-negative pathogens. These organisms form bacterial biofilms in the airway, making their eradication particularly difficult. Among these pathogens, Pseudomonas aeruginosa is clinically significant. Its prevalence in patients with CF ranges from approximately 20% by 2 years of age and gradually increases with age to nearly 70% in adults older than 45 years of age.7 The percentage of individuals infected with P aeruginosa has been declining over the past several years, however, and overall prevalence is now 44.6%. With the progression of lung disease, P aeruginosa is often the only organism recovered from sputum and may be present in several colonies, often with different antibiotic sensitivity patterns. The recovery of P aeruginosa, particularly the mucoid and biofilm forms, from the lower respiratory tract of a child or young adult with chronic lung symptoms is

highly suggestive of CF. Infection with P aeruginosa is a predictor of worse lung function and survival,61 making avoidance of initial infection desirable. In Denmark, for example, CF clinics segregate infected patients from those who have never grown P aeruginosa in sputum cultures.62 By following similar lines of reasoning, research on the feasibility and efficacy of the eradication of Pseudomonas following its initial isolation led to the development of recommendations for treatment strategies, especially with initial Pseudomonas infections in the airways of young children with CF, which may be in part responsible for the decreasing prevalence of this organism.63 Burkholderia cepacia complex is highly transmissible among patients with CF and is difficult to treat because it is often resistant to antimicrobial drugs. B cepacia complex currently consists of almost 20 distinct species, with the overall prevalence of B cepacia complex in the United States being 2.4%.7 The two most common species in patients with CF are B cenocepacia and B multivorans.5 A subset of patients manifest cepacia syndrome,64 a rapid clinical decline with fever and sepsis after initial infection, although the precise pathogen and host factors that trigger this dramatic and often fatal decompensation are unknown. Perhaps the B cenocepacia strain is more virulent and transmissible than the other strains.65 Because strong evidence exists that person-to-person spread of B cepacia complex occurs, particularly with highly transmissible strains expressing the cable pilus,66 stringent infection control measures are now advocated in all CF care settings. Several infection prevention and control measures—such as segregation of infected patients, closing of CF summer camps, a strong emphasis on hand hygiene, and contact isolation—have been successful at decreasing the transmission of this pathogen.67 Other gram-negative rods that may cause lung infection in CF include emerging pathogens such as Achromobacter xylosoxidans and Stenotrophomonas maltophilia.7 The prevalence of these bacterial species in patients in CF centers in the United States is 5.8% for A xylosoxidans and 12.6% for S maltophilia.7 The impact of these infections on the progression of disease in CF is unclear. Cross-infection does not seem likely, and the source of infection may be the environment.68 Because these organisms are often resistant to multiple medications,

infection prevention and control measures are typically used to combat their spread. Fungi and molds are frequently cultured from the respiratory secretions of CF patients. Invasive aspergillosis has only rarely been reported in CF, but allergic bronchopulmonary aspergillosis (ABPA) develops in 2% to 11% of CF patients.69 The prevalence of ABPA is tracked by the CF Foundation’s patient registry. Data from 29,497 patients in the 2016 registry found 5% had complications of ABPA.7 Other fungi may colonize the airways and evoke similar allergic responses. The diagnosis of ABPA is based on the presence of clinical features such as new infiltrates, wheezing, increased cough, expectoration of brown plugs, or an unexplained deterioration in lung function. The combination of these clinical findings plus evidence for immunologic sensitivity to Aspergillus or other fungi, including elevated titers of Aspergillus precipitating antibodies and high total immunoglobulin E (IgE) levels (>500 IU), should prompt consideration of this diagnosis. Therapy includes systemic corticosteroids and antifungal medications. Isolation of nontuberculous mycobacteria from appropriately processed CF sputum is relatively common and may occur in as many as 20% of adult CF patients.70 Data from a multicenter study suggest an overall prevalence of approximately 13%, with Mycobacterium avium complex being most common; however, both M abscessus and M fortuitum have a significant prevalence. M abscessus is thought to be more virulent and to cause more severe and invasive disease.71,72 The 2017 CF Foundation registry reports an overall prevalence of 12.7% for nontuberculous mycobacteria.7 Patients with high mycobacterial burdens and symptoms refractory to the treatment of typical bacteria may benefit from antimycobacterial therapy.

Infection Control Recommendations The sources of pathogens in CF include nature, contaminated objects, healthcare facilities, and respiratory care equipment. Moreover, strong epidemiologic evidence suggests that people with CF can transmit pathogens to others with CF. Infection control practices that have been successful in preventing transmission include hand hygiene, respiratory hygiene, care of respiratory equipment, and keeping patients with CF

apart from each other. In addition to standard precautions and transmission-based precautions, contact precautions are recommended for the care of all patients with CF, regardless of respiratory tract culture results, because they can potentially harbor pathogens in their respiratory secretions.67 Stop and Think Five hospitalized CF patients are ordered to receive high-frequency chest wall compression (HFCWC) four times per day, but the facility has only three HFCWC units. What would you do to prevent the risk of cross-contamination?

Major Respiratory Complications Hemoptysis, pneumothorax, and respiratory failure are major pulmonary complications that tend to occur in association with more severe lung disease. In the adult CF population, major hemoptysis and pneumothorax each occurs in approximately 1% of patients annually. Most patients who suffer massive hemoptysis or pneumothorax can be treated successfully. Respiratory failure, as the result of progressive airway obstruction and destruction, is the cause of death in 94% of CF patients. Although improved therapies have delayed the development of respiratory failure, at this time respiratory failure can be treated only by lung transplantation.

Hemoptysis Hemoptysis in CF may range from minor blood streaking of the sputum, requiring little intervention, to massive bleeding (more than 240 mL in 24 hours). Minor hemoptysis is common and usually self-limited but may indicate an exacerbation of lung disease. Massive hemoptysis in CF almost invariably comes from the bronchial artery circulation, which is at systemic arterial pressure. The new occurrence of any amount of bleeding may signal the presence of an increased infectious or inflammatory burden and the need for intensified treatment. Consequently, in a patient with a minor amount of hemoptysis, the clinician must determine whether the patient requires treatment with antibiotics and whether medications (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin, penicillin) or vitamin K deficiency may be contributing to the new onset of bleeding. Hemoptysis greater than 240 mL in 24 hours occurs in approximately 5% of patients73 and may lead to airway obstruction and asphyxiation. Hypotension, anemia, and inflammation also may result from massive hemoptysis. Less voluminous hemoptysis that persists for several days (e.g., 100 mL/day for 3 days) also should be considered a major bleeding event, because it may herald massive bleeding. In addition to correcting any hemostatic defects, the clinician should ensure these patients are

hospitalized and treated with antibiotics based on recent sputum culture results. Cough suppression and bed rest may be used during the acute presentation to lessen the likelihood of further bleeding but should not be continued for prolonged periods in patients with advanced lung disease who are likely to suffer from inadequate airway clearance. When bleeding is rapid, positioning the patient with the bleeding lung in a dependent position may help prevent soiling of the nonbleeding lung. Endotracheal intubation may be required if the patient cannot maintain a patent airway. A large orotracheal tube, which can be advanced into the main bronchus serving the nonbleeding lung, is preferable to doublelumen tubes because the small lumens of these latter devices limit airway suctioning. Attempts to localize the site of bleeding with chest radiography, CT scanning, and bronchoscopy may help direct invasive therapies aimed at the control of bleeding but often are not diagnostic and may delay therapy. With massive bleeding, bronchial artery embolization (BAE) is the therapy of choice and is usually directed at tortuous and hypertrophied bronchial arteries.74 Nonbronchial systemic collateral vessels are also frequently involved, especially in cases of recurrent hemoptysis after BAE.75 The use of non-ionic contrast material and of embolizing particles large enough to prevent distal tissue ischemia and the avoidance of sclerosant agents have made BAE relatively safe and successful in experienced hands. Even so, many patients experience rebleeding after BAE and may require further attempts at BAE to achieve a successful outcome.76 Studies have demonstrated a higher risk for rate of decline in lung function, need for lung transplantation, and death among adults with CF treated with BAE for hemoptysis.77 Surgical resection is occasionally required for bleeding refractory to repeated attempts at BAE in patients with adequate pulmonary reserve.

Pneumothorax Subpleural air cysts are probably responsible for the increased incidence of spontaneous pneumothorax in patients with CF. The incidence of pneumothorax is approximately 1% per year overall but increases with age. Pneumothorax occurs in 16% to 20% of adult patients.75 Most patients complain of a sudden increase in dyspnea or chest discomfort,

although others are asymptomatic. The presence of a newly detected pneumothorax usually mandates hospitalization, whether or not chest tube insertion is planned at the outset. Asymptomatic pneumothoraces that occupy less than 20% of the hemithorax may be observed with clinical monitoring to assess progression. In patients with larger pneumothoraces leading to symptoms, the clinician should perform a small tube thoracostomy. Once the pneumothorax has resolved and the air leak stopped, the chest tube(s) may be removed. Patients may require additional tubes when significant air collections persist after the initial tube placement. Chest tubes to evacuate air should generally be placed to water-seal rather than to suction because the negative pressure may inhibit the air leak from sealing. Chest tubes used to evacuate air are usually smaller than those needed to drain a parapneumonic effusion. Chest tubes should be removed as soon as practical, as discomfort associated with the tube can impair effective coughing and airway clearance. Further interventions may be necessary when an air leak results in recurrent or persistent pneumothorax. Talc pleurodesis has been used to cause an inflammatory reaction that leads to obliteration of the pleural space; this procedure is no longer considered to be a relative contraindication for eventual lung transplantation. A surgical approach, with either a small transaxillary thoracotomy or a thoracoscopic procedure, is typically used. Stapling across ruptured pleural blebs and pleural abrasion can be performed, with patients then demonstrating a relatively low rate of recurrence.76

Respiratory Failure Hypoxemic and hypercapnic respiratory failure occurs in the late stages of CF and accounts for most deaths. Treatment of hypoxemia may improve both the quality and the duration of life while delaying the development of cor pulmonale.78 As infection and inflammation progress, however, airway obstruction and parenchymal destruction worsen, causing ventilation-perfusion mismatch and hypoxemia. Other mechanisms that may contribute to hypoxemia include an increased partial pressure of carbon dioxide, intrapulmonary shunt, reduced mixed venous saturation resulting from increased oxygen consumption,

malnutrition, and weakness. The use of noninvasive mechanical ventilation (NIV) may facilitate ventilation and can be used in conjunction with supplemental oxygen therapy as needed. NIV can improve nocturnal ventilation, oxygenation, peak exercise capacity, exertional dyspnea, and sleep quality.79 Treatment of hypoxemic respiratory failure first seeks to correct reversible processes. This phase includes optimization of the treatment of airway infection, clearance of retained secretions, improving nutrition, and treating other complications that may be present. Supplemental oxygen by nasal cannula should be prescribed with the goal of maintaining an SpO2 of 90% or greater. Even when the patient has an adequate daytime SpO2, hypoxemia during sleep or exercise may occur and should be assessed, especially in the setting of severe lung disease (FEV1 ≤ 30% of predicted), low resting SpO2 (≤90%), or signs of cor pulmonale. Because spirometry poorly predicts the occurrence of exercise- or sleepinduced hypoxemia, a low threshold for screening should exist.80 This approach to the treatment of hypoxemic respiratory failure in CF improves exercise capacity,54 delays the development of cor pulmonale, and improves surviva1.53 Hypercapnic respiratory failure results from alveolar hypoventilation, primarily from airway obstruction and increased dead space ventilation. In addition, respiratory muscle weakness in association with muscle fatigue and malnutrition may contribute to this condition’s development. Acidosis that evolves gradually from hypercapnia usually is compensated by renal mechanisms, such that an adequate acid–base balance is maintained. Acute elevations in PaCO2 lead to acidosis and an impaired sensorium. Although hypercarbia often results from slowly progressive lung disease, the clinician should search for treatable causes of respiratory failure. Ventilatory assistance can be provided by NIV or with endotracheal intubation. The decision to use assisted ventilation with intubation should be based on the baseline severity of lung disease, the presence of a reversible precipitating process, and whether the patient has been accepted for lung transplantation.81 In the setting of an acute, reversible process such as pneumothorax, severe hemoptysis, or suboptimal treatment of the underlying CF lung disease, assisted ventilation may buy time needed to treat the acute,

superimposed process. Once the decision to ventilate a patient has been made, healthcare providers should implement airway clearance, suctioning, and antibiotics. In addition, the patient should start therapy for muscle weakness with nutrition and exercise (including ambulation with assisted ventilation). Successful liberation from mechanical ventilation depends primarily on the extent of the underlying lung disease rather than the severity of the acute respiratory event. In the patient awaiting lung transplantation who has accrued enough seniority to make organ availability a possibility within days or weeks, a trial of mechanical ventilation and intensive therapy may be reasonable, with the understanding that prolonged support may not be possible. This period of support may provide a bridge to successful transplantation or may allow the patient and family to address end-of-life issues with greater control. Patients with irreversible respiratory insufficiency are unlikely to benefit from invasive mechanical ventilation without the possibility of imminent lung transplantation. In such cases, the debilitating nature of advanced lung disease makes the probability of the patient’s liberation from mechanical support very low. NIV may relieve acute dyspnea and other symptoms of hypoventilation such as morning headaches, exertional dyspnea, and daytime lethargy.82 It may also be useful as a bridge to transplantation for patients with decompensated respiratory failure.82 In CF patients with severe airflow limitation and chronic respiratory failure, the use of nocturnal NIV appears to be well tolerated and can reduce complaints of daytime respiratory muscle fatigue, and dyspnea, albeit with no concomitant improvement in lung function.83 Studies examining the use of NIV in CF have yielded mixed results in terms of improved quality of life, daytime gas exchange, respiratory muscle function, and quality of sleep. As with conventional mechanical ventilation, NIV may help sustain patients with respiratory failure who are awaiting lung transplantation.83 Because of these mixed results, NIV use should be individualized and closely monitored. Polysomnography should be used to document the degree of gas exchange deterioration during sleep and the frequency of respiratory disturbances and to titrate airway pressures. Stop and Think

A patient with an FEV1 of 27% of predicted is awaiting lung transplantation. The physician has discussed NIV as a therapeutic option, but the patient is unclear about the rationale for therapy. How would you explain the risks and benefits to the patient?

Respiratory Recap Major Complications of Cystic Fibrosis ∎ Hemoptysis ∎ Pneumothorax ∎ Respiratory failure

Standard Therapy of Lung Disease Treatment of CF lung disease can be broadly categorized as therapies used to prevent deterioration of lung function and those used to treat exacerbations. Although newly introduced therapies aim to correct either the gene defect or the ion transport abnormalities that characterize CF epithelia, most of the available therapies either promote the physical removal of airway secretions or reduce airway infection and inflammation. Several types of therapies are often combined to provide optimal care for patients. When multiple expensive and labor-intensive treatment modalities are prescribed, clinicians should monitor patients for appropriate use and adherence (Table 37-2). TABLE 37-2 Airway Clearance Techniques and Medications for Cystic Fibrosis Agent

Rationale

Bronchodilator (βadrenergic agonist)

May protect against bronchospasm induced by expectorants and/or antibiotics; no proven effect on airway clearance

Hypertonic saline or mannitol

May improve airway surface fluid hydration, increase mucin secretion, and increase effective coughing

Dornase alfa

Decreases secretion tenacity by degrading DNA polymers

Airway clearance maneuvers and devices

Methods should be individualized to the patient and used more frequently when the patient is acutely sick

Antibiotic (TOBI, Cayston)

Treat lung infection

Although not addressed in detail here, nutritional support to achieve and maintain ideal body weight and treatment of complications such as CF-related diabetes are integral parts of the multidisciplinary care of patients and may directly affect the severity of lung disease and survival.

The development of specialized CF care centers where expertise from multiple disciplines is applied in an integrated fashion has greatly improved patients’ survival. Box 37-2 lists typical respiratory therapist roles in the management of patients with CF. BOX 37-2 Respiratory Therapist Roles in Cystic Fibrosis Management Evaluating the need for O2 therapy Monitoring oxygenation status and titrating O2 flow or FIO2 Administering aerosol therapies Providing assisted ventilation (via mask or endotracheal tube) Performing airway clearance maneuvers Performing spirometry and other pulmonary function testing Evaluating exercise tolerance Educating patients Proper use of inhaled medications Instruction on airway clearance techniques Respiratory equipment care and maintenance

Maintenance Therapy CF airway secretions are difficult to clear because of their higher tenacity —a property probably caused by inflammation and the presence of DNA/F-actin copolymers in sputum. If left untreated, retained phlegm leads to progressive airway obstruction and serves as a nidus for ongoing infection and inflammation. In an attempt to treat the progression of infection, inflammation, and lung destruction, airway clearance techniques have been developed to promote the expectoration of airway secretions. These techniques remain a cornerstone of CF therapy (Table 37-3). TABLE 37-3 Airway Clearance Techniques Technique

Description

Performed Independently?

Chest

CPT includes manual or mechanical percussion and

No

physical therapy (CPT)

vibration applied over individual lung segments in postural drainage positions, except head down or Trendelenburg. The head-down postural drainage positioning (tipping) should be avoided due to evidence of reflux and/or aspiration, particularly in infants. Mechanical percussors provide limited patient autonomy and may decrease fatigue in the caregiver.

Active cycle of breathing technique (ACBT)

Technique alternates (1) gentle breathing with the lower chest, (2) deep breathing with emphasis on inspiration, and (3) forced exhalation technique (FET) using the abdominal muscles and an open mouth/glottis (huff). ACBT may be combined with posture positions.

Yes

Autogenic drainage (AD)

Technique alternates (1) breathing at low lung volumes to loosen peripheral secretions, (2) breathing at low to midlung volumes to collect mucus from central airways, and (3) mucus evacuation by breathing at mid- to high lung volumes. It is performed in the sitting position and requires significant teaching and practice.

Yes

Positive expiratory pressure (PEP)

Pressure (10 to 20 cm H2O) is applied via an expiratory resistor attached to a mask or mouthpiece. Tidal breathing with slightly active exhalation is used. Forced exhalation and cough follow PEP to expectorate mucus. Nebulized medications may be delivered in conjunction with a PEP device.

Yes

Oscillatory PEP (OPEP)

A handheld device delivers airflow oscillations in addition to positive expiratory pressure. It is essential to achieve sufficient airflow and pressure through the device, and patients with very severe lung disease may not be able to perform this technique. The OPEP technique is tiring and adherence is poor. Some devices allow nebulized medications to be delivered in conjunction with OPEP therapy.

Yes

Highfrequency chest wall compression (HFCWC)

An inflatable vest linked to a compressed air delivery system provides air pulses at high frequency. Therapy is given over 20 to 30 minutes, with the patient sitting in an upright position.

Yes

Patients with CF can use several airway clearance methods, with little more than small trials and expert opinion available to guide clinicians to the best choice for a given patient. Chest physical therapy (CPT) by hand

percussion over the chest wall—the traditional means used to clear secretions—is usually effective but is considered time and labor intensive and has poor adherence. CPT has been shown to improve mucus clearance and pulmonary function in otherwise stable patients.84 This method requires a caregiver capable of performing the therapy correctly. Strong evidence argues against use of the head-down postural drainage positions for patients of any age because of the increased risk of gastroesophageal reflux.85 Alternative airway clearance therapies include breathing techniques such as autogenic drainage (AD) and the active cycle of breathing technique (ACBT), positive airway pressure adjuncts such as positive expiratory pressure (PEP) and oscillatory PEP (OPEP), and mechanical devices that deliver high-frequency chest wall compression (HFCWC). These alternatives to traditional CPT can be effectively self-administered, allowing patients to have more independence. Also, the treatment times are typically shorter than those required for CPT. Because no single method has been shown to be consistently superior and great variability exists among patients, different methods should be tried until the patient identifies those that he or she is willing and able to use.86 To achieve good patient outcomes, the respiratory therapist must understand the operation and limitations of the airway clearance devices available for use. Any therapy must take into consideration the patient’s age, ability to cooperate and to properly perform the therapy, level of motivation, and degree of pulmonary impairment. The use of airway clearance protocols can help match therapeutic goals to clinical needs and guide the selection and sequencing of therapy. Patient and family education should include how to perform the therapy as well as how to use and clean the equipment.87 Effective strategies for integrating multiple lengthy therapy sessions into the patient’s daily schedule should be reviewed as well.88 Patient acceptance of a technique is crucial if adherence is to be expected. In general, airway clearance therapies are some of the most time-intensive treatments used for CF and have the lowest rates of consistent adherence. Exercise has been shown to enhance airway clearance and has welldocumented benefits for health and well-being.89 The need for supplemental oxygen during exercise should be assessed periodically in those patients with severe airway obstruction.

Another strategy used to aid secretion removal is to modify the transportability of phlegm. Because DNA is the major polymer in CF secretions, human recombinant DNase I (dornase alfa; Pulmozyme) was developed and approved for use in CF in 1994.90 In a well-controlled 6month study, once-daily use of dornase alfa improved FEV1 by 6% above baseline and decreased the frequency of respiratory exacerbations by 28%. The response to dornase alfa varies, with some patients showing a clear benefit and others showing no change or actually worsening. Given this inconsistency, healthcare providers should carefully monitor the patient’s response. Because most patients who benefit show a response within 1 to 3 months of starting the drug, a therapeutic trial should be considered for as long as 3 months while the patient is monitored for improvement in lung function and clinical symptoms. The efficacy of dornase alfa over longer time periods has not been reported, and the timing of this therapy has been debated as well. In a Cochrane review, 99 trial reports, representing 48 studies that provided data on 122 participants, were reviewed to determine whether the timing of dornase alfa administration (before or after airway clearance therapy) affected clinical outcomes of patients with CF.91 The current evidence— derived from the small number of participants in this meta-analysis—did not indicate that inhalation of dornase alfa after using airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulized dornase alfa 30 minutes before using airway clearance techniques.92 The investigators reported, however, that for a small subset of children with well-preserved lung function, inhalation of dornase alfa before airway clearance may be more beneficial for small airway function than inhalation after airway clearance therapy.91 The studies included in their analysis relied on measures with high degrees of variability and differing levels of patient follow-up.93 The authors concluded that there was no strong evidence that one timing regimen was superior to the other and that the timing of dornase alfa inhalation was most likely largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day.91 The DNA polymer network copolymerizes with filamentous actin (Factin) from effete airways and inflammatory cells and from neutrophil extracellular traps (NETs).92 This effect increases the rigidity of these polymers. F-actin depolymerizing agents such as thymosin beta 4 have

been shown to be both effective as mucolytics and synergistic with dornase alfa in vitro but have not yet been studied in patients with CF.94 Several mucolytics have been used in CF, although none has been shown to improve lung function or other clinical outcomes. Among these agents, N-acetylcysteine (Mucomyst) is perhaps the most commonly used. This agent breaks disulfide bonds in mucins, thereby making them less viscous. Unfortunately, it may also increase epithelial inflammation. Although irritation can induce coughing, aerosol N-acetylcysteine has not been shown to be beneficial for patients with CF. Other mucolytic agents also have been used but have not been shown to have benefits for patients with CF. Studies indicate that N-acetylcysteine, when administered orally, may act more as an antioxidant than as a mucolytic.94,95 Hypertonic saline is used to promote hydration of periciliary fluid, induce coughing, and increase mucus secretion. To date, studies have examined the acute effect of hypertonic saline (3% to 12%) on mucociliary clearance.96,97 Studies of lung function suggest a benefit from this therapy,98 but some CF patients with coexistent asthma may not tolerate hypertonic solutions because of bronchospasm.98 Similarly, inhaled dry powder mannitol has been shown to improve the biophysical and transport properties of CF sputum.99 Because chronic airway infection causes progression of CF lung disease, oral and inhaled antibiotics are important parts of a standard CF care regimen. In general, patients use oral antibiotics episodically, when new respiratory symptoms develop or patients experience a minor decline in lung function. Scheduled cycles of oral antibiotics also may be used prophylactically in patients who have frequent exacerbations. Continuous use of an oral antibiotic designed to suppress infection with S aureus has been a common practice, especially in Europe. Long-term use of ciprofloxacin—an oral quinolone antibiotic with good activity against P aeruginosa—should be avoided because of the rapid emergence of resistance after 3 to 4 weeks of use. Because of the limited number of oral antibiotics available to treat P aeruginosa, inhaled aminoglycosides have been used in case of such infections. This route of administration has the benefit of achieving high drug levels in proximal airway secretions, with minimal systemic levels or toxicity. High drug concentrations in secretions may be particularly helpful

to treat bacteria resistant to the antibiotic concentrations that may be achieved via the intravenous route. Because of the natural concentration gradient of antibiotics in the airways, distal secretions are exposed to progressively lower concentrations, inevitably leading to the development of antimicrobial resistance. The best data for inhaled antibiotic efficacy exist for high-dose tobramycin. A preservative-free, concentrated preparation of tobramycin solution for inhalation (TOBI, Mylan) 300 mg twice a day, taken during alternate months, improves lung function and lessens the relative risk of hospitalization or treatment with intravenous antibiotics.100 Generic formulations of tobramycin are available, as well as tobramycin inhalation powder for administration using the Podhaler device. An alternative to inhaled tobramycin is aztreonam lysine (AZLI, Cayston), which has good in vitro activity against P aeruginosa.101 An approach embraced by the Danish CF Centre stresses measures aimed at delaying the acquisition of P aeruginosa and aggressive antibiotic treatment once this organism is cultured from sputum. These measures include the segregation of patients by microbiological status and attempts to eradicate Pseudomonas when this pathogen is initially cultured in a patient.58 When scheduled courses of intravenous antibiotics are given every 3 months, patients chronically infected with Pseudomonas achieved improved survival using this approach compared with historical controls.102 Significant concerns include the earlier development of bacterial antibiotic resistance, the lack of proven efficacy confirmed by controlled trials, the enormous healthcare resources involved, and the personal impact this approach has on patients. Liposomal amikacin is a formulation of amikacin that, when inhaled, enhances drug delivery and retention in CF airways. Dosing is once per day, which may positively impact adherence to therapy. Liposomal amikacin can successfully eradicate M abscessus103 and treat P aeruginosa. Amikacin liposome inhalation suspension is cleared by the FDA for treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen for adult patients who have limited or no alternative treatment options. It is delivered with the Lamira mesh nebulizer. Bronchodilators, especially those delivered by the inhaled route, are commonly prescribed in CF. Approximately one-fourth of patients with CF

have bronchial hyperreactivity,104 and bronchodilators may improve respiratory symptoms in these individuals. Whether these agents provide long-term benefits in CF is unknown. In general, inhaled β-adrenergic agents are used in patients with documented reversibility on spirometry or in those who receive symptomatic benefit. Inhaled anticholinergic agents, especially tiotropium, are well tolerated in children older than 4 years of age and adults with CF.105 Oral preparations, including theophylline, are not routinely used, have not been shown to confer a benefit in CF, and must be monitored carefully because of pharmacokinetic variability. There is a clear rationale for using anti-inflammatory agents to decrease neutrophilic inflammation and the harmful effects of neutrophil products. Initial studies designed to test this approach used high doses of corticosteroids. Although patients receiving 1 to 2 mg/kg of prednisolone on alternate days had a slowed decline in lung function (ΔFEV1 of –2% versus –6% in the placebo group, at 48 months), this regimen had unacceptable side effects.106 Glucose metabolism abnormalities and delayed linear growth limit chronic therapy with oral corticosteroids, although the risk–benefit ratio may favor their use in patients with ABPA. Inhaled steroids also have been studied in CF, but studies clearly indicate that, with the exception of patients who have concomitant asthma, these medications offer few, if any, benefits and some possible risks.107 An alternative means to decrease neutrophilic inflammation is highdose ibuprofen. In a 4-year study, young patients (5 to 13 years) with mild lung disease (FEV1 ≥ 60% of predicted) benefited from twice-daily ibuprofen at doses sufficient to achieve peak blood levels of 50 to 100 mg/L. In those who adhered to therapy, the annual rate of change in FEV1 was –1.5% versus –3.5% in the placebo group. Nutritional status and radiographic indices of disease activity also were improved in the treated group, and they experienced few side effects.108 Low-dose macrolide antibiotics (especially azithromycin) are effective as immunomodulatory medications and can decrease neutrophildominated airway inflammation and improve pulmonary function in patients with CF.109 A large multicenter study demonstrated significant lung function improvement and fewer intravenous antibiotic courses in subjects with CF on azithromycin.93 A meta-analysis of four studies with 296 participants concluded that azithromycin has a small but significant

treatment effect in improving pulmonary function in persons with CF.110 Stop and Think A patient with an FEV1 of 95% predicted reports that he does not adhere to his airway clearance therapy, complaining that the therapy is time consuming and he sees no benefit. How would you explain the benefits of airway clearance to the patient?

Respiratory Recap Maintenance Therapy for Cystic Fibrosis ∎ Airway clearance techniques ∎ Aerosolized dornase alfa ∎ Other mucus-modifying agents ∎ Antibiotics ∎ Anti-inflammatory medications

Exacerbations The course of CF lung disease is punctuated by periodic episodes of increased airway infection and inflammation that lead to worsened lung function. These exacerbation episodes occur more frequently and become more difficult to treat as lung disease progresses and bacterial resistance develops. When exacerbations inevitably occur, clinicians should advocate for an early and aggressive approach to reclaim lost lung function and to prevent early relapse with its associated risks. Access to a CF center for early detection and treatment of an exacerbation is critically important. It has been reported that children with better lung function actually had more office sick visits, which implies that they were able to be treated promptly for pulmonary problems.111 Typical features of an infectious exacerbation of CF lung disease include an increase in the frequency of cough and amount of sputum, diminished appetite, weight loss, fatigue, and a decrease in FEV1. Most patients do not develop a fever, so high fever should prompt the search for other etiologies, including infection with B cepacia complex or atypical organisms (e.g., respiratory viruses, mycobacteria) or indwelling catheter

infection. Leukocytosis is typically mild to moderate, and chest radiographs usually show little or no acute change. During the initiation of therapy for a CF exacerbation, clinicians should consider potential precipitating causes, including the presence of environmental allergens or irritants (e.g., tobacco smoke), inadequate airway clearance measures, allergic bronchopulmonary aspergillosis, and therapeutic nonadherence. The adequacy of airway clearance at home, the severity of the exacerbation, the baseline severity of lung disease, and the complexity of the treatment regimen being instituted should be weighed when deciding whether home therapy with intravenous antibiotics may be an option. In either environment, airway clearance maneuvers should be intensified, preferably to include airway clearance therapy at least four times daily. Antibiotics should be selected based on recent, pretreatment culture and sensitivity testing whenever possible. Every isolated organism is targeted when feasible, although patients often improve even when only selected organisms are targeted. There appears to be very little relationship between organisms cultured in sputum and therapeutic response to antimicrobials, including agents to which pathogens are resistant. P aeruginosa, B cepacia complex, and other gram-negative organisms (e.g., S maltophilia, A xylosoxidans) should be treated with two antibiotics from complementary drug classes. When both a gram-negative organism and S aureus are cultured, antistaphylococcal therapy must be added. The duration of therapy typically lasts 2 or 3 weeks but may be extended when the clinical response is slow. Pulmonary function testing near the end of a planned antibiotic course may be useful as an objective measure of the adequacy of therapy. Although some further improvement in lung function may occur even after completion of the antibiotic course, the return of lung function to pre-exacerbation levels is reassuring.

Lung Transplantation Lung transplantation has become an accepted therapy for end-stage CF lung disease. The relative paucity of donor organs and consequent long waiting times before organ availability mandate that patients be referred to transplant centers on a timely basis. With waiting times exceeding 2 years at some centers, close attention should be paid to clinical and

testing results that predict a 2-year survival probability of 50%—namely, an FEV1 of 40% of predicted, the rate of decline in lung function, and hypercapnia (PaCO2 ≥ 45 mm Hg). The presence of an accelerated clinical decline, characterized by more frequent exacerbations that respond incompletely to aggressive therapy, recurrent pneumothoraces, massive hemoptysis, or panresistant organisms, should prompt consideration for earlier referral.112 Optimal transplant candidates should not have significant nonpulmonary organ dysfunction (e.g., kidney, liver, heart), should be motivated and adherent with therapy, and should have adequate psychosocial support. The surgical approach now preferred is sequential bilateral transplantation rather than heart–lung transplantation. Alternatively, when a patient is not likely to survive until a cadaveric transplant can be performed, living donor lobar transplantation can be performed at some centers when healthy donors of sufficient size and correct blood type are available.113 In either case, survival after transplantation appears no different in CF than in transplantation for other indications. The five-year survival rate is approximately 48% and is limited primarily by opportunistic infections and chronic graft rejection, manifesting as bronchiolitis obliterans syndrome (BOS).114

Key Points Cystic fibrosis is a common inherited disorder that causes significant morbidity and premature mortality in affected individuals. Cystic fibrosis is the most common lethal genetic disease affecting the white population; it is inherited in an autosomal recessive pattern. Mutations in the CFTR gene result in several ion transport abnormalities, which in turn impair cough clearance and lung defense. Chronic infection and inflammation lead to progressive lung damage and respiratory failure in most patients with CF. Improvements in care, including better antibiotics and nutritional support, have greatly extended survival. Cystic fibrosis is a multiorgan disease, with many clinical manifestations. The combination of a typical CF clinical manifestation with evidence for abnormal CFTR is required for the diagnosis of the disease. Preventive care is the cornerstone of effective CF management. Close monitoring of lung function, therapies aimed at airway clearance and minimization of infection, and nutritional support are necessary elements in CF care. Lung transplantation is an appropriate therapy for patients with severe CF lung disease. Evaluation for transplant in appropriate candidates should occur before the local waiting time for donor availability exceeds the anticipated survival time.

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CHAPTER

38 Acute Respiratory Distress Syndrome Craig R. Rackley Christopher E. Cox Michael A. Gentile

© Andriy Rabchun/Shutterstock

OUTLINE Definition Incidence Etiology Clinical Manifestations Pathobiology Management Outcomes Prevention

OBJECTIVES 1. Define acute respiratory distress syndrome (ARDS). 2. List common risk factors for ARDS. 3. Recognize the clinical, radiographic, and pathophysiologic features of ARDS.

4. 5. 6. 7.

Describe the pathobiology of ARDS. Discuss pharmacologic and nonpharmacologic therapies for ARDS. Describe ventilation strategies for ARDS. Describe how ARDS affects long-term physical functioning and quality of life.

KEY TERMS acute respiratory distress syndrome (ARDS) ARDS network (ARDSnet) driving pressure extracorporeal membrane oxygenation (ECMO) high-flow nasal cannula (HFNC) lung injury score lung-protective ventilation mechanical ventilation oxygenation index (OI) PaO2/FIO2 plateau pressure positive end-expiratory pressure (PEEP) primary ARDS prone position secondary ARDS

Introduction Acute respiratory distress syndrome (ARDS) is characterized by diffuse damage to the alveolar-capillary membrane leading to noncardiogenic pulmonary edema and hypoxemia. ARDS is a worldwide public health issue with significant morbidity and mortality; it affects both medical and surgical patients of all ages. Respiratory therapists play an essential role in the early recognition of ARDS and contribute to the multidisciplinary team approach required to manage this life-threatening condition. An understanding of the epidemiology, diagnosis, and management of ARDS is essential in the care of these critically ill patients.

Definition The first clinical description of ARDS was published in 1967, when Ashbaugh et al identified 12 patients with trauma, aspiration, and pulmonary infection who presented with acute dyspnea, hypoxia, diffuse pulmonary infiltrates, and decreased pulmonary compliance.1 This condition was initially termed adult respiratory distress syndrome to distinguish it from neonatal acute respiratory failure, which had similar physiologic derangements but was due to inadequate surfactant production in immature lungs.2 Later, the name was changed to acute respiratory distress syndrome as it became apparent that diffuse lung injury from a variety of causes could affect both adult and pediatric populations. In 1994, the American–European Consensus Conference (AECC) defined ARDS as “an acute clinical illness characterized by the development of bilateral pulmonary infiltrates on chest radiograph and severe hypoxemia with a Pao2/Fio2 of less than 200 mm Hg in the absence of congestive heart failure.” The AECC also recognized a less severe form of ARDS, acute lung injury (ALI), with similar clinical findings but with a PaO2/FIO2 less than 300 but greater than 200.3 The AECC definitions were widely used to identify patients with ALI and ARDS for enrollment in clinical trials. These broad and simplistic definitions did not consider important physiologic factors affecting PaO2/FIO2 (i.e., positive airway pressure and lung compliance), and they ignore both etiologic and host factors that likely affect the biochemical and cellular pattern of the illness. The ARDS Definition Task Force convened in Berlin in 2011 to refine the definition of ARDS. These investigators initially proposed three mutually exclusive categories of ARDS based on degree of hypoxemia in addition to four other variables reflecting clinical characteristics: radiographic severity, respiratory system compliance, positive endexpiratory pressure (PEEP), and corrected expired volume per minute. While the degree of hypoxemia was associated with increased mortality and increased duration of mechanical ventilation, the ancillary clinical variables were not predictive of outcomes and were not included in the

final definition. The final Berlin definition of ARDS therefore stratified patients as having mild (PaO2/FIO2 of 201 to 300 mm Hg), moderate (PaO2/FIO2 of 101 to 200 mm Hg), or severe (PaO2/FIO2 < 100 mm Hg) ARDS and eliminated the term acute lung injury (Table 38-1).4 TABLE 38-1 AECC and Berlin Definitions of ARDS AECC Definition

Berlin Definition

Timing

Acute onset

Onset within 1 week of a known clinical insult or new or worsening respiratory symptoms

Chest imaging

Bilateral infiltrates

Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules

Origin of edema

PAWP ≤ 18 mm Hg or no clinical evidence of left atrial hypertension

Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment to exclude hydrostatic edema if no ARDS risk factor is present

Category: PaO2/FIO2

ALI: ≤300 mm Hg regardless of PEEP or CPAP ARDS: ≤200 mm Hg regardless of PEEP or CPAP

Mild: 201–300 mm Hg with PEEP or CPAP 5 cm H2O Moderate: 101–200 mm Hg with PEEP or CPAP 5 cm H2O Severe: ≤100 mm Hg with PEEP or CPAP 5 cm H2O

AECC, American–European Consensus Conference; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; CPAP, continuous positive airway pressure; PAWP, pulmonary artery wedge pressure; PEEP, positive end-expiratory pressure. Reproduced from Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American–European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149(3):818–824; ARDS Definition Task Force. Information from acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307(23):2526–2533.

Besides the PaO2/FIO2, two other severity indices in ARDS are the lung injury score and the oxygenation index (OI). The lung injury score incorporates the positive end-expiratory pressure (PEEP), PaO2/FIO2, extent of chest radiograph abnormality, and static lung compliance into a summary score that stratifies lung injury into either mild

to moderate or severe.5 The oxygenation index incorporates FIO2 and mean airway pressure (Paw) into its calculation: OI = [( aw × FIO2)/PaO2] × 100 The oxygenation index has been suggested as a severity score for the initiation of advanced modalities such as high-frequency oscillatory ventilation (HFOV) and extracorporeal membrane oxygenation (ECMO).6,7 In the future, it is likely that newer methods and measurements will be able to better characterize ARDS and risk-stratify those who develop it. These tools may include cytokine profiles, inflammatory cellular responses, genetic expression patterns, comorbidities, and accompanying organ injuries, which all have the potential to better stratify the various clinical phenotypes of ARDS. Respiratory Recap Acute Respiratory Distress Syndrome (ARDS) ∎ Abrupt onset of respiratory distress ∎ Hypoxemia ∎ Bilateral pulmonary opacities ∎ Not fully explained by heart failure or volume overload

Incidence Efforts to determine the prevalence of ARDS have resulted in widely varying estimates. An initial report by the National Institutes of Health in 1972 estimated 75 cases of ARDS per 100,000 population (approximately 150,000 cases of ARDS per year) in the United States.8 Other studies have often found lower estimates, ranging from 3 to 13.5 cases per 100,000 population.9–11 The most recent study suggested a range of 79 to 86 cases per 100,000 person-years.12 Approximately 10% to 15% of patients admitted to the intensive care unit (ICU) meet the diagnostic criteria for ARDS.13,14 Stop and Think You are caring for a patient with hypoxemic respiratory failure who was recently intubated. How would you know if the patient has ARDS?

Etiology Multiple clinical conditions have been associated with the development of ARDS (Box 38-1).15 Risk factors can be described as those that cause direct injury to the lungs (such as pneumonia, aspiration of gastric contents, inhalation of toxic gases, or pulmonary contusion)—called primary ARDS—and those that cause indirect injury to the lungs (such as sepsis, multiple trauma, pancreatitis, or transfusion of blood products) —called secondary ARDS. In the case of indirect injury, ARDS is thought to result from systemic inflammation, which promotes the release of pro-inflammatory mediators that lead to the migration of neutrophils to the alveoli. Overall, patients with sepsis are those at the highest risk to develop ARDS, with a 40% incidence.16 Secondary risk factors such as low serum pH, chronic lung disease, and chronic alcohol abuse have been associated with an increased risk for ARDS.17 If patients with ARDS from a direct lung injury subsequently develop sepsis or shock, they can develop an indirect lung injury as well. The distinction between direct and indirect injury thus is often blurred. BOX 38-1 Clinical Disorders Associated with ARDS Direct Lung Injury (Primary ARDS) Common causes Pneumonia Aspiration of gastric contents Less common causes Pulmonary contusion Fat emboli Near-drowning Inhalation injury Reperfusion pulmonary edema after cardiopulmonary bypass

Indirect Lung Injury (Secondary ARDS) Common causes Sepsis Trauma with shock and blood product transfusion Less common causes Drug overdose Cardiopulmonary bypass

Acute pancreatitis Transfusion of blood products Data from Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342(18):1334–1348. Reprinted with permission from Massachusetts Medical Society.

Respiratory Recap Risk Factors for ARDS ∎ Direct injury to the lungs such as pneumonia or aspiration ∎ Indirect injury to the lungs such as sepsis, multiple trauma, or acute pancreatitis

Clinical Manifestations Patients with ARDS are symptomatic with progressive dyspnea and acutely abnormal oxygenation. Hypoxemia is primarily the result of shunt caused by atelectasis and alveolar flooding. In addition, disturbance of the normally protective mechanism of hypoxic pulmonary vasoconstriction contributes to shunt and hypoxemia. In their first few days with ARDS, patients experience a decrease in lung compliance, partly because of alveolar and interstitial edema, but also due to surfactant function impairment. Decreased compliance and hypoxemia together lead to rapid, shallow breathing with increased minute ventilation and an increased work of breathing. Many patients with ARDS require mechanical ventilation. Chest radiographic findings show bilateral opacities reflecting inflammatory exudates and noncardiogenic pulmonary edema (Figure 38-1). The opacities may be confluent, patchy, or asymmetric and can be complicated by pleural effusions and heart failure. Because ARDS can represent a myriad of disease processes, the chest radiograph findings may range from mild infiltrates to diffuse, dense consolidation, with both extremes meeting the radiographic criteria for a diagnosis of ARDS. Chest radiographs in patients requiring higher levels of positive pressure ventilation may reveal evidence of barotrauma such as pneumothorax, pneumomediastinum, or pneumatoceles.

FIGURE 38-1 Anteroposterior supine radiograph of a patient with acute respiratory distress syndrome.

Despite the appearance of diffuse infiltrates on the frontal chest radiograph, ARDS is not a homogeneous process. Although not necessary for the diagnosis of ARDS, computed tomography (CT) of the chest better demonstrates the heterogeneity of this disease (Figure 382).18 More dependent portions of the lungs often demonstrate greater atelectasis than the more nondependent areas—which helps explain the different effects of positive airway pressure seen in these different regions of the lungs.18,19

FIGURE 38-2 Computed tomography of the chest of a patient with acute respiratory distress syndrome.

Some patients with ARDS longer than 3 to 7 days enter the fibroproliferative phase. Profound hypoxemia may subside, but poor lung compliance continues, in part because of the development of fibrosis. Rather than intrapulmonary shunting, the problem at this phase is increasing dead space resulting in increased minute ventilation requirements. Dead space in excess of 70% may occur and has been associated with high mortality.20 These patients may ultimately develop pulmonary hypertension and right heart dysfunction.21 Respiratory Recap Clinical Manifestations of ARDS ∎ Profound hypoxemia early in the disease course ∎ Decreased lung compliance ∎ Rapid shallow breathing pattern

∎ Increased dead space ∎ Bilateral opacities on chest x-ray ∎ Heterogeneity of disease on chest CT; dependent atelectasis

Pathobiology ARDS is characterized by acute alveolar inflammation, neutrophil activation, surfactant deficiencies, damage to the alveolocapillary membrane (increased permeability, neutrophil and bacterial migration), and development of proteinaceous pulmonary edema with alveolar collapse.22 Destruction of the type I alveolar epithelial cells leads to their detachment from their underlying basement membrane. This results in impairment of the normal anatomic barrier, which leads to increased permeability and resultant influx of protein-rich edema fluid into the interstitium and alveolar space (Figure 38-3). The newly denuded basement membrane becomes covered with a layer of fibrin, known as the hyaline membrane. These findings are described pathologically as diffuse alveolar damage. In patients with persistent lung injury (3 to 7 days after initial lung injury), the disease process progresses to a stage at which the basement membrane is replaced with a more fibrotic material enhanced by the proliferation of alveolar type II cells. Additional destruction of the pulmonary vasculature is caused by fibrosis and microthrombi in the capillary bed.23,24

FIGURE 38-3 (A) Normal alveolus. (B) Injured alveolus in the acute phase of the acute respiratory distress syndrome. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the airspace, which is filled with protein-rich edema fluid.

In the airspace, an alveolar macrophage secretes inflammatory cytokines, which act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete other cytokines. Neutrophils can release oxidants, proteases, leukotrienes, and other pro-inflammatory molecules, such as platelet-activating factor. A number of anti-inflammatory mediators are also present in the alveolar milieu. The influx of protein-rich edema fluid into the alveolus has led to the inactivation of surfactant. Adapted from Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342(18):1334–1348.

Description Although no clinically available marker exists that correlates with lung injury, bronchoalveolar lavage (BAL) results have provided a better understanding of the inflammation occurring in the alveolar space.25–27 Analysis of BAL fluid in patients with early ARDS reveals a high percentage of neutrophils; these cells are usually present in only trace amounts in a normal lung lavage. As lung injury progresses, neutrophils tend to be replaced with alveolar macrophages and lymphocytes. A higher mortality in patients with persistence of alveolar neutrophils is found, however, due to their destructive nature and release of cellular debris.28,29

Management Management of patients with ARDS involves a multidisciplinary approach. Early detection and treatment of the underlying and causative pathophysiology are paramount. This includes hemodynamic management, appropriate use of antibiotics, and surgical intervention when required. These actions are used in conjunction with supportive care involving lung-protective mechanical ventilation strategies and prevention of nosocomial infection. Notably, many of the current management approaches are outgrowths of several large clinical trials conducted by the National Institutes of Health’s ARDS Network (ARDSnet), a multicenter research consortium first assembled in 1994. Stop and Think You are caring for a mechanically ventilated patient with ARDS. How do you select an appropriate tidal volume and PEEP?

High-Flow Nasal Cannula Patients with ARDS often require intubation and invasive mechanical ventilation. However, many individuals with mild to moderate ARDS may avoid invasive mechanical ventilation and the risks associated with this intervention. The high-flow nasal cannula (HFNC) has emerged as an oxygen delivery device used to support patients with less severe ARDS. Using HFNC in patients with ARDS who require more than 6 L/min of oxygen via nasal cannula, but who do not have frank respiratory failure, reduces the risk of intubation and death compared to noninvasive positive pressure ventilation or oxygen delivered through a simple face mask.30 Mechanisms of HFNC include a small amount of CPAP, which improves alveolar recruitment, washout of upper airway dead space, and a higher level of oxygen delivery secondary to better peak inspiratory flow coverage.31–33

Mechanical Ventilation Evidence-based clinical practice guidelines for mechanical ventilation of patients with ARDS are shown in CPG 38-1.34 Patients with ARDS who present in respiratory failure or progress despite HFNC are not candidates for noninvasive ventilation (NIV); indeed, NIV might contribute to harm in this population.35 Endotracheal intubation should be performed before a patient progresses to full acute respiratory failure. Invasive mechanical ventilation required due to the severity of hypoxemia can be lifesaving for patients with ARDS and has the goal of supporting gas exchange without inducing further injury to the lungs. Because of the heterogeneity of the lungs of patients with ARDS, mechanical ventilation strategies include alveolar recruitment while avoiding overdistention of normal lung units.36 CLINICAL PRACTICE GUIDELINE 38-1 Clinical Practice Guidelines of the American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine for Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome Recommendations for the following interventions for the treatment of ARDS are strong:

▪

Mechanical ventilation using lower tidal volumes (4 to 8 mL/kg predicted body weight) and lower inspiratory pressures (Pplat < 30 cm H2O) (moderate confidence in effect estimates)

▪

Prone positioning for more than 12 hours per day in severe ARDS (moderate confidence in effect estimates) Recommendation against the following intervention for the treatment of ARDS is strong:

▪

Routine use of high-frequency oscillatory ventilation in patients with moderate or severe ARDS (high confidence in effect estimates) Recommendation for the following interventions for the treatment of ARDS is conditional:

▪

Higher positive end-expiratory pressure in patients with moderate or severe ARDS (moderate confidence in effect estimates)

▪

Recruitment maneuvers in patients with moderate or severe ARDS (low confidence in effect estimates) Additional evidence is necessary to make a definitive recommendation for or against the use of extracorporeal membrane oxygenation in patients with severe ARDS. Adapted from Fan E, Del Sorbo L, Goligher EC, Hodgson CL, Munshi L, Walkey AJ, et al. An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2017;195(9):1253–1263.

Prolonged exposure to large tidal volumes (VT) and high transpulmonary pressures can overdistend alveoli and contribute to a cascade of lung and systemic inflammatory responses that can worsen the underlying lung injury (ventilator-induced lung injury [VILI]). VILI can manifest as air leak (barotrauma), diffuse alveolar damage by overinflation (volutrauma), or shear stress when collapsed lung units repeatedly open and close (atelectrauma). Growing appreciation for VILI has led to an emphasis on avoiding alveolar overdistention and cyclic alveolar collapse and reexpansion.37 For much of the 20th century, VT was set at 10 to 15 mL/kg of predicted body weight to normalize gas exchange. What has been termed lung-protective ventilation reduces the VT to near-normal ranges (4 to 8 mL/kg predicted body weight), thereby decreasing the injurious alveolar stretch and subsequent release of inflammatory mediators. The use of a lung-protective ventilation strategy reduces mortality and should be employed in all patients with ARDS.38–44 The best evidence supporting lung-protective ventilation comes from the ARDSnet study of higher versus lower VT.38 In this study, 861 patients were randomized to a VT of 6 mL/kg (lung protective) or 12 mL/kg (traditional), based on predicted body weight, rather than actual body weight. Plateau pressure (Pplat) was limited to 30 cm H2O in the lungprotective group and to 50 cm H2O in the traditional group. A significant mortality difference was noted: 31% in the lung-protective group compared with 40% in the traditional group. In addition, levels of plasma interleukin-6, an important inflammatory cytokine, were noted to be lower in the lung-protective group. These data support the hypothesis that alveolar stretch can propagate systemic inflammation and subsequently lead to multiple organ dysfunction and death. Raising FIO2 improves PaO2 in low units but has little effect on PaO2 in the presence of shunt. Moreover, high FIO2 can cause lung damage through free-radical formation (oxygen toxicity). For this reason, minimize FIO2 exposure.45,46 PEEP improves oxygenation by maintaining alveolar recruitment, thereby reducing shunt. Increased alveolar recruitment with PEEP also improves lung compliance and likely reduces VILI from the shear forces that result when alveoli repetitively open and close.19,44 Nevertheless, PEEP also has some potential negative effects.

By increasing intrathoracic pressure, it can decrease venous return and cardiac output. Additionally, PEEP can result in overdistention of open alveoli, contributing to VILI and barotrauma.47 Overdistention can increase resistance to blood flow in ventilated areas, resulting in increased dead space. Investigators have proposed various mechanical (e.g., pressure– volume curve, stress index, best compliance, esophageal pressure) and radiographic (e.g., CT, electrical impedance tomography, ultrasound) approaches to optimize PEEP and FIO2 settings. None of these approaches has definitively demonstrated a benefit over standard PEEP/FIO2 tables, and their application may be impractical for routine use. PEEP/FIO2 tables were developed to assist clinicians in selecting the appropriate combinations of PEEP and FIO2 (Table 38-2). When higher levels of PEEP are used, avoid Pplat > 30 cm H2O and driving pressure >15 cm H2O. It is also important to avoid hyperoxemia (SpO2 > 95%), as outcomes are worse in the setting of excess oxygen administration.48 TABLE 38-2 ARDSnet Mechanical Ventilation PEEP/FIO2 Tables

Description Attention to blood pressure, tidal volume, plateau pressure, and cardiac output (directly or by assessment of end-organ perfusion) is also important. Large multicenter randomized trials have evaluated higher versus moderate PEEP levels and have failed to show superiority of higher PEEP levels.49–51 The results of a subsequent meta-analysis of these trials suggest that higher levels of PEEP are more effective in moderate to severe ARDS, whereas modest levels of PEEP are more

effective in mild ARDS.52 PEEP should be reduced slowly, as an abrupt reduction in PEEP may be associated with alveolar derecruitment and rapid arterial oxygen desaturation. Whether recruitment maneuvers should be used and whether PEEP titration should be incremental or decremental are areas of controversy. The driving pressure is defined as the difference between Pplat and PEEP in a patient receiving mechanical ventilation. In ARDS, a higher driving pressure is associated with barotrauma and mortality independent of PEEP, VT, or Pplat.53 For this reason, maintain the driving pressure at 15 cm H2O or less when providing mechanical ventilation to patients with ARDS. High-frequency oscillatory ventilation (HFOV) delivers small VT, increased mean airway pressure, and frequencies of 1 to 15 Hz (1 Hz = 60 breaths/min). Oxygenation is related to FIO2 and mean airway pressure, which maintains end-expiratory lung volume, potentially minimizing VILI.54 An observational study of adult patients with severe ARDS failing conventional ventilation reported a decrease in OI after applying HFOV.55 Another study reported that early institution of HFOV was a significant factor for improved mortality.56 Two large multicenter randomized controlled trials also compared the use of HFOV to standard lung-protective ventilation in patients with ARDS: One study demonstrated no difference in mortality, whereas the other demonstrated increased mortality in the HFOV group.57,58 Based on these results, routine use of HFOV is not recommended. Another mode of ventilation used in patients with ARDS is airway pressure release ventilation (APRV), which aims to increase the mean airway pressure through long inspiratory times in an effort to improve oxygenation.59 APRV is a form of inverse ratio ventilation (IRV) but differs from older approaches to IRV in that spontaneous breathing is allowed during the inflation time. In theory, this approach allows for better gas mixing and improved patient tolerance. Nevertheless, no large clinical trials have demonstrated any clinical benefit from this mode of ventilation, though the results of one study suggest that constraining VT to 6 mL/kg might be difficult with APRV.60

Pharmacologic Agents The use of neuromuscular blockade during early moderate to severe ARDS has been proposed as a way of improving patient–ventilator synchrony and minimizing ventilator-induced lung injury. An initial large study included patients with a PaO2/FIO2 < 150 randomized to either receive 48 hours of cisatracurium or placebo and demonstrated a reduction in barotrauma and mortality in the cisatracurium group.61 A follow-up meta-analysis confirmed these findings, but it was largely influenced by the aforementioned trial.62 In an attempt to confirm the findings of this initial study in patients with moderate to severe ARDS, an additional large randomized controlled trial was performed comparing a strategy of early neuromuscular blockade and deep sedation to usual care, which utilized lighter sedation.63 This study did not show a benefit in mortality or barotrauma with the use of neuromuscular blockade in this population. Notably, neither study demonstrated a difference in muscle weakness between survivors in each group—muscle weakness had previously been a major concern with the use of neuromuscular blocking agents in critically ill patients. The use of neuromuscular blocking agents should not be routinely used early in patients with ARDS, but it appears safe for short term use in patients where patient–ventilator synchrony is difficult to achieve despite adequate sedation. Given the inflammatory response in ARDS, the use of corticosteroids —potent inhibitors of inflammation—has been proposed as a treatment, but an appropriate balance of pro-inflammatory and anti-inflammatory mediators must be maintained.64 Corticosteroids used early in the course of ARDS have not proved beneficial.28,65–67 A randomized controlled trial sponsored by ARDSnet addressed the potential benefits of corticosteroids in late-stage ARDS.68 In this study, patients with ARDS of at least 7 days’ duration were randomized to either intravenous methylprednisolone or placebo. Although there appeared to be earlier extubations in the treated patients, at 60 days the hospital mortality rate and the number of ventilator-free days were the same in each group. These results do not support the routine use of corticosteroids for persistent ARDS. Other agents such as ibuprofen, ketoconazole, lisophylline, antioxidants, and statins have been shown to be ineffective as ARDS

treatments in large clinical trials.69–72 Some trials have investigated treatment with surfactant therapy.73,74 Several different surfactant replacement products and delivery approaches have been evaluated, but studies to date have not reported any improvement in survival with their use. Pulmonary vasodilators, such as inhaled nitric oxide (iNO) or inhaled prostacyclins, can decrease pulmonary artery pressure, improve right ventricular function, and improve matching, leading to improved 75–78 oxygenation. Despite these potential advantages, randomized controlled trials of iNO in patients with ARDS have not shown an effect on mortality or any other meaningful outcomes.79,80 Therefore, its routine use is discouraged, especially given its high cost. Although prostacyclins may transiently improve gas exchange in patients with ARDS their effect on patient outcomes remains unknown.81,82

Patient Position Changes in body position may improve ventilation-perfusion matching, reduce shunt fraction, and improve oxygenation, particularly in patients with more severe ARDS. The use of the prone position is based on restoration of ventilation to dorsal areas of the lung that are collapsed in the supine position. In a combined group of patients with moderate or severe ARDS, prone positioning was not shown to significantly improve mortality.83 However, in a large clinical trial of patients with more severe ARDS (PaO2/FIO2 < 150), such positioning led to an absolute reduction in mortality of 16.8% compared to standard low tidal volume ventilation.84 Prone positioning is an important tool in the management of patients with severe ARDS. Though complications are uncommon, they can include inadvertent removal of tubes and lines, pressure necrosis, and ocular injury. The risk of these complications can be minimized by ensuring that staff are well trained, are familiar with the procedure, and have the resources necessary to safely perform the maneuver.

Fluid Management Because the pathophysiology of ARDS is characterized by lung edema

formation, there has been long-standing interest in how best to manage fluids in these patients. Although fluid restriction and diuresis may improve gas exchange and mechanical function, increased fluid volume would be expected to improve cardiac output and oxygen delivery. An ARDSnet study showed that a strategy of even fluid balance led to shorter ventilator duration compared with a traditional strategy that usually results in 1 L or more positive fluid balance per day. Importantly, this conservative fluid strategy did not increase the incidence of shock or renal failure.85

Extracorporeal Membrane Oxygenation Despite maximal supportive care with mechanical ventilation, some patients with ARDS experience severe refractory hypoxemia. Extracorporeal membrane oxygenation (ECMO) uses venoarterial or venovenous approaches to remove CO2 and add O2 to blood. Venoarterial systems can provide complete cardiopulmonary support, whereas the simpler venovenous systems provide only support for pulmonary failure. Extracorporeal techniques provide adequate gas exchange with a lower inspired FIO2 and reduced ventilation pressures. Complications may include thrombosis, bleeding, and technical failure leading to hemodynamic compromise. While this approach appears to confer a survival benefit for patients with severe ARDS who are managed at an ECMO center and has a potential survival benefit in patients with severe ARDS the optimal timing of ECMO initiation remains unclear.86,87 This therapy should be reserved for patients with refractory hypoxemia and/or respiratory acidosis despite optimal medical management. Stop and Think What options are available to address refractory hypoxemic respiratory failure in a patient with ARDS?

Respiratory Recap Management of ARDS

∎ HFNC reduces risk of intubation and mortality. ∎ Effective ventilatory strategies include judicious PEEP, low tidal volumes, limited endinspiratory plateau pressures, and limited driving pressures to minimize VILI. ∎ Most pharmacologic interventions, including steroids, have not proven to be useful. ∎ Prone positioning improves oxygenation and outcomes in patients with severe ARDS. ∎ A conservative fluid management strategy may result in a shorter ventilator duration. ∎ ECMO can be an effective rescue therapy in severe ARDS.

Outcomes ARDS mortality rates declined from a range of 60% to 70% in the early 1980s to 30% to 40% in the mid-1990s.88,89 In the ARDSnet trials, the mortality rate associated with ARDS in patients participating in clinical trials decreased from 36% in 1996 to 22% in 2006.90 Although these trials may not be an exact representation of the general ARDS population, they do demonstrate the progress that has been made in the care of these patients. A large global cohort of real-world patients with ARDS had mortality rates ranging from 35% for those with mild ARDS to 46% for those with severe ARDS.14 Approximately one-third of the mortality occurs within the first 72 hours after onset. The cause of death in these patients is usually related to their underlying risk, such as sepsis or trauma. Only a minority (15%) of patients die from respiratory failure. The majority of ARDS mortality occurs in the setting of sepsis or multisystem organ failure.91,92 Assessments of pulmonary function, neuropsychiatric testing, and quality of life are important markers of outcome. Pulmonary function tests performed within two weeks of extubation have shown substantial restrictive impairments and impaired diffusing capacities.92 This abnormal diffusing capacity is consistent with the known vascular destruction that occurs as part of the acute process of ARDS. In these patients, pulmonary function improved at 3 months, and further improvement was seen at 6 months. Little additional improvement was noted after that time, however, and no further gains were noted at 1 year. At the end of 1 year, most pulmonary function tests had returned to normal or demonstrated mild to moderate restriction, with an abnormal diffusing capacity being most common. Whereas many patients require oxygen at the time of hospital discharge, a persistent need for supplemental oxygen at 1 year is extremely uncommon.91 The impact of ARDS on quality of life was assessed by comparing these patients with non-ARDS patients with similar levels of critical illness.91 ARDS survivors were noted to have lower health-related quality of life scores. These decrements in perceived quality of life may persist for more than a year. When tested at the 1-year interval, one-third of the patients had generalized cognitive decline, and 75% had at least one

impairment in memory, attention, concentration, or mental processing speed.93 Although the outcome measures of pulmonary function, quality of life, and cognitive functioning are not as clearly defined or as readily attainable as mortality rates, they do have a significant impact on the lives of the survivors.94 Better understanding of these deficits will allow future research efforts to focus on these issues to direct appropriate resources toward the care of these patients. Respiratory Recap ARDS Outcomes ∎ Mortality can be as high as 30% to 45%. ∎ Approximately one-third of patients who die from ARDS do so within the first 72 hours of onset. ∎ Mortality is usually not due to inability to support lung function. ∎ Most patients’ lung function returns to near-normal within 1 year of discharge. ∎ Many ARDS survivors have a lower than expected health-related quality of life and cognitive function.

Prevention The focus of ARDS management is now moving from treatment to prevention. Notably, the ARDS Network has morphed into the PETAL Network (Prevention and Early Treatment of Acute Lung Injury). It is becoming increasingly appreciated that many cases of ARDS might be prevented by early recognition, early implementation of lung-protective ventilation, and avoidance of excessive fluid administration and transfusion. Unfortunately, patterns of recognition of ARDS and implementation of lung-protective ventilation remain less than ideal.14

Key Points Current practice uses the Berlin definition of ARDS. Because of differences in definitions and study design, no clear national or worldwide incidence of ARDS has been defined. The most common risk factors for ARDS are sepsis, aspiration of gastric contents, transfusions, and severe trauma. ARDS is a heterogeneous disease that is characterized by alveolar inflammation and increased permeability of the alveolocapillary membrane. There are no proven effective drug therapies for ARDS. The most important therapeutic advance for the treatment of ARDS has been the identification of lung-protective ventilatory strategies. Use a tidal volume of 6 mL/kg ideal body weight, a driving pressure of 15 cm H2O or less, and a plateau pressure of less than 30 cm H2O in patients with ARDS. Use PEEP to maintain alveolar recruitment. Mortality for ARDS patients has decreased significantly since the 1980s. ARDS survivors may have mild to moderate pulmonary restriction and decreased diffusing capacity at 1 year. Decrements in quality of life and cognitive function are noted in ARDS survivors. The focus of ARDS management is moving from management to prevention.

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CHAPTER

39 Postoperative Respiratory Care Mark L. Simmons Rachel A. Newberry

© Andriy Rabchun/Shutterstock

OUTLINE Preoperative Assessment and Management Preoperative Testing Intraoperative Risk Factors Postoperative Respiratory Failure: Assessment and Management Atelectasis Pulmonary Emboli and Pulmonary Thromboembolic Disease Pneumonia Mechanical Ventilation for Respiratory Failure

OBJECTIVES 1. 2. 3. 4. 5.

List the steps in preoperative assessment and management. Identify factors that increase the risk of postoperative pulmonary complications. List the studies commonly performed during preoperative testing. Identify the intraoperative factors that contribute to postoperative pulmonary complications. Describe the common assessment and management practices employed to combat postoperative respiratory failure. 6. Discuss the etiology, risk factors, clinical manifestations, diagnostic findings, and management of postoperative atelectasis.

7. Discuss the etiology, risk factors, clinical manifestations, diagnostic findings, and management of postoperative thromboembolic disease and pulmonary embolism. 8. Discuss the etiology, risk factors, clinical manifestations, diagnostic findings, and management of postoperative pneumonia.

KEY TERMS atelectasis deep vein thrombosis (DVT) frailty heparin myocardial ischemia partial thromboplastin time (PTT) patient-controlled analgesia (PCA) pneumonia pulmonary embolism (PE) thrombolytic tissue plasminogen activator (TPA)

Introduction Postoperative pulmonary complications (PPCs) are unexpected postoperative pulmonary abnormalities that produce identifiable disease or dysfunction that is clinically important and requires therapeutic intervention. PPCs occur more frequently than postoperative cardiac complications and are a leading cause of postoperative morbidity and mortality.1 PPCs also result in longer times spent in the intensive care unit (ICU) and increased hospital stays. Most patients having thoracic or upper abdominal surgery will have a decrease in pulmonary function after surgery as a result of decreased lung volumes (atelectasis), diaphragmatic dysfunction, and ventilation-perfusion ( ) mismatch or gas exchange abnormalities. In addition, anesthesia may depress the postoperative respiratory drive. Inhibition of cough and impaired airway clearance contribute to risk of infection. Many patients compensate for a decrease in pulmonary function with their pulmonary reserves. PPCs occur in approximately 7% of patients with normal preoperative lung function. Postoperative respiratory failure is rare without preexisting cardiopulmonary or neuromuscular disorders. In patients with increased risk factors, however, pulmonary complications have been reported as high as 70%.2 This chapter addresses some of the preoperative and intraoperative factors that increase the risk of PPCs. Also included is management of the postoperative patient to prevent PPCs.

Preoperative Assessment and Management The goal of preoperative evaluation is to identify patients at risk for intraoperative or postoperative complications. Many factors have been identified as risk factors for postoperative complications (Box 39-1).1,3 BOX 39-1 Patient Factors Increasing the Risk of Postoperative Pulmonary Complications Age > 50 years Smoking history Chronic obstructive pulmonary disease (COPD) Obstructive sleep apnea (OSA) Low SpO2 Anemia Congestive heart failure American Society of Anesthesiology physical status classification (ASA) ≥ 2

An important first step in the preoperative management of nonemergent surgeries is obtaining a patient history and performing a physical examination. The history and physical exam may identify conditions that increase the risk of PPCs and identify indications for preoperative screening tests. The clinician should also consider any medications that the patient is taking when deciding which preoperative tests are appropriate. Detailed preoperative planning for surgery is necessary, including considerations for postoperative care. Nonelective and emergency procedures place the patient at higher risk because preoperative evaluation may not be completed and the surgery may need to be done regardless of the risk. If a patient at increased risk is identified, the clinician should determine a strategy for preventing complications. In some cases, this may mean postponement of surgery or a change in the anesthesia or surgical plan. Other interventions include modification of risk factors such as smoking. The use of pulmonary medications and deep breathing exercises also may be appropriate for the prevention of postoperative complications.

Age-Specific Angle The elderly are at increased risk for postoperative respiratory complications.

Age Approximately one-third of inpatient surgeries performed in the United States involve patients older than 65 years of age.4 When compared with patients younger than 50 years, older patients have an increased chance of postoperative pulmonary complications. Postoperative complications occur in half of patients older than 70 years. Narcotics and sedatives further compromise postoperative ventilatory function, leading to respiratory failure. Cardiopulmonary, hepatic, renal, and central nervous system reserves are reduced in the elderly, which increases their susceptibility to PPCs. Patients older than 75 years also have an increased inflammatory response. Collectively, all of these factors result in increased postoperative mortality rates.1,4–8 Box 39-2 lists surgical mortality risk factors for older patients.5,9 BOX 39-2 Surgical Mortality Risk Factors for Older Patients Cognitive impairment Functional dependence Malnutrition Preoperative institutionalization Frailty

Frailty is defined as a state of deterioration in physiologic reserves preventing maintenance of homeostasis. It is followed by high vulnerability to mild stressors and health impairment.10 Determining the presence of frailty involves assessing nutrition, physical activity, mobility, strength, and cognitive impairment. Nevertheless, there is no consensus on the best tool to measure frailty. Slow gait speed has a better predictive capacity for chronic disability ( 0.21, has been associated with increased oxidative stress and inflammation in critical care environments.34 As such, the target PaO2 in trauma patients is 80 to 100 mm Hg.

Hyperventilation Historically, hyperventilation had been a cornerstone in the care of patients with severe TBI. Hyperventilating to a PaCO2 of less than 25 mm Hg has been demonstrated to rapidly reduce ICP. The mechanism for this reduction is cerebral vasoconstriction, with an ultimate reduction of cerebral blood flow.35 Such an iatrogenic reduction in cerebral blood flow on top of the innate critical reduction of flow after injury may increase the risk of cerebral ischemia. Cohorts that received prophylactic hyperventilation showed a significantly reduced outcome at 3 and 6 months compared with those who did not receive such treatment.36 Because of this established risk, the use of prophylactic hyperventilation is not recommended. Instead, this approach should be used only as a temporizing salvage measure for the acute reduction of elevated ICP.37

Hypotension The resuscitation of the TBI patient begins immediately in the prehospital setting and continues throughout the patient’s evaluation and stay to defend against the deleterious effects of hypotension on secondary brain injury. Previous work has demonstrated that a single episode of hypotension (systolic blood pressure < 90 mm Hg) is associated with an increase in morbidity and a doubling of mortality.38 The correction of hypotension by fluid resuscitation has been shown to improve neurologic outcomes.39 When deciding whether resuscitation should occur, the clinician needs to consider the patient’s CPP. A systolic blood pressure greater than 90 mm Hg may not be appropriate if the CPP is compromised. These patients likely would benefit from a closely monitored environment in which care providers can quickly correct alterations in blood pressure.

Deficits The D of the primary survey comprises evaluation of the patient for any neurologic deficits. For a patient who has sustained a TBI, calculating the Glasgow Coma Scale (GCS) score is imperative. This scale is an objective clinical measurement of the severity of brain injury. The best

GCS score a patient can achieve is 15, whereas the worst is 3. Brain injury is categorized as minor if the score is between 15 and 13; moderate if the score is between 12 and 9; and severe if the score is less than 9. When calculating the GCS score, the clinician uses the highest score response for each of the eye, motor, and verbal components. Accurate scoring aids in the prediction of long-term outcomes from a variety of injury patterns. Respiratory Recap Primary Survey Issues of Head Injury ∎ Hypoxia ∎ Hyperventilation ∎ Hypotension ∎ Deficits

Secondary Survey Issues of Head Injury The secondary survey exam of a head-injured patient needs to include a thorough neurologic examination. Such an exam needs to be carefully documented so that all other clinicians who examine the patient have a clear understanding of the baseline exam. If changes should arise in the neurologic exam, care providers need to exclude a worsening of the neurologic injury. After the secondary survey is complete, an emergency head CT scan is the diagnostic study of choice for all patients with moderate or severe brain injury. Controversy exists over the indications for head CT in those with mild brain injury.40 Regardless, transport of the patient to the CT scanner occurs only after the patient is deemed hemodynamically normal. If the patient’s neurologic exam findings change during the hospital stay, a rapid repeat head CT is likely indicated.

Treatment of Head Injuries Medical therapy for the treatment of intracranial injuries focuses on the pharmacologic treatment of elevated ICP. Hyperosmolar agents— including mannitol and hypertonic saline—are the backbone of such therapy. Mannitol acts to lower ICP by creating an osmotic shift of water out of the brain and into the intravascular space. Although effective for acutely decreasing ICP, this potent diuretic may exacerbate hypotension due to hypovolemia. Because of this side effect, the use of mannitol is limited to patients who have signs of transtentorial herniation or progressive neurologic deterioration.41 Hypertonic saline is becoming a more popular option due to its known osmotic effects on the brain as well as its potential for achieving volume resuscitation. Hypertonic saline is used as both a bolus agent for treatment of acute ICP and a continuous infusion for prolonged treatment.41 Surgical treatment of TBI focuses on achieving a rapid decrease of ICP either by open evacuation of the hematoma, by removal of CSF via intraventricular drains, or by emergent craniectomy.42 All of these methods require the expertise of a neurosurgeon in the setting of emergency care. Emerging evidence indicates that the measurement of brain tissue oxygen levels by an intracranial catheter with the intended goal of manipulating oxygen delivery may have a beneficial effect.43–45 Nonetheless, placement of these catheters requires neurosurgical support, with values being interpreted by an experienced critical care team.

Ventilator Strategies in Trauma Patients Traumatic injury followed by injurious ventilation mimics a two-hit model of organ failure. As such, a lung-protective strategy should be considered standard care in trauma patients. The impact of intraoperative mechanical ventilation on pulmonary function has been well studied.46–48 Lellouche et al. evaluated the influence of 10-mL/kg ideal body weight tidal volumes in patients undergoing coronary artery bypass surgery and reported an association with postoperative organ dysfunction, morbidity, and mortality.48 Nonetheless, a lung-protective strategy remains an uncommon practice in patients with and without acute lung injury during surgery.49,50 Severgnini et al. studied 56 patients experiencing 2 hours of open abdominal surgery with the use of a lung-protective approach. Their results illustrate that the use of PEEP, recruitment maneuvers, and lower tidal volumes demonstrated improved clinical pulmonary infection scores, less frequent chest radiograph findings, and enhanced pulmonary function up to 5 days postoperatively.51 Futier et al. reported the use of low tidal volumes, PEEP, and recruitment maneuvers during open abdominal surgery to a lower incidence of postoperative pulmonary complications, compared to tidal volumes of 10–12 mL/kg and zero PEEP.52 The patients who were not exposed to a lung-protective strategy had a two- to three-fold increase in postoperative pneumonia, atelectasis, and reinstitution of ventilation. These findings support thorough reconsideration of intraoperative management of mechanical ventilation. Appropriate intraoperative ventilatory management may prevent postoperative pulmonary complications and reduce costs by avoiding both complications and potentially postoperative treatment. Brueckmann et al. evaluated the prevalence of reintubation subsequent to extubation in the operating room. Their conclusion was consistent with the previously described findings. Moreover, the researchers were able to predict reintubation rates in a 1000-patient cohort by combining risk factors and assigning each factor a score. Their 11-point scoring system included an American Society of Anesthesiologists Score > 3, treatment by a high-risk surgical service, a need for emergent surgical intervention, chronic pulmonary disease, and

history of congestive heart failure. Of note, this system also predicted severe postoperative pulmonary complications, especially the need for reintubation.53 Noninvasive respiratory support has a role in appropriately selected trauma patients. The authors of a clinical practice guideline offer a conditional recommendation for noninvasive ventilation for chest trauma patients with acute respiratory failure.54 High-flow nasal cannula might also have a role in patients with blunt chest trauma and hypoxemia.55

Key Points The mnemonic ABCDE provides for an orderly evaluation and treatment of traumatic injuries. The secondary survey of the trauma patient is a head-to-toe physical examination. Injuries to the chest can be broadly classified as involving either a blunt or penetrating mechanism. Traumatic airway and breathing injuries include laryngotracheal injuries, dislocation of the sternoclavicular heads, and pneumothorax. Three subtypes of pneumothoraces are distinguished: simple, open, and tension. Hemorrhage is classified into four categories, using vital signs to aid in the quantification of blood loss. Massive hemothorax is accumulation of more than 1500 mL of blood in the chest cavity. Treatment of both massive hemothorax and simple hemothorax focuses on the complete evacuation of fluid from the chest cavity. Cardiac tamponade is defined as the filling of the pericardial sac with blood from the heart, the great vessels, or pericardial vessels. Lethal injuries of the chest include tracheobronchial injuries, pneumothorax, hemothorax, pulmonary contusion, blunt cardiac injury, aortic injury, diaphragmatic injury, and esophageal injury. A flail chest results from two or more ribs that are fractured in two or more locations, sternal fracture, or costochondral separation. Pulmonary contusions often develop at 48 hours after injury, with maximal ventilation-perfusion mismatching occurring during this period. Although often underappreciated, the sequelae from bone pain of the thorax can be dramatic. Traumatic brain injuries can cause epidural hematoma, subdural hematoma, subarachnoid hemorrhage, or diffuse axonal injury. Prophylactic hyperventilation is not recommended; instead, this measure should be used only as a temporizing measure for the acute reduction of elevated ICP.

Correction of hypotension through fluid resuscitation improves neurologic outcome. Medical therapy for intracranial injuries focuses on pharmacologic treatment of elevated ICP. Surgical treatment of traumatic brain injuries focuses on rapidly decreasing ICP. A lung-protective strategy of mechanical ventilation should be considered the standard of care in trauma patients.

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36. Muizelaar JP, Marmarou A, Ward JD, Kontos HA, Choi SC, Becker DP, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 1991;75(5):731–739. 37. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. XIV. Hyperventilation. J Neurotrauma 2007;24(Suppl 1):87. 38. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. I. Blood pressure and oxygenation. J Neurotrauma 2007;24(Suppl 1):7. 39. Vassar MJ, Fischer RP, O’Brien PE, Bachulis BL, Chambers JA, Hoyt DB, et al. A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride: the effect of added dextran 70. The Multicenter Group for the Study of Hypertonic Saline in Trauma Patients. Arch Surg 1993;128(9):1013. 40. Stiell IG, Wells GA, Vandemheen K, Clement C, Lesiuk H, Laupacis A, et al. The Canadian CT Head Rule for patients with minor head injury. Lancet 2001;357(9266):1391–1396. 41. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM, et al. Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy. J Neurotrauma 2007;24(Suppl 1):14. 42. Hutchinson PJ, Kolias AG, Timofeev IS, Corteen EA, Czosnyka M, Timothy J, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med 2016;375(12):1119–1130. 43. Stiefel MF, Spiotta A, Gracias VH, Garuffe AM, Guillamondegui O, Maloney-Wilensky E, et al. Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg 2005;103(5):805–811. 44. Okonkwo DO, Shutter LA, Moore C, Temkin NR, Puccio AM, Madden CJ, et al. Brain oxygen optimization in severe traumatic brain injury phase-II: a phase II randomized trial. Crit Care Med 2017;45(11):1907–1914. 45. Narotam PK, Morrison JF, Nathoo N. Brain tissue oxygen monitoring in traumatic brain injury and major trauma: outcome analysis of a brain tissue oxygen-directed therapy. J Neurosurg 2009;111(4):672–682. 46. Fernández-Pérez ER, Sprung J, Afessa B, Warner DO, Vachon CM, Schroeder DR, et al. Intraoperative ventilator settings and acute lung injury after elective surgery: a nested case control study. Thorax 2009;64(2):121–127. 47. Licker M, Diaper J, Villiger Y, Spiliopoulos A, Licker V, Robert J, et al. Impact of intraoperative lung-protective interventions in patients undergoing lung cancer surgery. Crit Care 2009;13(2):R41. 48. Lellouche F, Dionne S, Simard S, Bussieres J, Dagenais F. High tidal volumes in mechanically ventilated patients increase organ dysfunction after cardiac surgery. Anesthesiology 2012;116(5):1072–1082. 49. Chaiwat O, Vavilala MS, Philip S, Malakouti A, Neff MJ, Deem S, et al. Intraoperative adherence to a low tidal volume ventilation strategy in critically ill patients with preexisting acute lung injury. J Crit Care 2011;26(2):144–151. 50. Hess DR, Kondili D, Burns E, Bittner EA, Schmidt UH. A 5-year observational study of lungprotective ventilation in the operating room: a single-center experience. J Crit Care 2013;28(4):e9–e15. 51. Severgnini P, Selmo G, Lanza C, Chiesa A, Frigerio A, Bacuzzi A, et al. Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function. Anesthesiology 2013;118(6):1307–1321.

52. Futier E, Constantin JM, Paugam-Burtz C, Pascal J, Eurin M, Neuschwander A, et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med 2013;369(5):428–437. 53. Brueckmann B, Villa-Uribe JL, Bateman BT, Grosse-Sundrup M, Hess DR, Schlet CL, et al. Development and validation of a score for prediction of postoperative respiratory complications. Anesthesiology 2013;118(6):1276–1285. 54. Rochwerg B, Brochard L, Elliott MW, Hess D, Hill NS, Nava S, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respiratory J 2017;50(2). 55. Lu X, Wu C, Gao Y, Zhang M. Bedside ultrasound assessment of lung reaeration in patients with blunt thoracic injury receiving high-flow nasal cannula oxygen therapy: a retrospective study. J Intensive Care Med 2018:885066618815649. doi:10.1177/0885066618815649. [Epub ahead of print].

CHAPTER

42 Burn and Inhalation Injury Daniel F. Fisher

© Andriy Rabchun/Shutterstock

OUTLINE Burn Injury Inhalation Injury Management of Inhalation Injury Case Studies

OBJECTIVES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Describe the four phases of burn management. Use the Lund-Browder chart to evaluate the extent of a burn injury. Compare first-, second-, third-, and fourth-degree burns. Explain the importance of replacing fluid volume for a burn patient. Describe the effects of circumferential burn wounds of the torso on ventilatory function. Discuss issues related to cutaneous heat and water loss in patients with a burn injury. Discuss the physiology of inhalation injury. Describe the current state of inhalation injury diagnosis and prognosis. List five predictable events in patients with inhalation injury. Describe the management of upper airway obstruction, bronchospasm, small airways obstruction, pulmonary infection, and respiratory failure in patients with an inhalation injury. 11. Understand the treatment options available for carboxyhemoglobinemia. 12. Identify some of the long-term effects that survivors of burn injury experience.

KEY TERMS allograft apoptosis burn burn shock carboxyhemoglobin (HbCO) carboxymyoglobin (MbCO) CO-oximetry eschar escharotomy fluid resuscitation full-thickness graft hyperbaric oxygen (HBO) therapy inhalation injury meshing sloughing split-thickness graft total body surface area (TBSA) xenograft

Introduction The term burn refers to injuries resulting from the denaturing and destruction of tissue proteins and bone caused by thermal, electrical, or chemical origin. A major burn is defined as an injury involving 20% or more of the total body surface area (TBSA). Approximately 400,000 hospitalizations and 3400 deaths occur each year from burn injury in the United States.1 However, survival from burn injury has improved dramatically over the past 40 years and now approaches 97% for those patients who have been referred to a burn center.1,2 This change first began with a realization that the natural history of burns can be influenced by prompt surgery; the early removal of eschar and rapid biological closure of the resulting open wounds prevent the otherwise inevitable development of burn wound sepsis. To support a patient with a serious burn injury and associated respiratory failure through the physiologically taxing trial of staged wound closure is not a simple undertaking. Patients who experience a major burn injury have better outcomes when cared for at a specialty burn center staffed with experienced personnel.

Burn Injury Phases of Burn Care The function of the skin is to maintain normothermia, protect the body from infection, and maintain fluid balance within the body. Any injury that damages this organ has an impact on these three factors. Patients with large burns typically have a deep, painful wound that puts them at risk for sepsis and progressive multiple-organ dysfunction from the break in skin integrity. Immediate clinical needs must be met, but an organized, overall plan of care must also be created. The initial evaluation of the burn patient should follow the recommendations established by the advanced trauma life support (ATLS) guidelines.2,3 Burn injuries have the potential to distract the caregiver from other injuries; therefore, the clinician must pay careful attention to ensure that a complete examination is performed. The patient must be screened for other injuries and comorbid conditions.2 This organized plan of care can be described as four phases of care (Table 42-1). TABLE 42-1 Four Phases of Burn Care Phase

Timing

Treatment Objectives

Initial evaluation and resuscitation

First 72 hours

To achieve accurate fluid resuscitation and perform a thorough evaluation

Initial wound excision and biological closure

Days 1 through 7

To identify and remove all full-thickness wounds and obtain biological closure

Definitive wound closure

Day 7 through week 6

To replace temporary covers with definitive ones and close small, complex wounds

Rehabilitation, reconstruction, and reintegration

Entire hospitalization and post discharge

Initially to maintain range of motion and reduce edema; subsequently to strengthen and prepare patients for return to community

Initial Evaluation and Resuscitation of the Burn The first phase, the initial evaluation and resuscitation, extends from day 1 (day of injury) through day 3. During this phase of care, the crucial events are to determine the size and extent of the injury, as well as to provide replacement intravascular volume. Both of these assessments can have a profound effect on the subsequent course of the injury. Providing adequate replacement fluid resuscitation for the prevention and treatment of burn shock has been recognized as the most important factor in treating patients with burn injury. Burn shock refers to a series of physiologic responses to the injury. First, capillary permeability increases, producing a resultant increase in microvasculature hydrostatic pressure. Along with these changes, fluids shift from the intravascular space to the interstitial space. This alteration in fluid distribution requires fluid resuscitation.1 Burn shock can result in multiple-organ dysfunction related to hypovolemia as well as the systemic release of inflammatory mediators from the wound.1 When untreated, burn shock is the major cause of morbidity and mortality in the burn patient.3 Determining the size of the wound with respect to the TBSA is a daunting task because of variation in practitioner experience as well as inherent calculation errors specific to each method used. The loss of skin integrity provides a conduit for insensible fluid loss through the patient. The rate of fluid lost through the burn wound can be predicted based on previous physiologic observations. In turn, the amount of fluid needed to replace the volume lost is a function of burn size, time, and overall body surface area. Many protocols are available for determining the rate of fluid replacement in burn injury. All resuscitation protocols consider both the body surface area affected and the presence of inhalation injury. The Parkland formula—one of the more common resuscitation formulas— calculates fluid requirement as follows: Fluid required = 4 mL × %TBSA × Weight (kg) The first half of the total amount of fluid needed is given during the first 8 hours post burn because of the rapid fluid shift within the first 8 hours post injury. The remainder is given over the next 16 hours and is

titrated based on urine output.4,5 Current evidence suggests that protocols such as the Parkland formula may not adequately predict requirements for fluid needs. The composition of the fluid—that is, albumin or crystalloid—used for burn resuscitation is a source of debate. Albumin has been recommended because of its effect on oncotic pressure within the vascular space and its rapid loss from both the interstitium and the surface of the affected area.6 The rationale for using albumin instead of a crystalloid-based solution for resuscitation is that the care team can give less fluid overall but still treat the hypovolemia associated with burn shock. Burned tissue has a dry, leathery appearance and does not easily allow for tissue expansion. If the eschar is circumferential to a limb or the trunk of the body, it can act as a tourniquet, severely restricting blood flow. Circumferential eschar around the thoracic region can make breathing difficult. In this situation, the burn surgeon will cut through the eschar (escharotomy; Figure 42-1), which allows for tissue expansion and ultimately improves perfusion. The resulting inflammation is the first stage of wound healing because inflammatory mediators recruit leukocytes and macrophages to initiate the proliferative phase.1

FIGURE 42-1 Escharotomy of the leg with a circumferential deep dermal burn. © Pthawatc/Shutterstock.

Burn Coverage Wound coverage for burns varies depending on the severity of the injury. First-degree burns require a dry, sterile dressing, whereas more severe full-thickness second- and third-degree burns may require excision of the damaged tissue and coverage of the area by skin grafting. Other kinds of dressings are also available. Some dressings are impregnated with silver ions (Ag++) because silver has antimicrobial properties; these dressings are applied topically to prevent infection. Other dressing materials combine biologically based components with a nonbiological substrate (Alloderm, Biobrane, and Integra). These products contain cultured cells from either human or animal (bovine, porcine) origin, usually placed on a silicone backing (Table 42-2). These products are used to provide

temporary coverage when insufficient donor skin is available to cover the wound area as well as to prepare the wound bed for subsequent grafting. A common goal for using biological dressings is to reduce scarring as compared with the outcomes seen with nonbiologically based dressings. TABLE 42-2 Wound Coverage for Burns Product Name

Classification

Characteristics

EpiDex

Autologous

Keratinocyte-based

Alloderm

Acellular

Human origin Dermal matrix

GraftJacket

Acellular

Human origin Tissue scaffold

Integra

Acellular

Bovine/shark origin Bilayer matrix

Biobrane

Acellular

Biocomposite dressing, nylon fibers in silicone with collagen

Dermagraft

Cellular

Bioabsorbable polyglactin mesh scaffold with human fibroblasts (neonatal origin)

Epicel

Cellular

Keratinocyte-based cultured epidermal autograft

Recell

Cellular

Autologous cell suspension of keratinocytes, fibroblasts, Langerhans cells, and melanocytes Sprayable after culture

Types of Grafts Allografts are skin grafts where the skin used comes from the patient being treated. The tissue forming the allograft originated from the patient, so it will not pose the same rejection risk as does foreign tissue.

Sometimes the area needing coverage exceeds the size of the graft. In such a case, the surgeon can expand the coverage area of the graft by meshing. In this process, the clinician passes the graft through a device that creates a matrix of small holes in the tissue, allowing it to be stretched. The holes in the meshed graft help with fluid drainage and decrease hematoma formation, allowing for a healthier graft. Xenografts refer to skin that comes from a donor (usually cadaver). This donated skin is usually stored frozen and thawed only when needed. Another source of xenograft skin is from animals, most typically porcine skin. Regardless of the source of the xenograft, it serves as a temporary covering to protect the patient from infection and to prepare the wound bed for healing. Grafts are classified as either a split-thickness graft or a fullthickness graft. Split-thickness grafts have a layer of dermis, whereas full-thickness grafts contain all of the components of the skin: epidermis, dermis, nerve endings, and even hair follicles.7 Full-thickness grafts are associated with less scar formation; thus, their use is reserved for areas where function or aesthetics (eyelids, face) are important.7 Aside from grafts, cultured epithelial cells can be used to regenerate skin biologically. Cultured epithelial autografts (CEA) take rates are approximately 70%.8 CEA can lead to graft blisters, however, and they remain fragile even after maturity.8,9 One study comparing autografts and engineered skin substitutes (ESS) showed a decrease in the number of graft operations the patient needed and more rapid closure of the wound with ESS. The authors did not investigate whether this technique leads to decreases in hospital stay owing to the small sample size and limitations of the laboratory producing the ESS.8

Wound Excision and Biological Closure The second phase of burn care, initial wound excision and biological closure, extends from day 1 through day 7. During this phase, surgery is performed that changes the natural history of the injury. Typically, this period involves a series of staged operations to excise and debride the wound and place temporary coverings over the denuded areas. The damaged or dead tissue needs to be removed (escharotomy) because it poses an infection risk and can have detrimental impacts on acid–base

and electrolytes.

Definitive Wound Closure The third phase of burn care, definitive wound closure, lasts from day 7 through week 6. It involves replacement of the temporary wound covers with a definitive cover, as well as closure and acute reconstruction of burns that have a small surface area but are highly complex, such as wounds on the face and hands. The success of graft healing depends on the patient’s nutritional status. If patients do not receive adequate nutrition to meet their caloric requirements, they will go into a catabolic state, which has a detrimental impact on graft and donor site healing. If a graft does not adhere to the wound and survive—graft take—then it will need to be treated as a wound with ensuing removal of the dead tissue.

Reconstruction, Rehabilitation, and Reintegration The final stage of burn care involves rehabilitation, reconstruction, and reintegration. Although this final stage actually begins during the resuscitation period, it becomes very involved and time consuming toward the end of the acute hospital stay. Because this is an ongoing process, the psychological health of the burn patient is crucial for a successful rehabilitation. Issues that need to be addressed include impaired function, altered body image, and retraining/reconditioning. Still considered investigational, limb (arm, hand) and facial transplantation have been used in the most severe cases where the underlying tissue was destroyed beyond any functionality, requiring its surgical removal.10 These new procedures are intended to restore function where a limb has been lost or extreme facial damage has occurred. During the night and early morning of February 20, 2003, the Station Nightclub in Rhode Island caught fire during a concert in which pyrotechnics were used. Approximately 100 people died as a result of this tragedy, and many survivors had massive burns. Long-term follow-up studies focusing on the physical and psychological well-being of survivors from mass-casualty incidents such as the Station Nightclub fire have shown that the mechanism of injury can also have long-lasting effects on the perception of pain and depression.11,12 Support groups for burn survivors become an important resource in

the recovery and rehabilitation phase, just as much as surgical intervention is an important measure. For example, the Phoenix Society for Burn Survivors (http://www.phoenix-society.org) provides peer support for newly burned patients as well as survivors of burn injury. Peer support has been helpful in reintegrating burn survivors into society.

Estimating Burn Size An extensive cutaneous burn wound has a profound influence on pulmonary function, and accurate evaluation of the wound is important in understanding this relationship. The process of calculating burn size and depth is the first, crucial step in assessment. This task can prove difficult even for an experienced burn surgeon, because the burn wound is a dynamic injury that will change based on both extrinsic and intrinsic factors, such as thrombosis of dermal blood vessels, amount of resultant edema, release of inflammatory mediators, and initial treatment of the wound.7,13 Clinicians should evaluate burns in terms of their extent, depth, and circumferential components (Box 42-1). An accurate estimate of TBSA involvement is critical to determine the course and aggressiveness of the resuscitative efforts. Estimation of the involved body surface area involvement in a burn wound remains one of the more challenging, yet crucial, tasks to be performed during the assessment of the injury. Various methods to determine body surface area, of widely varying complexity, have been developed and introduced over the past 200 years. These include paper templates used to cover the wound, mathematical formulas, estimation based on the proportion that a section of the body represents of the total surface area, computer models using digitized photographs, and small measuring devices intended to standardize the measuring area.14 BOX 42-1 Evaluation of the Burn Wound Extent Lund-Browder chart: An age-specific chart that accounts for changes in body proportions. It is the preferred method used to determine the extent of a burn injury. Wallace Rule of Nines: A rough method of estimation that makes the following assumptions

about adult body proportions: The head and neck are roughly 9%; the anterior and posterior chest are 9% each; the anterior and posterior abdomen (including buttocks) are 9% each; each upper extremity is 9%; each thigh is 9%; each leg and foot is 9%; and the genitals are 1%. Palmar surface of the hand: The palmar surface of a person’s hand (without the fingers) is approximately 1% of the body surface over all age groups. Computer programs/smartphone applications: These systems, which are typically based on either the Lund-Browder chart or the Wallace Rule of Nines, calculate involvement based on either photographs or drawings by the user.

Depth First degree: Red, dry, painful wounds that often are deeper than they appear; sloughing occurs the next day. Second degree: Red, wet, very painful wounds. Their depth, ability to heal, and propensity to form hypertrophic scars vary immensely. Third degree: Leathery, dry, insensate, waxy wounds that do not heal. Fourth degree: Wounds that involve underlying subcutaneous tissue, tendon, or bone.

The extent of the burn injury is best estimated with a Lund-Browder chart, which comprises a two-dimensional drawing of both the anterior and posterior surfaces of a generalized body. The Lund-Browder chart accounts for variance in body proportions with growth (Figure 42-2). Most Lund-Browder charts actually total up to 101% because demarcation of the body as described in the original text did not exactly coincide with the drawing, and this discrepancy has been carried on throughout the years.15 Alternative methods for determining burn size include the Wallace Rule of Nines, the palmar method, and a myriad of computer programs and smartphone applications.16,17 Despite ongoing development in this area, no single technique is considered the best option.

FIGURE 42-2 Lund-Browder chart for estimating body surface area involvement.

Description The Wallace Rule of Nines divides the body into sections representing 9%, or multiples of 9%, to estimate body surface area. This technique is a rapid method of estimating burn surface area and is frequently used by first responders. Nevertheless, the Rule of Nines tends to overestimate the extent of the burn, which can lead to excessive fluid resuscitation.14,18 The Rule of Nines also does not account for changes in body proportion with age and weight. For example, an infant’s head has significantly more surface area in proportion to the body than an adult’s head, but both account for the same area when using this technique. The palmar method (Rule of Palms) uses only the palmar surface of the patient’s hand (without fingers) as a basis for estimation. The underlying assumption is that the palmar surface represents approximately 1% of the body surface area. Realistically, data suggest that the palmar area is closer to 0.7% of TBSA. This difference in surface area has a 30% bias, which can lead to over-resuscitation. Most methods used for estimating TBSA assume normal body habitus. With morbidly obese patients (body mass index [BMI] > 31), the affected BSA is even less. Work has been done to incorporate various body types and shapes into different models using a Lund-Browder type of chart.18,19 Recently developed techniques using hand-held three-dimensional (3D) imaging of the affected area and tracing of the burn provide for a high level of reproducibility between clinicians with varying burn experience.20 Employing multiple scans of the burn will allow the computer-based system to account for the patient’s body size. These computer programs ensure that the calculated TBSA is reproducible and can be obtained quickly even by clinicians who may have limited burn experience. In addition, the injury maps can be sent along with the patient when he or she is transferred to a regional burn center. The initial injury is also better documented for evaluation by the burn surgeon when such techniques are used, and serial measurements can aid the surgeon in observing the progress in wound healing. Accurate burn maps also serve a more direct need—namely, determining the fluid requirements for the patient based on the severity of the injury. Inaccurate estimates can lead to improper fluid resuscitation.21

Providing too little fluid during the initial resuscitation can lead to organ system failure. Conversely, too much fluid will contribute to systemic edema, which decreases peripheral circulation, leading to collateral tissue injury. Burns are classified as first, second, third, or fourth degree (Figure 42-3). In addition, they are classified by the depth of the injury, ranging from superficial to full thickness to deep dermal. Even an experienced examiner may find it difficult to accurately determine the depth of a burn early on. As a general rule, depth usually is underestimated on the initial examination. A burn wound can be divided into three zones relative to the severity of tissue injury. The first zone is the central-most part of the burn —the portion that experienced the greatest amount of heat. The second zone is the zone of ischemia, or stasis. It has decreased perfusion in the surrounding tissue and is potentially viable. The third zone, the outermost margins of the wound, is characterized by increase blood flow and inflammation (Figure 42-4).1,7

FIGURE 42-3 Various degrees of burn severity. (A) First degree. (B) Second degree. (C) Third degree. (D) Fourth degree.

Description

FIGURE 42-4 The three burn injury zones. The centermost zone experiences the greatest injury and tissue damage. Blood coagulates and proteins denature in this area. The middle zone is characterized by an increased blood flow, which creates its bright red color. Inflammatory mediators and leukocytes are carried to this area. The outermost ring shows inflammation and should heal spontaneously.

Description An understanding of the physiologic aberrations that occur with serious burns allows clinicians to provide respiratory care in the burn unit. Successfully resuscitated burn patients manifest a sequence of predictable physiologic changes (Table 42-3). These changes can be anticipated, which aids in patient management. TABLE 42-3 Predictable Physiologic Changes in Burn Patients Time Frame

Change

Treatment Steps

Resuscitation period (days 0 to 3)

Massive capillary leakage

Fluid resuscitation

Post-resuscitation period (day 3 to 95% definitive wound closure)

Hyperdynamic and catabolic state with high risk of infection

Early wound closure to prevent sepsis (nutritional support is essential)

Recovery period (95% definitive wound closure to 1 year after injury)

Continuing catabolic state and risk of nonwound sepsis

Nutritional support essential; complications anticipated and treated

Inhalation Injury Inhalation injury is a generalized term describing damage to the lungs and upper airway by the inspiration of either superheated gases (temperatures greater than 150° C), steam, or noxious products of combustion such as acrolein and carbon monoxide (CO).22 Inhalation injury also refers to the damage resulting from breathing irritant substances such as chlorine gas, hydrogen sulfide, smoke, or direct aspiration of petrochemicals. Although frequently paired with thermal injury, inhalation injury more commonly results from chemical interactions between foreign substances with the lung tissue rather than thermal injury. Despite advances in burn care as well as post-injury resuscitation, inhalation injury remains a critical determinant of burn outcomes.23 Inhalation injury is responsible for the hospitalization of 20% to 30% of all burn patients, and at least 30% of those patients die due to their injuries.21,24 Early consequences of inhalation injury include increased alveolar permeability, acute pulmonary edema, and accumulation of both pro-inflammatory and anti-inflammatory cytokines that occur with acute respiratory distress syndrome (ARDS).25 Tissue damage resulting from inhalation injury can have an adverse and long-lasting effect on both gas exchange and hemodynamics.21 The severity of inhalation injury varies widely and cannot be predicted during the initial evaluation because of the poor correlation between diagnostic criteria and severity of injury as well as the delayed onset of symptoms. Inhalational injury coupled with thermal injury has a profound effect on mortality: Mortality rates for individuals who sustain an inhalation injury with a major burn are double those predicted based on age and burn size alone.9 Inhalational injuries can be divided into four phases based on varying pathology and treatment requirements: exudative, degenerative, proliferative, and reparative.26 It is important to note the surrounding environment and conditions where the injury occurred—that is, whether the exposure took place within an enclosed space, the ventilation of gases in the area, whether the injury was caused by thermal or chemical exposure, and duration of exposure. Although no specific treatment for

inhalation injury exists, supportive, lung-protective strategies for acute lung injury can be used in its management. Management involves providing the support required, thereby compensating for decrements in gas exchange while the injured endobronchial and alveolar mucosa regenerate. Smoke inhalation is the most common form of inhalation injury. The components of smoke depend on the burning material and the availability of oxygen where the fire has taken place. Smoke inhalation injury has been reported to affect 5% to 35% of hospitalized burn patients.9,26 The concentration of smoke inspired depends on the confines of the space where the fire is occurring as well as the duration of exposure. The larynx is often affected in thermal inhalation injury, resulting in upper airway dysfunction later in the healing process.27 The diagnosis and prognosis for inhalation injury are uncertain. Currently, diagnosis of inhalation injury is based on the history and clinical presentation of the patient on admission along with a diagnostic survey bronchoscopy. Although bronchoscopy is the standard for determining inhalation injury, it fails to predict outcome. Bronchoscopy does identify damage, but to date no scoring system has been developed that can also provide the clinician with an expected trajectory. Nevertheless, bronchoscopy is also helpful in providing a lavage cleanout of the bronchial tree, which may improve gas exchange while also reducing the risk of pneumonia and atelectasis.21 According to the International Society for Burn Injuries (ISBI) guidelines for the treatment of inhalation injury, clinical presentation is not an accurate method for diagnosing inhalation injury (Box 42-2).21,26 Little evidence supports the contention that a patient presenting with bronchoscopic findings of inhalation injury and a low PaO2/FIO2 will have a negative outcome. PaO2/FIO2 has wide variation during the resuscitative phase of burn care but does not predict outcome.21,27,28 BOX 42-2 ISBI Guidelines for Diagnosis and Management of Inhalation Injury Diagnosis Clinical features (traditional signs to suspect the presence of inhalation injury) Singed nasal hairs

Carbonaceous sputum Facial burns Also consider Flame burns, especially if the fire occurred within an enclosed space Prolonged extraction Extensive cutaneous burns Bronchoscopy Considered to be the current standard for diagnosing inhalation injury Allows for bronchial alveolar lavage Rudimentary staging of severity Pathologic markers Low total leukocyte count, low platelets, high urea, and high creatinine levels on admission are associated with an increased risk of death in burns with inhalation injury. Soluble urokinase plasminogen activator receptor (suPAR)

Management IV fluids to prevent hypovolemia and burn shock Ventilator strategy Use of lung-protective ventilation Items to consider, but with weak supporting evidence: High-frequency oscillatory ventilation High-frequency percussive ventilation Nebulizer therapy Aerosolized β2 agonists Aerosolized heparin with N-acetylcysteine Corticosteroids Extracorporeal membrane oxygenation Surfactant replacement Antimicrobial therapy Modified from Deutsch CJ, Tan A, Smailes S, Dziewulski P. The diagnosis and management of inhalation injury: an evidence based approach. Burns 2018;44(5):1040–1051.

Physiology of Inhalation Injury Inhalation injury involves the entire respiratory system, from the upper airway to the alveoli, to a variable and unpredictable degree. The physical and chemical properties, such as water solubility and chemical reactivity, of the inspired irritants are important to understand and may provide insight on how to treat the injury. Water-soluble gases will dissolve into the mucous layer of the upper airway. In contrast, gases and other particulates can form concentration gradients throughout the upper and lower airways.29

The pathophysiology of inhalational injury with subsequent smoke inhalation is divided into two subcategories: upper airway involvement and lower airway involvement.26 The structures of the upper airway, tongue, and oropharynx, including the larynx, act as a heat sink and absorb a large portion of the heat energy, confining the burns to the upper airway. Smoke and the irritating gases that are inspired along with the heated air can trigger bronchospasm and result in inflammation of the lung parenchyma, releasing histamines and cytokines. The major airways are denuded of their normal mucosal layer, which impairs the ciliary transport mechanism until resurfacing occurs.21,30 The smaller airways become obstructed with sloughed endobronchial debris and accumulated secretions (Figure 42-5).

FIGURE 42-5 Macroscopic picture of airway obstructive cast 48 hours after cutaneous burn and smoke inhalation in a sheep. (A) Trachea. (B) Bronchi. (C) Smaller bronchi. Reproduced from Enkhbaatar P, Cox RA, Traber LD, Westphal M, Aimalohi E, Morita N, et al. Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and

smoke inhalation. Crit Care Med 2007;35(12):2805–2810.

The morbidity of severe burns increases when these injuries are accompanied by smoke inhalation because of the stimulation of the inflammatory response and loss of small airways patency. The release of inflammatory mediators contributes to the worsening pulmonary status, ultimately resulting in ARDS. Animal models (specifically ovine) demonstrate that this systemic inflammatory response triggers an increase in cell death (apoptosis). Debris from sloughing of the dead cells as well as the hypersecretion of mucous glands contributes to the small airways occlusion. During the initial phase of the injury, superheated gas and liquid burn the upper airway, with resultant mucosal edema and airway obstruction presenting in later stages, which explains why the severity of an inhalational injury can be misleading during the primary evaluation of the patient. With the mucociliary transport system disrupted, along with the accumulation of cellular debris within the small airways, inhalation injury promotes changes in the lung that favor pneumonia.27 Pneumonia and tracheobronchitis frequently occur in partially obstructed lung units. The alveolar epithelium is disrupted by toxic products released by the burning of synthetic products, resulting in alveolar flooding. The clinically important sequelae include loss of airway patency secondary to mucosal edema, bronchospasm, intrapulmonary shunting from small airways occlusion, diminished compliance secondary to alveolar flooding and collapse, pneumonia secondary to loss of ciliary clearance, and respiratory failure secondary to a combination of the previously stated factors. Stop and Think You are the respiratory therapist covering the emergency department (ED) when you get a call that a patient is arriving after sustaining a flash flame injury to the face and upper torso while working on his car. Upon the patient’s arrival to the ED, you hear stridor and notice that his moustache and nasal hairs are singed. What would you consider next to manage the patient?

Diagnosis of Inhalation Injury

Inhalation injury can occur with or without concurrent thermal injury, although it is frequently associated with burns. The process of diagnosing an inhalation injury is difficult in itself because of the lack of a standard definition of what constitutes an inhalation injury, variable inclusion criteria, and the absence of generally accepted and applied methods for quantifying inhalation injury.22 Diagnosing inhalation injury is also difficult because of the pattern of heat distribution within the structures of both the upper and lower airways, and the chemical reactivity and water solubility of the inspired agent(s).21,28,29 The diagnosis of inhalation injury has traditionally been made based on the history and conditions where the burn occurred: enclosed space, elevated HbCO, and soot around the nose and/or mouth as well as bronchoscopic findings. The physical presentation alone is not sufficient to make this diagnosis. Physical findings coupled with the bronchoscopic exam provide for a stronger assessment of inhalation injury, although the severity remains difficult to predict.21,28 Many sources have sought to develop an approach that would improve the diagnosis and determination of the severity of an inhalation injury.27,31 The abbreviated injury score is one such approach that stratifies the severity of the inhalation injury. Other scoring systems may add a fixed value to the final score if an inhalation injury is present.32,33 Some patients who have an inhalation injury will present with an initial PaO2/FIO2 that is relatively benign. Then, after the initial resuscitation and the redistribution of fluids within the tissue, the patient may experience a significant change in the PaO2/FIO2. Nevertheless, the PaO2/FIO2 does not correlate well with the severity of inhalation injury or outcome.28 Acute changes could reflect changing lung compliance and airway resistance. It has even been suggested that much of the morbidity/mortality associated with inhalation injury is actually due to ventilator-induced lung injury (VILI).31 Inhalation injury should be suspected if carbonaceous material surrounds the patient’s nose and mouth, if the fire occurred in a closed area, and if the patient has singed skin or nasal hairs. Although a limited number of tests have been proposed to aid in the diagnosis of inhalation injury, including inflammatory mediators, PaO2/FIO2, and CT scans, they are either inconclusive or not readily available.25,27,31 Current methods of diagnosing inhalation injury include history,

physical examination, chest radiograph, bronchoscopy, PaO2/FIO2, and radioisotope scanning (if available). Because no specific preemptive therapies for inhalation injury exist and because current diagnostic measures only loosely predict the degree of subsequent pulmonary dysfunction, diagnostic tests are used solely for general evaluation and prognosis. The underlying difficulty with diagnosis is that, much like a cutaneous burn, inhalation injuries evolve over time and involve the entire respiratory system to a variable degree. Another difficulty with diagnosing and grading inhalation injury is the lack of consensus and validated grading systems for inhalation injury.23 For these reasons, patients at risk for this diagnosis generally are classified simply as having or not having sustained inhalation injury, with no effort made to quantify the degree of injury. The circumstances surrounding the burn can provide clues to the burn surgeon as to whether the patient has an inhalation injury. Burns sustained in a closed space and aspiration of hot steam or liquid are pertinent points of the history. Physical findings suggesting the diagnosis include carbonaceous debris in the mouth or sputum, singed nasal hairs, and facial burns. The chest radiograph generally is normal initially, which is consistent with the evolution of these injuries over time. In addition to bronchoscopy, invasive measures sometimes used include radioisotope scanning and determination of the serum HbCO level. Although logistically more complicated in young children, most clinicians use bronchoscopy as the gold standard for the diagnosis of inhalation injury. Bronchoscopic findings include carbonaceous endobronchial debris and mucosal pallor and ulceration (Figure 42-6). One study has suggested that the inflammatory mediators found in pulmonary secretions can be used to score the extent and severity of the inhalation injury. Two findings from this study were surprising: The early rise of a specific mediator actually was a positive sign for a positive outcome, and the severity of the injury did not correlate with the level of the cytokines. This system remains to be validated in a large population study.

FIGURE 42-6 Bronchoscopic image of airway after sustaining inhalation injury. Note the carbonaceous buildup and inflammation of the airway wall.

Two types of radioisotope imaging have been used to diagnose inhalation injury: intravenous administration of technetium-99 or inhalation of xenon-133. Normal lungs rapidly clear both radioisotopes, and asymmetric or delayed clearance is consistent with the diagnosis of inhalation injury, which could indicate an increase in physiologic dead space (VD). Although physiologically sound, xenon and technetium scanning have not been widely used in this setting because of their logistic difficulty and expense.21,22 In small clinical series, tracheobronchial cytologic studies and biopsy have been reported to facilitate the diagnosis of inhalation injury, but these techniques have not been widely used because of logistic difficulties and potential complications. Work continues to identify biological markers for grading the severity of inhalation injury.34

Management of Inhalation Injury When a diagnosis of inhalation injury is suspected or confirmed, management is supportive only. Treatment of inhalation injury can be broken down into several main categories: ventilator management, pharmacologic treatment to aid pulmonary function using aerosolized medications, early tracheostomy, and use of evidence-based medicine to optimize patient outcomes. No prophylactic or preemptive therapies for inhalation injury are available. Prophylactic antibiotics do not have any clear-cut value, and such use may potentially promote selection of antibiotic-resistant strains colonizing the airway.35 Although many patients demonstrate reactive bronchospasm and benefit from early institution of nebulized β2-agonists, corticosteroids have not been shown to be effective in the treatment of symptoms of inhalation injury.36 The practice of nebulizing heparin alone or with N-acetylcysteine has been studied as a means to prevent or lessen the effects of small airways obstruction resulting from the sloughing of epithelial cells, excessive mucus production, and formation of fibrin casts in a sheep model.36 Several recent studies have shown an improvement in inhalation injuries after liberating the patient from the ventilator, albeit without any change in mortality. This therapy has been undertaken by several burn centers, but the supporting evidence is anecdotal with small sample sizes, which prevents definitive conclusions.37 Equally important is maintaining high humidity within the ventilator circuit so as to prevent a humidity deficit of the airways, which could result in the desiccation of the secretions of the distal airways. Good pulmonary hygiene is crucial for maintaining a patent airway.38 Lung-protective strategies should be used in the ventilator management of these patients. A low-tidal-volume (VT) approach similar to the ARDSnet protocol is an acceptable method of managing these patients because it keeps ventilating pressures low; higher pressures would exacerbate the existing lung injury.39 The use of low tidal volumes in pediatric patients with burns has been questioned, albeit without strong supporting evidence for abandoning this practice. Other practices to consider are permissive hypercapnia and prone positioning.

Respiratory Recap Management of Inhalation Injury ∎ Upper airway obstruction should be bypassed with endotracheal intubation or a tracheostomy; pay careful attention to the endotracheal tube’s position and patency. ∎ Treat bronchospasm with inhaled bronchodilators. ∎ Provide adequate humidification of the airway to lessen the chances of secretion desiccation. ∎ Manage pulmonary infection with a focus on the pathogenic organisms identified by sputum culture. ∎ Manage respiratory failure with positive end-expiratory pressure and low tidal volumes to avoid alveolar overdistention, maintain alveolar recruitment, and prevent subsequent ventilator-induced lung injury.

Acute Upper Airway Obstruction During inhalation injury, airway obstruction caused by mucosal edema evolves over time (usually within the first 4 to 24 hours after injury) and ideally is anticipated and managed with intubation.28 Early intubation for airway protection should be considered in the patient with suspected inhalation injury. Intubation attempts of these often-difficult airways can be approached in a studied manner if the impending obstruction is anticipated. After resuscitation has occurred, edema of the upper airway can change the anatomic structures from a relatively easy intubation to a difficult airway requiring a well-experienced anesthesiologist or even a surgical airway. Failure to recognize impending airway obstruction can result in serious morbidity and even mortality in burn patients. Clinicians should be alert in cases involving hot liquid aspiration, which can lead to sudden loss of airway patency and late sequelae of upper airway burns. The critical importance of the initial airway evaluation and proper control cannot be overemphasized, and this need continues throughout the period of intubation. Oral endotracheal tubes are easy to place and subjectively more comfortable for the patient than nasal endotracheal tubes. Secure the tube in a manner that allows room for stabilization and easy adjustment as facial edema changes, but that does not permit gross movement of the airway that might induce unintended extubation. Because the lips are not reliable landmarks, the clinician should measure the endotracheal

tube placement by noting the centimeter mark at the incisor or gum. This information can be posted near the head of the bed for quick reference during routine and emergency airway care. Regularly verify the security of the endotracheal tube, because reintubation after accidental extubation can prove difficult in burn patients, who commonly have significant facial and oropharyngeal edema. Clinicians who care for these patients should be equipped to deal with sudden airway emergencies and have the appropriate equipment on hand for managing a difficult, unstable airway. Maintenance of endotracheal tubes in burn patients is complicated by shifts in extravascular volume. The method used to secure the tube should facilitate simple loosening and tightening as needed to provide for adjustments coinciding with changes in facial edema. A unique concern that arises in securing the airway in patients with burns is the need for a method that can function in a high-relative-humidity heated environment. Adhesive tape is seldom useful when patients have facial burns; instead, cloth ties can be effectively used to secure tubes. Another aspect of airway care is maintaining adequate pressure in the cuff of the airway to prevent or at least minimize leakage and aspiration of trapped material from the oropharynx into the lungs. Elevating the head of the bed, if physiologically possible, at a 30-degree supine angle will also help minimize silent aspiration and potential ventilatorassociated pneumonia (VAP). The proper indication and optimal timing for tracheostomy in the burn patient remains the subject of debate. The consensus is that adult burn patients in whom protracted intubation is expected are candidates for tracheostomy, ideally after anterior neck burns have been addressed. Stop and Think While caring for a mechanically ventilated patient who has sustained 45% TBSA burns, you notice that her oxygenation has been falling over the past few hours and her urine output has decreased. What could be the cause of these changes, and how would you adjust the ventilator?

Bronchospasm Intense bronchospasm from aerosolized irritants is common during the first 24 to 48 hours after injury, especially in young children. This condition is well managed with inhaled β2-agonists in most patients, although some require low-dose epinephrine infusions or parenteral or inhaled steroids. Heliox may be an option if the oxygen requirement is minimal. Use of continuous nebulization of high-dose β2-agonists is another option. Recent evidence, however, has pointed to increased mortality when patients with ARDS are routinely treated with β2agonists.40,41 The ventilator management strategy for patients with burns and/or inhalation injury is not significantly different from that for any other critically ill patient needing respiratory support. Some points of emphasis specific to burns and inhalation injuries include the need for monitoring airway pressures, assessment of lung compliance and resistance, and good pulmonary hygiene techniques. Thoracic escharotomies may be required to provide adequate chest excursion, allowing the patient to breathe more freely. Until this is done, high airway pressures may be necessary to overcome the decreased compliance of the chest wall. Techniques used to minimize auto-PEEP include decreasing VT to 4 to 6 mL/kg, decreasing the respiratory rate, and using shorter inspiratory times and higher inspiratory flows. If the intrinsic positive end-expiratory pressure (PEEP) hinders the patient’s ability to trigger, matching with applied PEEP may be necessary. In case of severe air trapping, some degree of carbon dioxide retention is acceptable (permissive hypercapnia). Monitoring of both plateau airway pressure (Pplat) and airways resistance should be performed routinely to assess respiratory mechanics. Age-Specific Angle Intense bronchospasm caused by aerosolized irritants is a particular problem in children because of their smaller airways.

Small Airways Obstruction

During the first 24 hours after inhalation injury, airway obstruction is essentially limited to the bronchial airways. Major components of this obstructive material include mucus from extensive glandular secretion, inflammatory cells, fibrin, and exfoliated epithelial cells.28 As necrotic endobronchial debris sloughs, pulmonary hygiene often becomes increasingly difficult. Thus, an aggressive program of pulmonary hygiene, including suctioning and bronchoscopy, is an important component of care. Along with aggressive airway clearance, it is important to provide adequate humidification of inspired gases. Therapeutic bronchoscopy can facilitate clearance of the airways and evaluation of the condition of the airway mucosa. Small endotracheal tubes can suddenly become occluded, so staff members should be prepared to respond to this event promptly (Box 42-3). Pulmonary hygiene is an essential component of the management of patients with inhalation injury. It is crucial to provide 100% relative humidity to these patients and to decrease the risk that a humidity deficit might lead to thickened pulmonary secretions and increase the chances of occluding the endotracheal tube. BOX 42-3 Evaluation and Initial Management of Deterioration of the Patient–Ventilator System A sudden deterioration of the patient–ventilator unit requires immediate assessment for any of four problems: mechanical malfunction, obstruction of the artificial airway, displacement of the endotracheal tube from the trachea or into the main stem bronchus, or pneumothorax. 1. Assess the patient and observe the patient’s inspiratory efforts (if any) and compare them with the cycling of the ventilator. Auscultate breath sounds: a. If wheezing is present, provide β2-agonists. b. If the breath sounds are coarse, suction the airway. c. If the breath sounds are unilaterally decreased, consider a main stem intubation or pneumothorax. d. If the breath sounds are absent bilaterally, consider an occluded artificial airway. 2. Observe the monitors. a. Is the patient hemodynamically stable? b. Check the SpO2 and provide maximal inspired oxygen. In an emergency, oxygen buys time. 3. Check the ventilator. a. Determine which alarms are being triggered. This knowledge is helpful in troubleshooting mechanical problems. b. Check the ventilator waveforms. Look at the flow-time curve to determine

whether the patient is receiving adequate flow or whether the inspiratory time is either too long or too short. c. Are the parameters on the ventilator set correctly for the patient’s needs? If the patient was initially paralyzed and is now able to move and spontaneously trigger the ventilator, it is possible that changes will need to be made. d. Is the ventilator functioning as expected? If not, remove the patient from the ventilator, manually ventilate, and exchange with another ventilator. 4. If care providers cannot quickly assess and correct the problem, it may be necessary to disconnect the patient from the ventilator and provide manual ventilation with a bagvalve device while troubleshooting the problem. For patients who require high levels of positive end-expiratory pressure (PEEP), alveolar derecruitment will occur if the patient is manually ventilated without PEEP. 5. If the patient cannot be manually ventilated, the tube may be severely occluded, and extubation followed by mask ventilation may be required. 6. In the event that a new airway cannot be passed into the trachea, a surgical airway (cricothyroidotomy, tracheostomy) may be required.

The main components of bronchial and small airways casts are fibrin and cellular debris. The use of mucolytic agents in treating small airways obstruction has been shown not to be as effective as was once believed. Specifically, these agents have not been shown to be effective in either clinical practice or animal models.38

Pulmonary Infection Pulmonary infection develops in 30% to 50% of patients with an inhalation injury. Pneumonia without the presence of inhalation injury increases the mortality of burn injury by as much as 40%.24 It frequently is difficult to distinguish between pneumonia and tracheobronchitis (purulent infection of the denuded tracheobronchial tree), but the difference often has little practical clinical importance. Infection typically occurs toward the end of the first postinjury week; patients with serious inhalation injuries may deteriorate at this time. A patient with newly purulent sputum, fever, and perhaps diminished gas exchange should be treated with antibiotics, to be adjusted as necessary based on sputum culture information. The pathophysiology of inhalation injury, which involves injury to endobronchial mucosa with hampered mucociliary clearance, makes good pulmonary hygiene a particularly important component of management.

Respiratory Failure Respiratory failure is common in individuals with inhalation injury, though it is caused as often in these patients by sepsis as by inhalation injury. As in other forms of respiratory failure, the lung volume that can be recruited with mechanical ventilation is limited, and over-vigorous attempts to force high pressures into the lungs will exacerbate the underlying injury. Such patients do well with a volume-targeted, pressure-limited ventilation strategy (Box 42-4). If this approach fails, innovative methods of support should be considered, such as extracorporeal membrane oxygenation (ECMO) or inhaled nitric oxide. Prone positioning also has been shown to improve oxygenation. With adequate personnel, the patient can be quickly and safely repositioned while special attention is given to maintenance of the airway and central lines.42 BOX 42-4 Therapeutic Responses to Progressive Respiratory Failure Address bronchospasm with nebulized β2-agonist agents. Address poor chest wall compliance that occurs secondary to overlying eschar with escharotomies. Ensure ventilator synchrony with adequate opiate and benzodiazepine infusions. Propofol or ketamine might also be used. Neuromuscular blockade occasionally may be required. Reset the endpoint of ventilation to a physiologic pH (7.2 or higher). Allow gradual onset of hypercapnia as long as the patient does not have a head injury. Reset the endpoint of oxygenation to an arterial saturation of at least 88%, a level typically associated with an arterial oxygen content of 55 mm Hg or higher. Utilize a lung-protective, low-tidal-volume approach to ventilation. Follow the ARDSnet guidelines for adjusting tidal volumes based on predicted body weight. Keep plateau pressure (Pplat) below 30 cm H2O and driving pressure less than 15 cm H2O. Choose the optimal positive end-expiratory pressure (PEEP). Lengthen inspiratory time to a target mean airway pressure of 20 to 25 cm H2O, as long as auto-PEEP is not detectable. If these measures are inadequate, consider the use of adjuncts such as inhaled nitric oxide or extracorporeal support.

In patients who do not respond to more conservative measures to treat their inhalation injury, ECMO might be considered as an alternative. Several small studies have described the use of venovenous ECMO in burn patients. In general, evidence is lacking for the use of ECMO in the burn/inhalation injury patient with regard to outcome.43

Questions often arise about the use of a specific ventilator mode or ventilator in patients with inhalation injury. Some of these modes include high-frequency oscillatory ventilation (HFOV), volume diffusive respiration (VDR), and airway pressure release ventilation (APRV). Each of these ventilation techniques has the common goal of maintaining alveolar recruitment and gas exchange. Both HFOV and VDR require specialpurpose ventilators. HFOV has recently been evaluated in several large randomized controlled studies, which have shown either no difference or a negative impact on outcomes.44,45 In VDR, the clinician applies pressure-controlled ventilation with superimposed subtidal oscillations that facilitates clearance of endobronchial debris. Although some data have been encouraging, burn patients with inhalation injury and respiratory failure can be very well managed with any other mode of ventilation with which the burn center is comfortable, paying particular attention to tidal volume, airway pressure, and aggressive pulmonary hygiene.27,28 APRV consists of two levels of continuous positive airway pressure (CPAP) that aid in the recruitment of alveoli, resulting in improvements in both oxygenation and carbon dioxide removal. It has been used both as a first-line method of ventilation and as a rescue form of ventilation when the patient’s lung function is extremely compromised. Some evidence suggests that APRV improves gas exchange, but the studies have generally involved either animal models or very small sample sizes. One concept of APRV that needs to be considered is the potential for wide variation in pleural pressures that may contribute to VILI. More evidence is needed before this mode of ventilation can be recommended. Ventilator discontinuation and extubation of burn patients follow the general guidelines applicable to other patients. This patient group has some unique aspects that care providers must take into consideration (Box 42-5). Balancing the pain medication needs of patients with large wounds and donor sites with the need for an alert sensorium for extubation creates a challenge for clinicians. Combining spontaneous breathing trials with routine periodic sedation discontinuation may enable the clinician to better assess the patient’s mental status.46,47 BOX 42-5 Important Considerations in Ventilator Discontinuation

and Extubation of a Patient with a Burn Injury Sensorium: The patient must be awake and alert enough to protect the airway. Airway patency: Upper airway edema must be resolved to the extent that an air leak is audible around the endotracheal tube (with the cuff deflated if the tube is cuffed) at a moderate inflating pressure (20 to 30 cm H2O). Muscle strength: Strength must be adequate for ventilation. An indirect measure of this property is an unassisted tidal volume of 6 to 10 mL/kg and a maximum inspiratory pressure (PImax) less than –20 cm H2O. Compliance: Combined chest wall and lung compliance must be high enough that work of spontaneous breathing is not excessive. Respiratory system compliance should be at least 50 mL/cm H2O. Gas exchange: The PaO2/FIO2 should be greater than 200 mm Hg. Spontaneous breathing trial (SBT): The successful completion of an SBT.

Burn care, including management of inhalation injuries, is an evolving field. To date, most studies have been limited to small sample sizes or retrospective in nature, in part because the incidence of burn injury in the United States has decreased. Another problem with burn research is the lack of uniform methods of reporting injury, TBSA, mechanism of burn, or severity score. Many burn databases utilize different parameters, which makes pooling patient information difficult. Moving to common data elements with standard definitions will improve the researcher’s ability to pool data and derive stronger conclusions.48

Carbon Monoxide Exposure Many patients injured in structural fires inhale carbon monoxide (CO), and many become obtunded from a combination of CO, anoxia, and hypotension. CO poisoning results in more than 50,000 emergency department (ED) visits annually in the United States alone.49 Carbon monoxide is produced from incomplete combustion or combustion in a low-oxygen atmosphere. This compound binds avidly to heme-containing enzymes, particularly hemoglobin and the cytochrome proteins, which inhibits cellular respiration. CO also binds to myoglobin, forming carboxymyoglobin (MbCO), with heart muscle taking up about three times as much CO as skeletal muscle does. The formation of carboxyhemoglobin (HbCO) results in an acute physiologic anemia, much like an isovolemic hemodilution. An HbCO concentration of 50% is

physiologically similar to an isovolemic hemodilution to 50% of a baseline hemoglobin level. Moreover, CO causes a leftward shift of the oxyhemoglobin dissociation curve, which decreases oxygen release to the tissue. Thus, the routine occurrence of unconsciousness at this HbCO level makes it clear that other mechanisms are involved in the pathophysiology of CO injury. CO binding to the cytochrome system in the mitochondria, which interferes with oxygen utilization, is likely more toxic than CO binding to hemoglobin. Many patients with severe CO exposure also have been exposed to cyanide compounds, which are released from burning synthetics. The degree of exposure rarely is such that specific treatment is required. For unknown reasons, 5% to 25% of patients with serious CO exposure develop delayed major neurologic sequelae. These patients can be managed with 100% isobaric oxygen or with hyperbaric oxygen (HBO) therapy. The half-life of HbCO is about 5 hours when breathing 21% oxygen at ambient pressure, about 74 minutes when breathing 100% oxygen at ambient pressure (range 26–148 minute), and less than 30 minutes when breathing 100% oxygen at 3 atm. If serious exposure has occurred and is manifested by overt neurologic impairment or a high HbCO level, HBO is reasonable if it can be administered safely. Some evidence indicates that neurologic impairment with CO poisoning can be delayed, with the effects persisting over the long term. When patients have inhalation injury, care providers should administer 100% oxygen until a safe HbCO level is reached. MbCO dissociates more slowly than HbCO, which can account for the rebound of HbCO observed in patients several hours after receiving normobaric oxygen. In the setting of inhalation injury, the HbCO level should be measured with CO-oximetry. In the presence of HbCO, traditional pulse oximetry is unreliable and potentially misleading. Two-wavelength pulse oximetry does not measure HbCO. In fact, the pulse oximeter displays high O2 saturation (SpO2) despite significant HbCO, causing the clinician to believe that HbCO is not present. New-generation multiple-wavelength pulse oximeters allow for noninvasive measurement of HbCO. These portable, noninvasive devices can be part of emergency medical services crew equipment, providing HbCO measurements closer to the time of exposure. Because HbCO does not affect gas exchange in the lungs, a patient

with HbCO who is breathing 100% oxygen may have a very high PaO2 (more than 400 mm Hg) despite low hemoglobin oxygen saturation as measured by CO-oximetry. The high PaO2 competes with CO for hemoglobin binding sites, resulting in eventual displacement of CO from the hemoglobin. For this reason, HbCO measurements taken close to the time of exposure are more informative than later measurements. HbCO measurements taken at the hospital can be less because treatment with normobaric oxygen may have already started prior to the patient’s arrival in the ED. HBO has been proposed as a means to improve the prognosis of patients who suffer serious CO exposure, but its use remains controversial. On a busy burn service, the question of which patient to treat in the hyperbaric chamber commonly arises. Most patients who undergo HBO therapy are treated in a monoplace hyperbaric chamber (Figure 42-7). Treatment regimens vary, but a typical CO poisoning protocol is 3 atm for the first treatment, then 2 atm or 3 atm for subsequent treatments, for 90 minutes, with two 10-minute air breaks to reduce the incidence of oxygen toxicity seizures. Providing HBO to a patient in a monoplace chamber severely limits access to the patient during treatment, so patients in unstable condition are poor candidates for this therapy. Other relative contraindications include wheezing and air trapping, which increase the risk of pneumothorax, and high fever, which increases the risk of hyperoxia-induced seizures.

FIGURE 42-7 Monoplace hyperbaric chamber. Courtesy of ETC BioMedical Systems Group.

If a patient must be mechanically ventilated during HBO, adequate preparation measures before the chamber door is closed can prevent most complications. Prior to the patient’s entry into the chamber, the airway must be well positioned and adequately stabilized because patients who inadvertently awaken during the therapy may attempt selfextubation. For the same reason, patients must be well restrained before HBO regardless of their mental status. The endotracheal tube cuff must be switched from air-filled mode and refilled with an appropriate volume

of sterile water; this conversion prevents collapse of the cuff during the compression phase of the treatment. Patients must be evaluated for bronchospasm and aggressively treated with bronchodilators just before treatment. Suctioning of both the lower respiratory tract and the oral pharynx is helpful because such care cannot be provided while the patient is in the hyperbaric chamber. Prophylactic myringotomies are recommended for unconscious or intubated patients to prevent tympanic membrane rupture. Providing mechanical breathing support at hyperbaric pressures can be technically difficult. Key considerations include patient and practitioner safety, the type of chamber utilized (monoplace versus multiplace), physiologic monitoring needs, and sedation requirements. The design of monoplace chambers prevents clinicians from responding immediately in the event of a medical emergency. Multiplace chambers typically have a clinical attendant in the chamber to respond to a crisis. Stop and Think You are caring for a mechanically ventilated patient in HBO. The patient begins to cough, causing the ventilator to pressure limit. The chamber is pressurized to 3 atm absolute and cannot be opened for 2 minutes. What can you do?

Ventilators used with monoplace HBO chambers are usually modified versions of a pressure-limited, time-cycled device, although some HBOcapable ventilators are commercially available (Figure 42-8).49 A base rate is maintained, but all spontaneous breathing efforts are unassisted. Patients who suddenly awaken during therapy and who cough or inspire vigorously can aspirate oral secretions, leading to an increase in airway pressure and a reduction in tidal volume. These same clinical signs may occur with other clinical complications, such as a kinked endotracheal tube, main stem intubation, pneumothorax, or bronchospasm. Assessment and ascertaining the cause are difficult because the clinician is isolated from the patient. If clinically appropriate, the best course may be to adequately sedate the patient so as to avoid spontaneous breathing during the course of treatment.

FIGURE 42-8 Two commercially available hyperbaric-capable ventilators. (A) Sechrist 500A. (B) Providence Global Medical Atlantis. (A) Courtesy of Sechrist Industries.

Respiratory Recap Carboxyhemoglobinemia ∎ Measure carboxyhemoglobin with CO-oximetry. ∎ Administer 100% oxygen. ∎ Consider hyperbaric oxygen therapy, particularly in patients with neurologic depression or delayed neurologic sequelae.

Stop and Think You are working in a hospital that does not have an HBO chamber. A patient presents with CO poisoning. What therapy would you recommend?

Hydrogen Cyanide Poisoning Although carbon monoxide poisoning is the more common condition treated with inhalation injury, hydrogen cyanide (HCN) poisoning can also be present and can result in similar problems with cellular respiration. HCN is produced by the combustion of nitrogen-containing compounds (such as those found in synthetic materials used in furniture) in a lowoxygen atmosphere. Like CO, HCN binds to the cytochrome oxidase system and inhibits cellular metabolism, resulting in tissue and systemic acidosis. The treatments available for HCN poisoning do have risks, and often care may be supportive.

Case Studies Case 1. Minor Burn with Smoke Inhalation A 5-foot 10-inch, 47-year-old man was found unconscious on a smoldering mattress with minor burns to the right arm, chest, and thigh. Respirations are shallow and erratic, pulse is 110 beats/min, blood pressure is 140/90 mm Hg, and there is no apparent cyanosis. The patient cannot be aroused and is orally intubated at the scene. He is manually ventilated at an FIO2 of 1.0 and transported to the ED. On admission, the patient is mechanically ventilated with continuous mandatory ventilation, pressure control at 20 cm H2O, inspiratory time of 1 second, respiratory rate of 12 breaths/min, PEEP of 5 cm H2O, and FIO2 of 1.0. The tidal volume is approximately 500 mL (equivalent to approximately 7 mL/kg predicted body weight). A chest radiograph reveals that the endotracheal tube is 3.5 cm above the carina, with no evidence of pneumothorax or other chest trauma. The patient’s pupils are sluggish but reactive. The heart rate and blood pressure are 110 beats/min and 140/90 mm Hg, respectively. The SpO2 is 100%. A toxicology screen is drawn. The arterial blood gas values are pH 7.45, PaCO2 34 mm Hg, and PaO2 360 mm Hg. The HbCO level as assessed by CO-oximetry is 38%. Auscultation of the chest reveals mild diffuse bronchospasm, which resolves with administration of albuterol (six puffs via pressurized metered-dose inhaler [pMDI]). There is no evidence of air trapping or auto-PEEP. Because of the patient’s depressed level of consciousness and elevated CO level, the care team decides to treat him with HBO. At the HBO treatment center, the airway is restabilized, the patient’s oropharynx and endotracheal tube are suctioned, and an additional four puffs of albuterol are delivered via pMDI. The endotracheal cuff is deflated and refilled with the same volume of sterile water to prevent collapse of the cuff during HBO therapy. Bilateral myringotomies are performed to avoid inadvertent rupture of the patient’s eardrums. All intravenous fluids and medications are transferred to specialized infusion pumps designed to operate within the HBO chamber. The patient is

connected to a specialized HBO mechanical ventilator at the following settings: VT 500 mL, respiratory rate 12 breaths/min, FIO2 1.0, and PEEP 0 cm H2O. The patient is placed in the HBO monochamber, and the chamber is pressurized to 3 atm absolute. After approximately 15 minutes at this pressure, the patient’s VT becomes erratic, and the peak inspiratory pressure increases by 15 cm H2O. The patient becomes progressively more awake and attempts to remove the endotracheal tube. Initial attempts to sedate him fail, and anesthesia is induced with propofol. The patient is maintained with periodic boluses of propofol for the duration of the treatment, and no further complications occur. After the HBO treatment, the patient is admitted to the burn intensive care unit, and all sedation is withdrawn. Assessment of ventilatory mechanics and level of consciousness demonstrates intact ventilatory function and responsiveness to commands. The patient is extubated, observed for 12 hours, transferred to a non-ICU floor, and subsequently discharged.

Case 2. Second- and Third-Degree Burns (70% TBSA) with Severe Inhalation Injury A 5-foot 6-inch, 67-year-old unconscious woman is rescued from a kitchen fire with severe burns over much of her body. Assessment at the scene found significant facial burns and carbonaceous debris in the upper airway. Respiratory rate is 46 breaths/min and labored. The patient is orally intubated, manually ventilated with 100% oxygen, and transported to the emergency department. On admission, the patient’s heart rate is 135 beats/min and blood pressure is 150/100 mm Hg. Profound wheezing is noted throughout all lung fields. The patient is mechanically ventilated with volume control and a VT of 475 mL (8 mL/kg predicted body weight), respiratory rate of 16 breaths/min, descending ramp flow pattern, peak inspiratory flow adjusted to provide an inspiratory time of 1 second (approximately 50 L/min), PEEP 5 cm H2O, and FIO2 1.0. The arterial blood gas values with these settings are as follows: pH 7.35, PaCO2 66 mm Hg, and PaO2 82 mm Hg. The HbCO level is 27%. Ventilator graphics indicate flow present

at end-exhalation and decreased peak expiratory flow. Total PEEP is 17 cm H2O (12 cm H2O of auto-PEEP). Pplat is 31 cm H2O. Albuterol is administered via nebulizer continuously over the next hour but has little effect on the total PEEP. The ventilator is adjusted to address the significant amount of autoPEEP by of applied PEEP to counterbalance auto-PEEP, and VT is reduced to 415 mL (7 mL/kg PBW). The inspiratory time is kept at 1 second for synchrony. On reassessment, the patient’s total PEEP is 6 cm H2O. Although air trapping is reduced, the diffuse bronchospasm remains refractory to aggressive beta-agonist therapy. HBO therapy is not used due to the risk of barotrauma. Over the next several days, the patient’s arterial blood gas values deteriorate, requiring increases in PEEP to 18 cm H2O and FIO2 of 0.6 to 1.0. Air trapping remains a problem, and ventilator strategies are modified to include permissive hypercapnia. Bronchoscopy is performed several times to facilitate pulmonary hygiene, and it reveals significant airway injury and edema. By the fifth day of hospitalization, the patient shows signs of sepsis (increased fever and labile blood pressure) and purulent sputum. Appropriate antibiotic therapy is instituted, and blood pressure is supported with vasopressors. Oxygenation worsens dramatically on day 6 despite various maneuvers to recruit lung volume. Blood pressure becomes progressively unstable, and the patient has cardiopulmonary arrest. Cardiopulmonary resuscitation is performed but is unsuccessful.

Key Points Respiratory failure is a leading cause of morbidity and mortality in the burn unit. An organized plan of care for patients with burn injury proceeds through four phases: initial evaluation and resuscitation, initial wound excision and biological closure, definitive wound closure, and rehabilitation. Burn wounds should be evaluated for extent, depth, and circumferential components. Adequate fluid resuscitation is vital during the first 24 hours after burn injury. Approximately 20% of burn injury patients suffer inhalation injury. Five predictable events occur in patients with inhalation injury: acute upper airway obstruction, bronchospasm, small airways obstruction, infection, and respiratory failure. Clinicians who care for burn patients should be prepared to deal with airway emergencies. Lung-protective ventilation strategies should be used for patients with inhalation and burn injury. HbCO is treated with 100% oxygen, hyperbaric oxygen therapy, or both.

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CHAPTER

43 Sepsis Dean R. Hess Neil R. MacIntyre

© Andriy Rabchun/Shutterstock

OUTLINE Pathogenesis Recognition Treatment Implications for Respiratory Care

OBJECTIVES 1. 2. 3. 4. 5. 6.

Define sepsis. Define septic shock. Discuss the pathogenesis of sepsis. Use the qSOFA to identify patients with sepsis. Describe the roles of fluid resuscitation and vasopressors in sepsis management. Discuss the ventilator management of patients with sepsis.

KEY TERMS biogenesis

fluid resuscitation lung-protective ventilation strategy myotrauma quick SOFA (qSOFA) sepsis sepsis-induced diaphragm dysfunction (SIDD) septic shock Sequential Organ Failure Assessment (SOFA) Surviving Sepsis Guidelines vasopressors

Introduction Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.1 It affects virtually all organ systems, including the lungs. Although anyone can acquire sepsis, it is most common in older adults, pregnant women, children younger than 1 year of age, individuals with chronic conditions (diabetes, renal disease, lung disease, cancer), and persons with compromised immune status. Sepsis affects more than 19 million people each year worldwide, with a reduction in hospital mortality having occurred in recent years. In 2014, 1.3 million American adults survived a hospitalization for sepsis.2 Patients with sepsis are usually treated in the emergency department and critical care unit, and many require mechanical ventilation. Thus, it is important for respiratory therapists to understand sepsis and its treatment.

Pathogenesis The normal response to infection localizes and controls bacterial invasion, with repair of injured tissue. This response includes activation of phagocytic cells, primarily macrophages, and production of both proinflammatory and anti-inflammatory mediators. Sepsis occurs when this response involves normal tissues remote from the site of infection. The balance of pro-inflammatory and anti-inflammatory mediators regulates the inflammatory response. With sepsis, the release of pro-inflammatory mediators leads to a more generalized multiple-organ response. Note that sepsis is the result of the host response, rather than the infection per se. Widespread cellular dysfunction occurs as the result of sepsis. Cellular ischemia results in cellular hypoxia. Pro-inflammatory mediators cause sepsis-induced mitochondrial dysfunction, leading to histologic hypoxia.3 Mitochondria are repaired or regenerated by a process called biogenesis. Interestingly, inhaled low doses of carbon monoxide might enhance mitochondrial biogenesis.4,5 Pro-inflammatory cytokines may delay apoptosis (programmed cell death) in activated macrophages and neutrophils, thereby prolonging the inflammatory response and contributing to multiple organ failure.6 The excess inflammation of sepsis may be followed by immunosuppression.7 Hypotension due to diffuse vasodilation represents a severe expression of circulatory dysfunction in sepsis, caused by the release of vasoactive mediators including prostacyclin and nitric oxide. Hypotension may result from redistribution of intravascular fluid.6 Encephalopathy is common with sepsis and might occur before failure of other systems. Acute kidney injury often requires renal replacement therapy.8 Sepsis also affects hepatic, adrenal, and gastrointestinal function.8 Severe sepsis is commonly associated with altered coagulation, frequently leading to disseminated intravascular coagulation.9 Respiratory failure is common with sepsis. Indeed, sepsis is a common cause of acute respiratory distress syndrome (ARDS). Pulmonary vascular endothelial injury disturbs capillary blood flow and enhances microvascular permeability, which results in interstitial and alveolar pulmonary edema.6 Sepsis is also a common cause of

diaphragm dysfunction.10

Recognition The Sequential Organ Failure Assessment (SOFA), previously called the Sepsis-Related Organ Failure Assessment, has been used to score the severity of organ dysfunction in sepsis (Figure 43-1).1 A higher SOFA score is associated with an increased likelihood of mortality.11 The score grades abnormality by organ system and accounts for clinical interventions. However, laboratory variables are needed for full computation, which might not be available. A change in the baseline SOFA score of 2 points or more suggests organ dysfunction. The baseline SOFA score should be assumed to be 0 unless the patient has preexisting acute or chronic organ dysfunction. A SOFA score of 2 or more is associated with a mortality risk of approximately 10% in a general hospital population with presumed infection.12

FIGURE 43-1 Sequential (Sepsis-Related) Organ Failure Assessment score. From Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine, Intensive Care Med. 1996;22(7):707-10. Permission conveyed through Copyright Clearance Center, Inc. Republished with permission of Springer Science and Bus Media B V.

Description

The quick SOFA (qSOFA) uses simple bedside criteria to identify adult patients with suspected infection who are likely to have poor outcomes.1 The qSOFA uses three criteria to suggest the presence of sepsis: respiratory rate $ 22/min, altered mentation, and systolic blood pressure # 100 mm Hg. Septic shock is a subset of sepsis. Patients with septic shock have persistent hypotension requiring vasopressors to maintain mean arterial pressure $ 65 mm Hg and have a serum lactate level . 2 mmol/L despite adequate volume resuscitation. Hospital mortality in these patients is greater than 40%.1 The algorithm in Figure 43-2 can be used to identify patients with sepsis and septic shock.

FIGURE 43-2 Operationalization of clinical criteria identifying patients with sepsis and septic shock. From Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315(8):810-810. Copyright© 2016 American Medical Association. All rights reserved. Reproduced with permission from JAMA.

Description

Treatment The treatment of sepsis is informed by the Surviving Sepsis Guidelines.13,14 Therapy is directed primarily toward fluid resuscitation, antimicrobial therapy, and the use of vasoactive medications. For resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of intravenous crystalloid fluid, preferably lactated Ringer’s solution, should be administered within the first 3 hours. Following the initial fluid resuscitation, additional fluid administration is guided by frequent reassessment of the patient’s hemodynamic status. Dynamic— rather than static—variables are used to predict fluid responsiveness. Dynamic techniques include passive leg raises, fluid challenges with stroke volume measurements, and pulse pressure variation in response to intrathoracic pressure changes with mechanical ventilation. The use of central venous pressure alone to guide fluid resuscitation is not recommended. The initial target mean arterial pressure target is usually greater than 65 mm Hg in patients with septic shock requiring vasopressors. Resuscitation to normalize lactate as a marker of tissue hypoperfusion is suggested. Figure 43-3 shows an algorithm to guide fluid resuscitation in patients with sepsis.

FIGURE 43-3 Application of fluid resuscitation in septic shock. Reproduced from Dellinger RP, Schorr CA, Levy MM. A Users’ Guide to the 2016 Surviving Sepsis Guidelines. Crit Care Med 2017;45(3):381-385.

Description Appropriate microbiologic cultures (including blood) are obtained before starting antimicrobial therapy.13,14 Intravenous antimicrobials are initiated as soon as possible and within 1 hour. Empiric broad-spectrum therapy with one or more antimicrobials is administered to cover all likely pathogens. This antimicrobial therapy is narrowed once pathogen identification and sensitivities are established and/or adequate clinical

improvement is noted. Antimicrobial treatment duration of 7 to 10 days is usually adequate for most serious infections associated with sepsis and septic shock. Vasopressors are often needed to increase mean arterial pressure to more than 65 mm Hg in patients with septic shock.13,14 Norepinephrine is the first-line vasopressor, with vasopressin or epinephrine being added if needed to raise the arterial pressure to the target. Dopamine can be used as an alternative vasopressor, but low-dose dopamine for renal protection is not recommended. Dobutamine can be used with persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents. Vasopressor dosing should be titrated to an endpoint reflecting perfusion. Patients requiring vasopressors should have an arterial catheter placed to continuously monitor the response to vasopressor titration. Sepsis can compromise adrenal function so that stress doses of hydrocortisone may be helpful in septic shock requiring vasopressors. Red blood cell transfusion should occur routinely only when hemoglobin concentration decreases to less than 7 g/dL.13,14 However, in severe sepsis with tissue hypoxia, higher hemoglobin targets may facilitate oxygen delivery. Protocolized early goal-directed therapy based on mixed venous oxygen saturation is no longer recommended.15

Implications for Respiratory Care Many patients with sepsis, and particularly those with septic shock, develop respiratory failure. Noninvasive ventilation should be used cautiously in these patients with de novo acute hypoxemic respiratory failure.16 In contrast, the use of high-flow nasal cannula may be associated with a reduced need for intubation. Close monitoring is required, however, and often it is advisable to intubate and provide invasive mechanical ventilation. Mechanical ventilation for the patient with sepsis should be a lungprotective strategy, just as in any other patient with ARDS (Box 431).14,17–19 These patients may have both a lower lung compliance and a lower chest wall compliance. The lower chest wall compliance is the result of fluid resuscitation and the systemic inflammatory response and might require higher levels of PEEP. The lower lung compliance is due to the direct effects of sepsis (noncardiogenic) and the large volume of fluid administered (cardiogenic). With sepsis, patients have both a high shunt (requiring higher PEEP and FIO2) and higher dead space (requiring higher minute ventilation). In the setting of PaO2/FIO2 < 150, consider the use of prone position and neuromuscular blockade. In the setting of PaO2/FIO2 < 100, consider the use of extracorporeal life support. With resolving respiratory failure, the ventilator discontinuation potential should be evaluated daily through the use of spontaneous breathing trials. When the patient tolerates a spontaneous breathing trial, prompt consideration should be given to extubation. BOX 43-1 Mechanical Ventilation for the Patient with Sepsis Tidal volume: 4 to 8 mL/kg predicted body weight; target 6 mL/kg; maintain plateau pressure < 30 cm H2O unless low compliance of chest wall impedes adequate ventilation. Respiratory rate: A rate as high as 35 breaths/min might be necessary due to high carbon dioxide production, high dead space, and metabolic lactic acidosis. PEEP: Use the ARDSnet lower PEEP table for PaO2/FIO2 > 200 and the higher PEEP table for PaO2/FIO2 < 200. Higher PEEP might be necessary in the setting of decreased chest wall compliance resulting from fluid resuscitation; esophageal manometry might be useful for PEEP titration with stiff chest wall.

FIO2: Target SpO2 of 88% to 95%; avoid both hypoxemia (SpO2 < 88%) and hyperoxemia (SpO2 > 95%). Recruitment maneuvers: The role of recruitment maneuvers is controversial but should be considered for PaO2/FIO2 < 100. In the setting of septic shock, hemodynamics must be monitored carefully if a recruitment maneuver is used. Mode: Volume control or pressure control per individual bias; spontaneous mode such as pressure support when respiratory failure is resolving. The role of unconventional modes such as airway pressure release ventilation is unknown.

Diaphragm atrophy developing during mechanical ventilation strongly impacts clinical outcomes. In one study, the development of decreased diaphragm thickness was associated with a lower daily probability of liberation from mechanical ventilation, prolonged intensive care unit (ICU) stay, and a higher risk of complications.20 Sepsis-induced diaphragm dysfunction (SIDD) can be important in mechanically ventilated patients with sepsis. In contrast to ventilator-induced diaphragm dysfunction (VIDD), in which neuropathic abnormalities do not have a major role in muscle weakness, the mechanism of SIDD appears to be a combination of impaired neural transmission and myopathic changes.10 As with VIDD, diaphragm-protective ventilation should be used in patients with SIDD. The risk of diaphragm injury (myotrauma) appears related to both too little muscle activity (over-assistance) and too much muscle activity (under-assistance). Excessive diaphragm activity might also lead to patient self-inflicted lung injury due to excessive tidal volume (stress and strain) and pendelluft. A diaphragm-protective ventilation strategy also needs to be lung protective. In the future, techniques such as diaphragm ultrasound, esophageal manometry, and diaphragm electromyopathy might be found to be useful to monitor the diaphragm to determine the level of support.21,22

Key Points Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis affects virtually all organ systems, including the lungs. The balance of pro-inflammatory and anti-inflammatory mediators regulates the inflammatory response. Sepsis occurs when the release of pro-inflammatory mediators leads to a more generalized multiple-organ response. Hypotension due to diffuse vasodilation is a severe expression of circulatory dysfunction in sepsis. Respiratory failure is common with sepsis, including ARDS and diaphragm dysfunction. A higher SOFA score is associated with an increased likelihood of mortality. The quick SOFA (qSOFA) tool uses simple bedside criteria to identify adult patients with suspected infection who are likely to have poor outcomes. Patients with septic shock have persistent hypotension requiring vasopressors to maintain mean arterial pressure $ 65 mm Hg and having a serum lactate level > 2 mmol/L despite adequate volume resuscitation. The treatment of sepsis is informed by the Surviving Sepsis Guidelines. For resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid should be administered within the first 3 hours. Intravenous antimicrobials are initiated as soon as possible and within 1 hour. Vasopressors are often needed to increase mean arterial pressure to more than 65 mm Hg in patients with septic shock. Mechanical ventilation for the patient with sepsis should be consistent with lung-protective ventilation, as in any other patient with ARDS. Sepsis-induced diaphragm dysfunction (SIDD) can be important in mechanically ventilated patients with sepsis.

References 1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315(8):801–810. 2. Prescott HC, Angus DC. Enhancing recovery from sepsis: a review. JAMA 2018;319(1):62– 75. 3. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002;360(9328):219–223. 4. Fredenburgh LE, Kraft BD, Hess DR, Harris RS, Wolf MA, Suliman HB, et al. Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia. Am J Physiol Lung Cell Mol Physiol 2015;309(8):L834–846. 5. Fredenburgh LE, Perrella MA, Barragan-Bradford D, Hess DR, Peters E, Welty-Wolf KE, et al. A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS. JCI Insight 2018;3(23). 6. Neviere R. Pathophysiology of sepsis. UpToDate. Available at https://www.uptodate.com/contents/pathophysiology-of-sepsis/print. Accessed April 2, 2019. 7. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011;306(23):2594–2605. 8. Sun Z, Ye H, Shen X, Chao H, Wu X, Yang J. Continuous venovenous hemofiltration versus extended daily hemofiltration in patients with septic acute kidney injury: a retrospective cohort study. Crit Care 2014;18(2):R70. 9. Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010;38(2 Suppl):S26– S34. 10. Petrof BJ. Diaphragm weakness in the critically ill: basic mechanisms reveal therapeutic opportunities. Chest 2018;154(6):1395–1403. 11. Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working Group on “Sepsis-Related Problems” of the European Society of Intensive Care Medicine. Crit Care Med 1998;26(11):1793–1800. 12. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315(8):762–774. 13. Dellinger RP, Schorr CA, Levy MM. A users’ guide to the 2016 Surviving Sepsis Guidelines. Crit Care Med 2017;45(3):381–385. 14. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017;45(3):486–552. 15. Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, et al. Early, goal-directed therapy for septic shock: a patient-level meta-analysis. N Engl J Med 2017;376(23):2223–2234. 16. Rochwerg B, Brochard L, Elliott MW, Hess D, Hill NS, Nava S, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J 2017;50(2). 17. Hess DR, Thompson BT. Ventilatory strategies in patients with sepsis and respiratory failure. Curr Infect Dis Rep 2005;7(5):342–348. 18. Serpa Neto A, Schultz MJ, Festic E. Ventilatory support of patients with sepsis or septic

shock in resource-limited settings. Intensive Care Med 2016;42(1):100–103. 19. Zampieri FG, Mazza B. Mechanical ventilation in sepsis: a reappraisal. Shock 2017;47(1S Suppl 1):41–46. 20. Goligher EC, Dres M, Fan E, Rubenfeld GD, Scales DC, Herridge MS, et al. Mechanical ventilation-induced diaphragm atrophy strongly impacts clinical outcomes. Am J Respir Crit Care Med 2018;197(2):204–213. 21. Goligher EC, Brochard LJ, Reid WD, Fan E, Saarela O, Slutsky AS, et al. Diaphragmatic myotrauma: a mediator of prolonged ventilation and poor patient outcomes in acute respiratory failure. Lancet Respir Med 2019;7(1):90–98. 22. Schepens T, Dres M, Heunks L, Goligher EC. Diaphragm-protective mechanical ventilation. Curr Opin Crit Care 2019;25(1):77–85.

CHAPTER

44 Neuromuscular Dysfunction Francis C. Cordova John Mullarkey Gerard J. Criner

© Andriy Rabchun/Shutterstock

OUTLINE Overview Pathophysiology of Neuromuscular Disease on Respiratory Failure Evaluation of Respiratory Function in Patients with Neuromuscular Disease Assessment of Respiratory Muscle Function Upper Motor Neuron Disorders Lower Motor Neuron Disorders Disorders of the Peripheral Nerves Disorders of the Neuromuscular Junction Inherited Myopathies Acquired Inflammatory Myopathies Treatment of Neuromuscular Dysfunction

OBJECTIVES 1. Discuss the effects of neuromuscular disease on respiratory function during wakefulness and sleep.

2. Discuss the relevance of clinical history, physical examination, and pulmonary function testing in the evaluation of respiratory function in patients with suspected neuromuscular disease. 3. Describe the clinical manifestations of neuromuscular disease associated with upper motor neuron lesions, lower motor neuron lesions, disorders of peripheral nerves, disorders of the neuromuscular junction, and inherited and acquired myopathies. 4. Discuss the treatment of respiratory dysfunction in patients with neuromuscular disease. 5. Describe the role of respiratory muscle training, assisted coughing, glossopharyngeal breathing, mechanical ventilatory support, and diaphragmatic pacing.

KEY TERMS acid maltase deficiency amyotrophic lateral sclerosis (ALS) Becker muscular dystrophy (BMD) botulism Cheyne-Stokes breathing cholinergic crisis critical illness polyneuromyopathy (CIPNM) diaphragmatic pacing Duchenne muscular dystrophy (DMD) facioscapulohumeral muscular dystrophy (FSH) glossopharyngeal breathing Guillain-Barré syndrome (GBS) Lambert-Eaton syndrome (LEMS) limb-girdle muscular dystrophy maximum expiratory pressure (MEP or PEmax) maximum inspiratory pressure (MIP or PImax) mitochondrial myopathy mouth occlusion pressure (P0.1) multiple sclerosis (MS) muscular dystrophy myasthenia gravis (MG) myasthenic crisis myotonic dystrophy neuromuscular disease (NMD) Parkinson disease postpoliomyelitis syndrome sniff test stroke systemic lupus erythematosus (SLE) tetraplegia transdiaphragmatic pressure (Pdi)

Introduction Neuromuscular disease (NMD) comprises a diverse group of neurologic and muscle disorders, whose progression invariably leads to respiratory failure and death. Advances in critical care medicine and application of noninvasive ventilation (NIV) coupled with advances in critical care medicine have led to the improvement in survival of patients with neuromuscular disorders. Early diagnosis, careful monitoring of declining respiratory function, and early institution of ventilator support are integral parts of caring to ensure best possible outcomes. This chapter discusses the etiology, pathophysiology, and treatment of ventilatory dysfunction in the setting of NMD.

Overview Although the list of diseases usually classified as neuromuscular disorders includes a heterogeneous and pathologically diverse composite of neurologic and muscular diseases (Table 44-1), they all lead to a stereotypic clinical course of ineffective cough, recurrent pulmonary infections, and ventilatory insufficiency in advanced disease. Chronic respiratory failure, in association with pulmonary sepsis, is the most common cause of death in these patients. Some neuromuscular disorders remain unrecognized until an intercurrent illness leads to acute respiratory failure. In such cases, neuromuscular dysfunction is suspected only once patients cannot be liberated from mechanical ventilation. Neuromuscular dysfunction frequently contributes to the need for prolonged mechanical ventilation.1 TABLE 44-1 Levels of Pathologic Injury in Neuromuscular Diseases Level

Disease

Upper Motor Neurons Cerebral Spinal cord

Stroke Trauma

Lower Motor Neurons Anterior horn cells

Poliomyelitis Amyotrophic lateral sclerosis Phrenic nerve injury Diabetes mellitus Guillain-Barré syndrome

Peripheral nerves

Neuromuscular junction

Critical illness polyneuropathy Myasthenia gravis Lambert-Eaton syndrome Botulism Aminoglycosides

Muscle

Dystrophy Acid maltase deficiency Corticosteroids

Acute intensive care myopathy

Pathophysiology of Neuromuscular Disease on Respiratory Function The ventilation changes that occur in chronic NMD can best be understood by studying their impact on the functional components of the respiratory system. NMD affects control of breathing, respiratory muscle function, lung and chest wall mechanics, and upper airway function. Commonly observed changes in the respiratory system found in patients with moderately advanced chronic neuromuscular dysfunction include normal or high central respiratory drive (except in certain diseases that affect the brain stem, such as poliomyelitis); a restrictive ventilatory pattern manifested as a reduction in forced vital capacity in the absence of airflow obstruction, and a decrease in total lung capacity associated with an increase in residual volume; a reduction in respiratory muscle strength; and upper airway dysfunction that may cause airway obstruction. These pathologic changes may present as subtle signs of respiratory insufficiency during restful breathing but can become magnified during sleep and exercise (Figure 44-1).

FIGURE 44-1 Pathophysiology of respiratory failure in patients with neuromuscular diseases. From Hill NS, Braman S. Noninvasive ventilation in neuromuscular disease. In: Cherniack NS, Altose MD, Homma I, eds. Rehabilitation of the patient with respiratory disease. New York, NY: McGraw-Hill; 1999. Permission conveyed through Copyright Clearance Center, Inc. Republished with permission of McGraw-Hill.

Description

Control of Breathing Patients’ ventilatory responses to hypoxemia and hypercapnia challenges are used to assess the response of the peripheral and central chemoreceptors to chemical stimuli. The central chemoreceptors, which are located in the medulla and midbrain, play a major role in adjusting ventilation to maintain acid–base homeostasis. Central chemoreceptor neurons in the medulla are located on the ventral surface and near the retrotrapezoid nucleus (RTZ). The RTZ neurons not only respond to changes in pH in the central nervous system environment, but also receive input from the carotid bodies. These chemoreceptor neurons also

express a high level of Phox2b, a gene mutation that cause congenital central hypoventilation syndrome. The peripheral chemoreceptors, which are located in the carotid and aortic bodies, are sensitive to changes in PaO2, and to a lesser extent to changes in PaCO2 and pH. Thus, the central chemoreceptors are more sensitive to hypercapnia, whereas the peripheral chemoreceptors are more responsive to hypoxemia. In normal individuals, the relationship between oxygen saturation and ventilation is linear, such that a 1% decrease in oxygen saturation will trigger an increase of approximately 1 L/min in minute ventilation. A much steeper linear increase in minute ventilation is seen during the hypercapnic breathing test. For every 1 mm Hg rise in PaCO2, ventilation increases by 2.5 to 3 L/min. The normal increases in ventilation that occur in response to hypoxemia and hypercapnia become disturbed in some neuromuscular disorders. Patients with neuromuscular disorders exhibit hypoventilation out of proportion to the severity of the respiratory muscle weakness. The blunted ventilatory responses to hypoxemic and hypercapnic challenges observed in patients with chronic NMD may be related to an increased work of breathing due to respiratory muscle weakness. Abnormal chest wall and lung mechanics, a defective afferent input from diseased respiratory muscles, upper airway involvement, and upper motor neuron disorders may all contribute to hypoventilation in some neuromuscular disorders. A more accurate test of central respiratory drive that is independent of underlying respiratory mechanics is the mouth occlusion pressure (P0.1). P0.1 refers to the maximum negative mouth pressure generated during the first 100 milliseconds of inspiration during complete airway occlusion. Because P0.1 is obtained during early inspiration, it is not influenced by volitional effort. In addition, because this pressure requires only a fraction of maximum inspiratory muscle strength, its measurement remains valid even in the presence of moderately severe inspiratory muscle weakness. In contrast to studies that used ventilation to assess central respiratory drive, P0.1 is normal, or sometimes increased, in patients with NMD despite the presence of substantial muscle weakness. P0.1 in patients with Duchenne muscular dystrophy, myotonic dystrophy, and a

variety of other NMDs is one- to two-fold higher than in normal controls.2,3 Thus, central respiratory drive, as measured by P0.1, is usually preserved in patients with underlying NMD. Respiratory Recap Control of Breathing ∎ The central respiratory drive is sensitive to changes in PaCO2 and PaO2. ∎ The mouth occlusion pressure (P0.1) is an accurate measure of respiratory drive. ∎ Respiratory drive is preserved in patients with NMD.

Respiratory Muscle Function The respiratory muscles comprise the muscles of the upper airway, diaphragm, chest wall, and abdomen. Respiratory muscles can be further divided into inspiratory and expiratory muscles. The inspiratory muscles produce rib cage expansion and generate negative intrathoracic pressure, thereby facilitating inspiratory flow. During rest, exhalation is passive; it is driven by the lung and chest wall elastic recoil pressures. In contrast, active contraction of the expiratory muscles occurs under conditions in which increased expiratory flow is required, such as during coughing, exercise, and airways obstruction. Table 44-2 lists the innervation of the different respiratory muscles and their major functions. TABLE 44-2 Innervation of the Respiratory Muscles Muscle Group

Nerve

Upper airways Palate, pharynx Genioglossus

Glossopharyngeal, vagus, spinal accessory Hypoglossal

Inspiratory Diaphragm Scalenes Parasternal intercostals Sternocleidomastoid

Phrenic Cervical (C4 through C8) Intercostal (T1 through T7) Spinal accessory Intercostal (T1 through T12)

Lateral external intercostals Expiratory Abdominal Internal intercostals

Lumbar (T7 through T11) Intercostal (T1 through T12)

Patients with moderate to severe respiratory muscle weakness due to NMD often complain of fatigue, poor sleep quality, and dyspnea, especially on exertion. However, a significant percentage of these patients may be asymptomatic despite moderate to severe weakness of the inspiratory and expiratory muscles. According to one report, 27% of patients with moderately advanced NMD and severe reduction in both inspiratory and expiratory muscles have no respiratory complaints.4 Another study reported that as many as 50% of patients with severe respiratory muscle weakness due to chronic NMD are asymptomatic.5 It is unclear why such a poor correlation exists between the extent of respiratory muscle weakness and clinical symptoms exhibited by the patient. It is possible that the presence of significant respiratory muscle weakness is masked by the inability to achieve significant exercise because of generalized muscle weakness that leads to a sedentary lifestyle. Whatever the case, a substantial number of patients may have significant neuromuscular impairment of the respiratory system that may go initially unnoticed. The type of underlying neuromuscular disorder determines the pattern and severity of respiratory muscle weakness. Some diseases cause global respiratory muscle dysfunction, whereas others produce preferential weakness of the inspiratory or expiratory muscles. Moreover, decreases in inspiratory and expiratory muscle strength may not correlate with general muscle strength assessment. Primary muscle diseases (e.g., polymyositis) may cause more significant impairment of the respiratory muscles compared with the neuropathies. The relationship between inspiratory muscle strength and the onset of ventilatory insufficiency is not linear. Once PImax decreases to less than 30% of predicted, hypercapnia ensues (Figure 44-2).6 The clinical course of respiratory muscle dysfunction in different forms of NMD may also vary: It can be relentlessly progressive (amyotrophic lateral sclerosis [ALS]), reversible with therapy (Guillain-Barré syndrome, myasthenia gravis), or

improve with time (critical care myopolyneuropathy).

FIGURE 44-2 Relationship between respiratory muscle strength and PaCO2 in patients with myopathies. Data suggest that hypercapnia does not occur until the respiratory muscle strength is less than 30% of predicted. Red and blue circles represent patients with and without concomitant lung disease, respectively. Adapted by permission from BMJ Publishing Group Limited. From Braun NMT, Arora NS, Rochester DF. Respiratory muscle and pulmonary function in polymyositis and other proximal myopathies. Thorax 1983;38(8):616–623.

Description

Respiratory Recap Respiratory Muscle Function ∎ Isolated or combined inspiratory, expiratory, and bulbar weakness can be seen in NMD. ∎ Respiratory muscle weakness can be present in the absence of respiratory muscle weakness.

Lung and Chest Wall Mechanics Lung volume studies in patients with chronic respiratory muscle weakness often show a restrictive ventilatory pattern with a reduction in total lung capacity (TLC) and forced vital capacity (FVC). Both inspiratory and expiratory reserve volumes also decrease by a moderate extent. The decrease in FVC is mainly due to respiratory muscle weakness, and it generally parallels the progression of the underlying NMD in the absence of concomitant airflow obstruction. However, because of the sigmoidal shape of the pressure–volume curve, vital capacity is relatively preserved until respiratory muscle weakness becomes well advanced (Figure 44-3). The decline in FVC is out of proportion to the reduction in inspiratory muscle strength, likely due to a decrease in lung compliance.7 The exact cause of reduced lung compliance in patients with NMD remains speculative. Proposed explanations include failed maturation of normal lung tissue in congenital NMD; the presence of microatelectasis or macroatelectasis; an increased alveolar surface tension caused by breathing chronically at low tidal volumes; and an alteration in lung tissue elasticity.

FIGURE 44-3 Relationship between inspiratory muscle strength and vital capacity. The orange line represents the regression line calculated in 25 patients with NMD showing the disproportionate fall in vital capacity for the given degree of inspiratory muscle weakness. The blue line represents the predicted relationship between vital capacity and inspiratory muscle strength. Adapted by permission from BMJ Publishing Group Limited. Modified from De Troyer A, Borensteinm S, Cordier R. Analysis of lung volume restriction in patients with respiratory muscle weakness. Thorax 1980;35(8):603–610.

Description Patients with NMD have a rapid, shallow breathing pattern similar to the pattern seen with interstitial lung disease. The exact mechanism is unclear, but is thought to occur secondary to changes in lung and chest

wall elastic recoil. Animal studies have demonstrated that breathing at small tidal volumes is associated with reductions in lung compliance and may lead to increased alveolar surface tension. In addition, the lower ventilatory demand induced by a sedentary lifestyle leads to lower lung mechanical stress and over time may result in a reduction in lung tissue elasticity. Similar to the changes seen in the lungs, a reduction in chest wall compliance occurs in patients with chronic NMD.8,9 The mechanisms are unclear, but this effect may be caused by increased rib cage stiffness due to decreased distensibility of chest wall structures (i.e., tendons, ligaments, costovertebral and costosternal articulations). In patients with type 1 spinal muscular atrophy, the relative preservation of diaphragm strength in the face of marked weakness of the intercostals commonly leads to chest wall deformity characterized by sternal recession and a small bell-shaped chest. Although a low vital capacity is almost always seen in moderately advanced NMD, the changes in functional residual capacity (FRC) and residual volume (RV) vary depending on the type, severity, and stage of NMD. In general, patients with NMD have moderate reductions in TLC and FRC, with a normal or high RV.

Gas Exchange Abnormalities Hypercapnia and hypoxemia are late findings in patients with NMD. Hypercapnia with a relatively normal FVC, PImax, and PEmax should raise the possibility of sleep-related breathing disorders (e.g., obstructive sleep apnea, obesity hypoventilation syndrome), the presence of parenchymal lung disease such as chronic obstructive airway disease, or problems with central respiratory drive such as chronic hypoventilation syndrome or hypothyroidism. Even with normal daytime gas exchange parameters, significant hypoxemia and alveolar hypoventilation may occur during sleep, especially during rapid eye movement (REM) sleep, when the activity of the accessory muscles is diminished. In advanced NMD, evidence of alveolar hypoventilation on blood gas examination is likely when the FVC is less than 55% of predicted (Figure 44-4) or when the respiratory muscle strength (average of percent predicted PImax and

PEmax) is less than 30%. In addition, hypercapnia is likely if the FVC is less than 1 L. However, hypercapnia in the setting of advanced NMD may have an abrupt onset, especially in patients with repeated pulmonary infections. Ventilation-perfusion inequality due to atelectasis is the most common cause of hypoxemia in these patients.

FIGURE 44-4 Relationship between vital capacity and PaCO2, showing that hypercapnia occurs when the vital capacity is less than 50% of predicted. Red and blue circles represent patients with and without concomitant lung disease, respectively. Adapted by permission from BMJ Publishing Group Limited. Reproduced from Braun NMT, Arora NS, Rochester DF. Respiratory muscle and pulmonary function in polymyositis and other proximal myopathies. Thorax 1983;38(8):616–623.

Description

Respiratory Recap Respiratory Mechanics ∎ Lung volume shows a restrictive pattern due to reduced chest wall and lung compliance. ∎ The breathing pattern is rapid and shallow. ∎ The decrease in FVC is relatively attenuated until the respiratory muscle weakness is severe.

Respiratory Recap Gas Exchange Abnormalities ∎ Daytime hypercapnia is likely when FVC is less than 55% or respiratory muscle weakness is less than 30%. ∎ Hypercapnia is a late sign of respiratory muscle weakness.

Sleep and Neuromuscular Disease Sleep-related breathing disorders such as impaired sleep quality and REM-related hypopneas are common in patients with various forms of NMD. Significant nocturnal gas exchange abnormalities may be present and even unsuspected when daytime hypoxemia and hypercapnia are absent. In addition, a sleep study usually shows an increased number of awakenings, sleep fragmentation, and disorganization, along with reduced total sleep time. Several physiologic changes occur in the respiratory system during sleep, especially during REM sleep. Supine position and sleep decrease FRC and tidal volume. Other causes of decreased minute ventilation compared to wakefulness include decreased chemosensitivity to hypoxemia and hypercapnia, and decreased pharyngeal dilator activity leading to an increase in upper airway resistance. Thus, alveolar hypoventilation, causing a rise in PaCO2 of 2 to 3 mm Hg, occurs during sleep in normal individuals. An inhibition of accessory inspiratory muscle activity during REM sleep may lead to a significant reduction in alveolar ventilation in patients with underlying diaphragm weakness.

Hypoventilation during sleep is the major cause of sleep-related oxygen desaturation. In patients with chronic respiratory failure and nocturnal oxygen desaturation (patients with chronic airways obstruction, obesity hypoventilation, NMD), minute ventilation has been shown to decrease by 21% during non-REM sleep and by 39% during REM sleep compared with wakefulness (Figure 44-5).10 The decrease in minute ventilation is mainly due to a decrease in tidal volume and occurs independently of the underlying lung disease. Phasic REM sleep– induced changes in breathing pattern superimposed on the rapid, shallow breathing pattern commonly observed in patients with NMD will lead to further increases in dead space ventilation, resulting in more profound degrees of hypoxemia and hypercapnia. In addition to these sleepinduced breathing abnormalities, weakness of the pharyngeal muscles in some NMDs may predispose patients to obstructive sleep apnea and hypopnea due to loss of upper airway tone, especially during REM sleep. Sleep worsens ventilatory failure in patients with diaphragm weakness due to loss of accessory muscle activity during REM sleep.

FIGURE 44-5 Both panels show the decrease in tidal volume and minute ventilation with no change in respiratory rate during transition from nonrapid eye movement (NREM) sleep to rapid eye movement (REM) sleep. Hypoventilation due to a decrease in tidal volume during REM sleep appears to be the main reason leading to nocturnal oxygen desaturation in patients with limited

pulmonary reserve. Modified from Becker HF, Piper AJ, Flynn WE, McNamara SG, Grunstein RR, Peter JH, Sullivan CE. Breathing during sleep in patients with nocturnal desaturation. Am J Respir Crit Care Med 1999;159(1):112–118. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. Reprinted with permission of the American Thoracic Society. Copyright © 2015 American Thoracic Society.

Description If nocturnal hypoventilation is severe and remains clinically unrecognized, daytime hypercapnia and hypoxemia may ensue even in the absence of severe respiratory muscle dysfunction. Nocturnal gas exchange abnormalities usually precede abnormalities in daytime arterial blood gas results.11,12 Most patients with normal nocturnal gas exchange are unlikely to have abnormal daytime values. Abnormalities in daytime gas exchange and certain parameters of respiratory mechanics are useful in predicting the subset of patients with NMD who are at risk for severe nocturnal oxygen desaturation. The degree of REM-related oxygen desaturation is directly related to the severity of daytime hypercapnia and hypoxemia. Absolute values for vital capacity, as well as the decrement in vital capacity measured in the supine compared with the seated position, also correlate with the nadir in oxygen saturation measured during REM sleep. In one study, the mean decrease in FVC measured in the seated compared with supine posture was 21%.12 In patients with primary myopathies, inspiratory vital capacity less than 60% is associated with the development of REM-associated hypopneas. Nocturnal hypopneas occur during REM and non-REM sleep once the vital capacity is less than 40% and the maximum inspiratory pressure (MIP or PImax) is greater than –30 cm H2O.12 Figure 44-6 shows the evolution of respiratory failure in patients with NMD.

FIGURE 44-6 Respiratory insufficiency in patients with NMD is manifested initially as a sleeprelated breathing disorder during REM sleep and later in NREM sleep. Chronic hypercapnic respiratory failure ensues once forced vital capacity (FVC) is less than 20% of predicted or in the presence of chest infection. Reproduced with permission from the American College of Chest Physicians. From Simonds AK. Recent advances in respiratory care for neuromuscular disease. Chest 2006;130(6):1882.

Description

Stop and Think Based on the respiratory pathophysiology of NMD, how would you explain to a patient the benefits of nocturnal noninvasive ventilation?

Respiratory Recap

Sleep-Disordered Breathing ∎ Nocturnal hypoventilation is common and may herald the onset of daytime hypercapnia. ∎ FVC less than 40% and maximum inspiratory pressure less than 30 cm H2O predict REM- and non–REM-associated hypoventilation.

Upper Airway Function Some forms of NMD involve the bulbar muscles and, therefore, impair upper airway function. Upper airway dysfunction is commonly manifested by chronic cough aggravated during swallowing, recurrent aspiration, stridor, obstructive sleep apnea, and hypopnea. In patients with chronic neuromuscular disorders, upper airway dysfunction is more common in those who exhibit respiratory muscle weakness than in those without such weakness. The flow-volume loop is a useful screening tool to detect significant upper airway dysfunction. An abnormal flow-volume loop has a high sensitivity and specificity in predicting bulbar and upper airway involvement in patients with neuromuscular dysfunction.13,14 Figure 44-7 shows a typical flow-volume loop in a patient with motor neuron disease with bulbar involvement. Sawtoothing of the flow contour can occur in patients with Parkinson disease.14 In addition, variable extrathoracic obstruction that reverses with drug therapy has been described in patients with myasthenia gravis.13 Certain features of the flow-volume curve have been shown to correlate with reduced maximum static inspiratory and expiratory mouth pressures: a reduced peak expiratory flow, decreased slope of the ascending limb of the maximum expiratory curve, a drop-off of the forced expiratory flow near residual volume, and a reduction in forced inspiratory flow at 50% of vital capacity (Figure 448).15,16

FIGURE 44-7 An example of a flow-volume loop in a patient with motor neuron disease, showing inspiratory flow limitation suggestive of partial upper airway obstruction. Reproduced with permission from the American College of Chest Physicians from Vincken W, Ellecker G, Cosio M. Detection of upper airway muscle involvement in neuromuscular disorders using flow-volume loop. Chest 1986;90(1):52–57.

Description

FIGURE 44-8 Analysis of the effort-dependent portion of the flow-volume loop to detect respiratory muscle weakness. These four parameters are (1) peak expiratory flow (PEF); (2) ratio of PEF to the exhaled volume at which PEF was achieved (VPEF); (3) rapid vertical drop of forced expiratory flow (FEF) at residual volume; and (4) forced mid-inspiratory flow. EVC, expired vital capacity; FIF, forced inspiratory flow; IVC, inspired vital capacity. Reproduced from Vicken W, Ellecker G, Casio M. Flow-volume loop changes reflecting respiratory muscle weakness in chronic neuromuscular disorders. Am J Med 1987;83(4):673–680. © 1987, with permission from Elsevier.

Description Dysphagia may be the initial complaint with glossopharyngeal muscle weakness in patients with NMD. Bulbar muscle weakness should be suspected in patients with NMD who have chronic cough and recurrent pneumonia, even in the absence of dysphagia.16 Swallowing is a complex neuromuscular behavior that requires coordinated bulbar muscle contraction, intact pharyngeal sensory input and adequate production of saliva, and normal esophageal, respiratory, and cortical functions. Both bulbar and respiratory muscle weakness can disrupt normal swallowing function and can lead to not only repeat infections but also undernutrition, dehydration, and pulmonary fibrosis. Depending on the type of neuromuscular disorder, dysphagia can be intermittent, as in myasthenia gravis; rapidly progressive, as in ALS; or slowly progressive, as in muscular dystrophy. Patients suspected of bulbar muscle weakness should be referred to a speech-language pathologist for evaluation of dysphagia. Swallowing dysfunction can often be confirmed with modified barium swallow study or fiberoptic endoscopy. Respiratory Recap Upper Airway Muscles ∎ Weakness of the bulbar muscles leads to recurrent aspiration, pneumonia, and upper airway obstruction. ∎ The flow-volume loop is useful in detecting upper airway obstruction.

Evaluation of Respiratory Function in Patients with Neuromuscular Disease Clinical History The diagnosis of the etiology of muscle weakness may not be readily made on initial clinical evaluation because of the overlapping syndromes among the different NMDs. The predominant signs and symptoms of a particular NMD depend on the patient’s age at the presentation of the clinical symptoms; the acuity, severity, and clinical course of the disease; and the pattern of neuromuscular weakness. Diseases that predominantly affect the pump function of the respiratory system will present as dyspnea, weak cough, and recurrent respiratory tract infections, whereas diseases that primarily affect the limb muscles will present as impaired patient mobility early in the disease evolution. Once respiratory muscles are affected in advanced NMD, respiratory failure may occur abruptly due to an intercurrent illness or slowly over months and years, culminating in chronic hypercapnic respiratory failure. However, in some NMDs a typical presentation will help with the diagnosis. For example, an acute ascending paralysis of the lower extremities suggests Guillain-Barré syndrome, waxing and waning of neurologic symptoms is commonly seen in multiple sclerosis, and skeletal muscle weakness with repetitive action of a particular muscle group is highly suspicious of myasthenia gravis unless proven otherwise. In the majority of the NMDs, respiratory muscle weakness occurs insidiously and is typically associated with weakness of other skeletal muscle groups. However, as many as 50% of patients with significant respiratory muscle weakness may be asymptomatic until they present with overt respiratory failure.2 Thus it comes as no surprise that acute respiratory failure has been reported as the initial presentation in patients with motor neuron disease, myasthenia gravis, adult-onset acid maltase deficiency, and mitochondrial myopathy. In clinical practice, pulmonary physicians and respiratory therapists are involved in the care of these patients when they develop either acute respiratory failure or acute or chronic hypercapnic respiratory failure.

Respiratory Recap Acute Respiratory Failure in Neuromuscular Disease Weak cough, inability to clear oral secretions, and failure to liberate from mechanical ventilation should prompt NMD workup.

In patients who develop acute respiratory failure, the nature of the NMD is often not clinically apparent, and the clinical history may be dominated by the symptoms of the precipitating illness that led to respiratory failure. These patients often require intubation and mechanical ventilation and appropriate treatment of the precipitating intercurrent illness. In most cases, respiratory muscle weakness due to a NMD comes to light only after the patient has failed multiple attempts at ventilator liberation. In patients who have chronic stable NMD, such as ALS or congenital myopathies, progressive respiratory muscle weakness occurs over months and years, eventually leading to chronic progressive hypercapnic respiratory failure. The challenge to physicians and respiratory therapists is to detect early signs of respiratory muscle weakness before the onset of fulminant respiratory failure; to prevent complications such as aspiration, recurrent respiratory tract infections, and cor pulmonale; and to preserve remaining lung function. Some studies have shown that early institution of NIV may attenuate the decline in respiratory muscle function in certain diseases.17 The common symptoms of respiratory muscle weakness are dyspnea (especially with activity), inability to clear secretions, and weak cough; frequent respiratory tract infections and choking episodes are often elicited several months before these patients seek medical attention. The presence of chronic headache, lethargy, and somnolence suggests significant daytime and nocturnal hypercapnia. Nocturnal hypercapnia usually heralds the onset of chronic respiratory failure. Respiratory Recap Signs of Respiratory Muscle Weakness ∎ Subcostal retraction is a sign of diaphragm weakness and heralds impending respiratory failure.

Tachypnea and use of the respiratory accessory muscles at rest are signs of respiratory ∎ muscle weakness.

Physical Examination A thorough physical examination and a detailed neurologic assessment may reveal a previously undiagnosed neuromuscular disorder. This is particularly true in patients who have mild respiratory muscle weakness but develop acute respiratory failure due to increased ventilatory demand from an acute illness such as an infection and metabolic disorders. In patients with early or mild neuromuscular weakness, respiratory muscle weakness may not be detected on routine physical examination. Limb muscle weakness is often recognized only after the patient fails multiple ventilator liberation attempts. Nevertheless, certain physical examination findings indicate significant respiratory muscle weakness. Tachypnea at rest is very common with the onset of respiratory muscle weakness. As the respiratory muscle weakness progresses, the increase in respiratory rate may be followed by signs of high respiratory workload such as nasal flaring, recruitment of the accessory muscles, intercostal and subcostal retractions, and paradoxical movement of the thorax and abdomen during tidal breathing. Abnormal paradoxical motion of the rib cage and abdomen may indicate either impending respiratory failure or diaphragm weakness. Indeed, paradoxical inward movement of the abdomen on inspiration that worsens with recumbent position is typically seen in diaphragm weakness.

Arterial Blood Gas Measurements Abnormalities in arterial blood gas values occur late in patients with respiratory muscle weakness and should not be relied on before ventilatory support is initiated. Hypoxemia is commonly the result of microatelectasis due to ineffective cough and retained secretions causing ventilation-perfusion mismatch or intrapulmonary shunting. More important, alveolar hypoventilation due to respiratory muscle weakness or decreased central respiratory drive may also contribute to hypoxemia. Hypoxemia due mainly to alveolar hypoventilation may be detected by a

normal alveolar–arterial PO2 gradient. Pulse oximetry is useful in detecting hypoxemia but is an insensitive indicator of hypoventilation. Hypercarbia is a late finding in severe respiratory muscle weakness. In fact, hypercarbia does not occur until the respiratory muscle strength falls to less than 50% of predicted. Careful analysis of the pH and bicarbonate level can help in the presence of acute or chronic hypercapnic respiratory failure. Sleep-induced breathing disturbances may also lead to hypercarbia and should be evaluated in susceptible patients. Respiratory Recap Gas Exchange ∎ Hypoxemia is caused by retained secretions and atelectasis. ∎ Hypercarbia is caused by alveolar hypoventilation.

Pulmonary Function Tests Spirometry and lung volume studies are helpful in the initial evaluation as well as in the follow-up of patients with NMD. Spirometry results show a restrictive pattern characterized by a reduction in FVC and a normal FEV1/FVC. Moreover, there is a decrease in effort-dependent expiratory flow, such as peak expiratory flow, whereas FEV1 and measurement of mid-expiratory flows (FEF25–75% or FEF50) are often greater than normal in these patients because of decreased lung compliance resulting in increased lung elastic recoil. Lung volume studies demonstrate a low total lung capacity but a high residual volume due to expiratory muscle weakness. The diffusion capacity is normal. Serial measurement of FVC is helpful in following the progression of respiratory muscle weakness in patients with chronic NMD and in the timing of institution of NIV. In patients with rapidly progressive respiratory muscle weakness such as that seen in Guillain-Barré syndrome, daily measurement of FVC ( –30 cm H2O, and PEmax < 40 cm H2O. Other indications for intubation and ventilatory support include respiratory distress, inability to handle oral secretions, hypoxemia (PaO2 < 70 mm Hg on room air, or alveolar–arterial PO2 difference > 300 mm Hg with FIO2 of 1.0), and hypercapnia. Six parameters identified as predictors of acute respiratory failure are time of onset to admission less than 7 days, inability to cough, inability to stand, inability to lift the elbows, inability to lift the head, and increased liver enzymes. In one study, more than 85% of patients with GBS who had at least four of these factors required mechanical ventilation.67 In another study, independent predictors for the need of mechanical ventilation in the first week after admission included fewer days between onset of weakness and admission, facial bulbar weakness, and severe muscle weakness.66 Neurophysiologic testing is helpful in predicting the need for mechanical ventilation. Patients with the demyelinating form of GBS require mechanical ventilation more often than do patients with axonal or equivocal findings on electrophysiology. The risk of acute respiratory failure is 2.5% if the proximal/distal compound muscular amplitude potential ratio is greater than 55% and FVC is greater than 80%. With patients having GBS, it is prudent to initiate early intubation and assisted ventilation to avoid complications that may arise from emergent intubation. Arterial blood gas analysis is used to ensure adequate oxygenation and ventilation. Hypercapnia is a late sign of ventilatory failure. The average PaCO2 at the time of intubation when VC is less than 12 mL/kg was 43 mm Hg in two large series of patients with GBS.66,67 In some patients with GBS, upper airway dysfunction due to bulbar involvement leads to inability to swallow oral secretions and increased risk of aspiration. The presence of nasal voice, abnormal gag reflex, dysarthria, and poor mobility of pharyngeal muscles suggests bulbar muscle dysfunction. The swallowing mechanism can be assessed at the bedside by asking the patient to drink sips of water and observing for coughing. Once significant bulbar dysfunction is observed, intubation may be necessary to protect the airway even if respiratory muscle

strength is adequate. Delaying intubation might increase the risk of earlyonset pneumonia.68 Autonomic dysfunction occurs in 65% of patients with GBS. Common manifestations of this condition include labile blood pressure, sinus tachycardia, diaphoresis, urinary retention, and ileus. Autonomic dysfunction is especially prevalent in patients who require mechanical ventilation and during the progressive and plateau phases of the illness. Particular care should be observed during endotracheal suctioning because it can precipitate tachyarrhythmias, bradyarrhythmias, and asystole from vagal stimulation. Patients may be overly sensitive to vasoactive medications. Management of severe ileus includes bowel rest and therapeutic trials of erythromycin or neostigmine. The use of promotility agents is contraindicated in patients with dysautonomia. Aggressive pulmonary toilet is needed to prevent and treat atelectasis. Atelectasis may require bronchoscopy. Subcutaneous heparin is preferred for deep venous thrombosis prophylaxis compared with pneumatic boots. Corticosteroids may be harmful. Spontaneous breathing trials are initiated when FVC exceeds 8 to 10 mL/kg, oxygenation is adequate with an FIO2 of 0.4 or less, and there is an ability to double minute ventilation. Immune modulation using plasma exchange or intravenous immunoglobulin infusion is the mainstay of therapy in GBS. In multicenter trials, plasmapheresis (250 mL/kg every 2 days for a total of 5 treatments) using either albumin or fresh frozen plasma as replacement fluid showed short-term benefits in early motor recovery and ambulation, reduced the number of patients who required assisted ventilation, and shortened the duration of mechanical ventilation.69–71 A meta-analysis of six randomized controlled trials of patients with GBS confirmed the clinical benefits of plasma exchange compared to supportive care alone.72 Intravenous immunoglobulin therapy is equally effective when compared to plasmapheresis in the treatment of severe GBS. However, patients treated with IV immunoglobulin are less likely to discontinue therapy compared to patients treated to plasma exchange.73 Immunotherapy should be started within 2 weeks of onset of symptoms. In patients with rapidly deteriorating clinical symptoms, however, plasmapheresis still offers some benefit if the duration of the disease is more than 3 weeks. Intravenous immunoglobulin (IVIG) within 2 weeks of

the onset of GBS may be as effective as plasma exchange therapy. Approximately 10% of patients experience a relapse of neurologic symptoms after plasma exchange treatment due to antibody rebound. In such circumstances, additional plasma exchange treatment or IVIG treatment is helpful. Because IVIG is easier to administer, it is preferred over plasma exchange unless there are contraindications to its use, such as low serum immunoglobulin A, the presence of uncontrolled hypertension, and a hyperosmolar state. Sequential treatment consisting initially of plasmapheresis followed by IVIG does not confer any additional benefit as compared to either treatment alone. A meta-analysis showed that plasmapheresis was not superior in terms of efficacy and safety compared to immunoglobulin in the treatment of GBS.74 The results of a meta-analysis reported that patients treated with glucocorticoids showed no difference in disability grade compared to patients who did not receive glucocorticoid treatment.73 With the advent of modern ICU care, mortality from GBS dropped from 15% in the 1970s to less than 5%. Potential complications include pneumonia, recurrent aspiration, and pulmonary thromboembolic disease. Prognosis for recovery is good, but only 15% of patients have no neurologic residual effects. Factors associated with poor prognosis are older age, lower mean compound muscle action potential amplitudes during distal stimulation (less than 20% of normal), need for ventilatory support, and rapid progression to severe weakness in less than 1 week. Stop and Think Over 48 hours, the vital capacity of a patient with Guillain-Barré syndrome has progressively decreased to 15% of predicted. What would you recommend regarding the patient’s respiratory care needs?

Respiratory Recap Guillain-Barré Syndrome ∎ Ascending symmetric paralysis of the lower extremities is a common presentation. ∎ Acute respiratory failure is a serious complication in one-third of patients. ∎ Bulbar muscle weakness increases the risk of aspiration and may warrant early intubation.

∎ Indications for ventilatory support include an FVC less than 12 mL/kg, respiratory distress, inability to handle oral secretions, hypoxemia, and hypercarbia. ∎ Autonomic dysfunction is common and can cause hemodynamic instability.

Critical Illness Polyneuropathy and Neuromyopathy Critical illness polyneuromyopathy (CIPNM) is a flaccid paralysis of the upper and lower extremities. It is a common sequela of severe sepsis and multisystem organ failure in surgical and medical patients. The incidence of CIPNM depends on the severity of illness, the diagnostic criteria used, and the timing of examination from the onset of the critical illness. In prospective studies, 25% to 63% of patients who required mechanical ventilation for at least 7 days developed CIPNM.75 Patients with sepsis have the highest incidence of CIPNM, with rates approaching 70% to 100%. Axonal polyneuropathy was initially identified as the main pathologic change in ICU-acquired weakness, but EMG and muscle biopsy studies showed that acute myopathy coexists with polyneuropathy, and often exists as a separate clinical entity. Four categories of CIPNM are recognized: myopathy, neuromuscular junction abnormalities, neuropathy, and polyneuromyopathy (Table 44-4). In one study, biopsy of the quadriceps femoral muscle showed neuropathic changes in 37% of patients, myopathy in 40%, and both neuropathic and myopathic changes in 23%.76 Muscle necrosis was also present in 30% of the muscle biopsy specimens. TABLE 44-4 Acute Weakness Syndrome in the Intensive Care Unit Category of Critical Illness Polyneuromyopathy

Description

Myopathy

Acute necrotizing myopathy Disuse atrophy

Neuromuscular junction abnormalities

Myasthenia-like syndrome Prolonged neuromuscular blockade

Neuropathy

Critical illness polyneuropathy

Acute motor neuropathy Polyneuromyopathy

Combination of neuropathy and myopathy

Several risk factors, other than severe sepsis and multisystem organ failure, have been identified in the development of CIPNM. These include prolonged use of corticosteroids and neuromuscular blocking agents, persistent hyperglycemia, hyperosmolality, immobility, use of aminoglycosides, and prolonged mechanical ventilation.77 Global measures of the severity of critical illness, such as the Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III and the Sequential Organ Failure Assessment (SOFA) score, are important predictors of the occurrence of CIPNM. Aggressive control of stress-induced hyperglycemia has been reported to decrease the incidence of CIPNM.78–80 In one study, intensive insulin therapy to maintain normoglycemia (blood glucose levels between 80 and 110 mg/dL) decreased the incidence of critical illness polyneuropathy by 44% compared with conventional insulin therapy (blood glucose level between 180 and 200 mg/dL). The risk of CIPNM correlated with the mean blood glucose level. In patients who required mechanical ventilatory support for more than 7 days, intensive insulin therapy decreased the duration of mechanical ventilation. In addition, CIPNM resolved faster in the intensive insulin treatment group compared with the control group, which partially explained the decreased duration of mechanical ventilation.81 In multivariate analysis, independent predictors of the development of polyneuropathy include conventional insulin treatment and vasopressor support of more than 3 days. In a large multicenter controlled trial, researchers randomized subjects to either intensive glucose control or conventional glucose control. The glucose target for the intensive glucose group was 81 to 108 mg/dL, whereas the target of the conventional group was less than 180 mg/dL. Contrary to the prior studies, increased 90-day mortality was observed in the intensive glucose group compared to the conventional glucose control group; there was no difference in ventilator days or ICU length of day. The incidence of CIPNM was not assessed in this study.82 The pathogenesis of CIPNM is not well understood. An exaggerated immune response to severe injury is thought to be the main pathogenic

pathway leading to nerve and muscle injury. Both systemic and local inflammatory responses mediated by tumor necrosis factor alpha and interleukins-1 and -12 and the recruitment of T helper 1 cells, monocytes, macrophages, and neutrophils lead to endothelial cell injury, increased microvascular permeability, and endoneurial edema, resulting in decreased blood flow to the nerve and muscle tissue. The ultimate outcome of this injury is primary axonal degeneration of the sensory and motor fibers and muscle atrophy with loss of contractile proteins and membrane inexcitability. In animal models, sepsis triggers enhanced muscle protein proteolysis through the ubiquitin–proteosome and calpain system, causing myofibrillar degradation and disruption of the sarcomeres. Moreover, animal models of critical illness myopathy reveal altered membrane expression and function of the sodium channels. Such critical illness myopathy may be due to not only selective myosin loss, but also electrical inexcitability of muscle fiber membrane caused by defective sodium channel regulation.83 CIPNM is often suspected initially when patients fail mechanical ventilation as they recover from their life-threatening illnesses or in the presence of new symmetric weakness of both upper and lower extremities. Approximately one-third of these patients have difficulty being liberated from the ventilator, and 70% have evidence of peripheral neuropathy.84,85 The muscle weakness is most prominent in the lower extremities and is accompanied by muscle wasting and reduced or absent tendon reflexes. Facial muscle weakness, presence of asymmetric weakness of the limbs, or pyramidal signs should prompt further workup to rule out other neurologic causes of weakness. Assessment of peripheral muscle strength can sometimes be difficult in uncooperative patients because of the use of sedative-hypnotic agents or the presence of either delirium or metabolic encephalopathy. Nevertheless, if motor strength assessment is possible, the clinician can perform a standardized muscle examination to assess the degree of weakness in individual muscle groups. The diagnosis of CIPNM is supported by nerve conduction and EMG (electroneuromyography [ENMG]) studies, which typically show the presence of axonal polyneuropathy with or without the presence of concomitant myopathy. In axonal polyneuropathy, ENMG testing shows a reduction in the amplitude of the compound action potential with normal

conduction velocity on motor nerve stimulation, and spontaneous electrical activity on muscle needle recording. This ENMG pattern can be seen in 70% to 100% of ICU patients with severe sepsis and after 5 to 7 days of mechanical ventilation. On ENMG, the presence of a prolonged compound muscle action potential and a short duration and low amplitude of motor unit potentials on voluntary activation suggest a myopathic pattern. Creatine phosphokinase (CPK) levels are either normal or slightly elevated in CIPNM. Muscle and nerve biopsies can confirm the diagnosis but are not routinely indicated. Muscle biopsy usually shows type II fiber atrophy and occasionally type I atrophy and muscle necrosis. Immunohistochemistry and electron microscopy show a loss of myosin thick filaments. In the right clinical setting, extensive neurologic testing or biopsy of the nerve or muscle is not required to make a confident diagnosis of CIPNM. The differential diagnosis of muscle weakness in the ICU encompasses multiple central nervous system pathologies, including head and spinal cord injury. In acute spinal injury, spinal shock may cause quadriparesis and areflexia mimicking polyneuropathy. Muscle weakness associated with ptosis and bulbar weakness suggests a neuromuscular junction disease such as myasthenia gravis. Axonal variants of Guillain-Barré syndrome are distinguished by the presence of weakness before admission to the ICU, a preceding history of C jejuni infection, and a positive serologic test for anti-GM1 or anti-GD1a antibodies. Prolonged use of neuromuscular blocking agents, especially in the presence of hepatic and renal failure, can lead to persistent neuromuscular blockade due to delayed clearance of the drugs. Because no specific treatment for CIPNM exists, avoidance of recognized risk factors is important in decreasing the incidence and the morbidity and mortality associated with this disease process. Preventive measures include appropriate blood glucose control, avoidance or minimization of corticosteroids and/or neuromuscular blocking agents, early mobilization and physical therapy, and institution of a daily interruption of sedation to avoid sedation-related immobilization. Early mobilization in patients on mechanical ventilation improves both shortand long-term functional recovery. When physical and occupational therapy are implemented at the start of respiratory failure, early mobilization leads to improved functional independence at the time of

hospital discharge, decreased duration of mechanical ventilation, decreased delirium, and increased walk distance. Early mobilization is safe even in critically ill patients.86–88 For patients who survive the acute phase of their injury, CIPNM prolongs the ICU and hospital length of stay, extends the duration of mechanical ventilation, and increases mortality. Indeed, CIPNM is a predictor of prolonged mechanical ventilation. Clinical recovery of nerve function often takes a long time and is usually associated with residual weakness that causes persistent functional impairment. In patients with acute respiratory distress syndrome followed for 1 year, muscle wasting and weakness were the most significant extrapulmonary complications that contributed to persistent functional impairment.89 Long-term follow-up shows that approximately one-third of the patients with CIPNM had persistent neurologic deficits in the form of absent or reduced deep tendon reflexes, glove-and-stocking sensory loss, muscle atrophy, painful hyperesthesia, and persistent severe disability due to quadriparesis, quadriplegia, or paraplegia.90,91 Respiratory Recap Critical Illness Polyneuromyopathy ∎ Critical illness polyneuromyopathy is the most common cause of weakness in the ICU. ∎ Acute ICU myopathy is the most common form of CIPNM. ∎ CIPNM often leads to failure to liberate from ventilatory support in patients with severe sepsis and multisystem organ failure. ∎ Quadriparesis in an awake ICU patient following severe sepsis is the usual presentation. ∎ Control of hyperglycemia can decrease the incidence of CIPNM.

Stop and Think What would you recommend to reduce the risk of critical illness polyneuromyopathy in mechanically ventilated patients?

Disorders of the Neuromuscular Junction Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune disorder characterized by impaired transmission of neural impulses across the neuromuscular junction due to the destruction of the postsynaptic acetylcholine receptors. The most common neuromuscular transmission disorder, it has an estimated incidence of 10 to 20 cases per million people and a prevalence of 100 to 200 cases per million. Younger women of childbearing age are affected twice as frequently as men. Thymic tumors are seen in 10% of cases, mostly in older men. The typical presentation of the patient with MG is fluctuating weakness of the involved voluntary muscles that improves with rest or with the administration of anticholinesterase agents (positive Tensilon test), or both. Ocular, facial, and neck muscles are commonly involved. In the generalized form of the disease, variable involvement of bulbar, limb, and respiratory muscles also occurs. Bulbar muscle weakness such as dysarthria, dysphagia, and fatigable chewing is the initial presenting symptom in 15% of cases. Approximately 50% to 60% of patients with the ocular form of the disease progress to generalized weakness involving the oropharyngeal muscles, diaphragm, and other respiratory muscles and limbs within the first two years of the onset of symptoms. Respiratory muscle weakness is seen in one-third of patients and may occur in the absence of peripheral muscle weakness. On physical examination, the clinician can elicit fatigability of the involved muscles by asking the patient to do a repetitive or sustained muscle activity, such as looking upward for several minutes to elicit lid or ocular muscle weakness. The Tensilon test can be done at the bedside to confirm the diagnosis of MG. Tensilon (edrophonium), a short-acting inhibitor of acetylcholinesterase, can be given intravenously to elicit a transient improvement in muscle weakness. However, the test is now seldom performed because of limited availability of edropphonium. A positive Tensilon test highly suggests MG, but a positive test has also been reported in patients with Lambert-Eaton syndrome, botulism, and ALS.92

In patients with moderately generalized MG, pulmonary function testing reveals a mild reduction in FVC and a moderate reduction in both inspiratory and expiratory strength, indicating respiratory muscle weakness. Antibodies to acetylcholine receptors are seen in 80% of patients with generalized myasthenia and 60% of those with ocular myasthenia. The concentration of the acetylcholine receptor antibodies does not correlate with the severity of disease. Acetylcholine receptor antibodies have been found in Lambert-Eaton syndrome and in systemic lupus erythematosus. The presence of anti–muscle-specific kinase (anti-MuSK) antibodies identifies a subgroup of patients with MG who have a higher incidence of bulbar weakness (100% versus 58%) and respiratory failure (46% versus 7%) compared with seronegative patients.93 Greater involvement of the respiratory muscles was also reported in patients who tested positive for anti-MuSK. Electrodiagnostic studies are nonspecific for MG but characteristically show a 10% to 15% decrease in amplitude of the action potential during slow repetitive stimulation in 77% of patients with MG. Single-fiber EMG is abnormal in 92% of the patients and is thought to be the most sensitive test, even in patients with a negative serum antibody against acetylcholine receptor or a normal repetitive nerve stimulation test. Respiratory muscle weakness can occur in the absence of peripheral muscle weakness, but typically occurs late in the disease process. In patients with moderately generalized MG, performance of pulmonary function tests before the administration of Mestinon (pyridostigmine) reveals mild reduction in FVC and moderate reduction in both maximum static inspiratory (46% of predicted) and expiratory pressures (48% of predicted). As in patients with other chronic NMD, the breathing pattern of patients with MG is rapid and shallow. After Mestinon treatment, FVC, FEV1, PImax, and PEmax show significant improvement, although respiratory muscle strength does not completely normalize. Arterial blood gas examination is unreliable in predicting the severity of respiratory muscle weakness. Acute respiratory failure usually occurs in the setting of either myasthenic or cholinergic crisis or as the initial presentation of the disease. Myasthenic crisis refers to an exacerbation of MG leading to respiratory failure that necessitates the use of mechanical ventilation.

This is usually precipitated by discontinuation or decrease in the dosage of anticholinergic medications, surgery (thymectomy), administration of neuromuscular blocking medications (e.g., aminoglycosides, curare-like drugs), or emotional crisis. Myasthenic crisis is confirmed by performing Tensilon testing that results in an improvement in muscle strength. Approximately 15% to 20% of patients with MG experience myasthenic crises, often in the first year of illness. Thymomas are associated with a more fulminant course of MG and are present in one-third of patients who experience myasthenic crises. The initiation of corticosteroid therapy can paradoxically cause a transient increase in muscle weakness during the first and second weeks of therapy, especially in patients with severe bulbar symptoms and generalized MG. Cholinergic crisis is worsening of motor weakness due to an excess of anticholinesterase medications, which causes depolarizing blockade at the myoneural junction. This condition can be diagnosed and differentiated from myasthenic crisis by the presence of muscarinic symptoms such as hypersalivation, sweating, an increase in bronchial secretions, nausea and vomiting, and diarrhea. In addition, these symptoms may worsen with Tensilon testing. Nicotinic symptoms such as fasciculations and cramps are rare. A brittle crisis occurs when the disease is difficult to treat and the patient alternates between myasthenic and cholinergic crises. Surgery after thymectomy can precipitate acute respiratory failure. In one series, the mean duration of mechanical ventilation was 8 days, with 32% of patients requiring tracheostomy for prolonged mechanical ventilation.94 Postoperative care of these patients has important implications because respiratory failure usually occurs within 24 hours of surgery in more than 50% of patients. Serial measurements of VC, PImax, and PEmax are helpful in detecting the onset of respiratory failure. Clinicians should recognize that the dosing schedule of anticholinesterase medications will affect the measurement of respiratory parameters. The maximum improvement in respiratory muscle strength occurs approximately 2 hours after the drug is given and then slowly declines before the next dose is given. Consequently, care providers should measure VC, PImax, and PEmax 30 minutes before giving the next dose of anticholinesterase agents. No single respiratory parameter

reliably predicts the need for mechanical ventilation. Once VC is less than 15 mL/kg, PImax is greater than –30 cm H2O, and PEmax is less than 30 cm H2O, assisted ventilation should be considered.95,96 Other clinical signs of impending acute respiratory failure include signs of upper airway obstruction due to vocal cord paralysis or inability to handle secretions due to severe bulbar involvement. Flow-volume loop analysis may show variable extrathoracic airway obstruction with the characteristic inspiratory plateau seen in cases of upper airway obstruction. Bilateral basal atelectasis on chest radiograph signifies poor clearance of airway secretions due to a weak cough and is often accompanied by a rapid, shallow breathing pattern. Hypercapnia is a late sign of respiratory muscle fatigue. Several clinical parameters have been proposed as predictors of postoperative respiratory failure after thymectomy. Severity of disease (Osserman groups 3 and 4), especially with the presence of bulbar symptoms and low VC, appears to be the most important factor in predicting postoperative respiratory failure. In patients who develop respiratory failure following transsternal thymectomy, independent predictors of postoperative myasthenic crises causing acute respiratory failure include preoperative bulbar symptoms, higher serum levels of acetylcholine receptor antibodies (>100 nmol/L), and intraoperative blood loss.94,95 Patients with MG may also experience sleep-related breathing disturbances. Abnormal sleep study results in MG patients usually reveal mixed central apneas and hypopneas. Patients should be asked about sleep-related symptoms such as daytime hypersomnolence, nocturnal and early morning awakening, and morning headaches. Older patients with moderate obesity and daytime alveolar hypoventilation and restrictive lung defect should undergo sleep studies to screen for sleep apnea and nocturnal hypoventilation. The incidence of sleep apnea is higher in patients with a longer duration of MG. Treatment of MG includes anticholinesterase agents, high-dose corticosteroids, and plasmapheresis in patients who are refractory to steroids and immunosuppressive therapy. Anticholinesterase agents are the first-line treatment. Although most patients will improve significantly with this treatment, only a few will regain normal function. Remission can be induced in as many as 80% of patients with corticosteroids. Initiation

of corticosteroid therapy may cause temporary worsening of muscle weakness, usually on days 6 to 10 of therapy. Thus, clinicians should closely observe these patients for signs of respiratory insufficiency. Other immunosuppressive agents (e.g., azathioprine, cyclosporine) are also useful in MG either alone or in combination with steroids. Thymectomy has been shown to improve survival and clinical symptoms even in the absence of thymoma in patients with MG compared with patients who were treated medically. In patients who are younger than 55 years, thymectomy is recommended to prevent malignant transformation of the thymoma. As many as 80% of patients with no thymoma will improve clinically following thymectomy, but the response may be delayed. Because no randomized controlled studies have documented the benefit of thymectomy in MG, and given the presence of confounding variables such as age, gender, and severity of disease, the American Academy of Neurology recommends thymectomy in patients with nonthymomatous autoimmune MG only as an option to increase the probability of remission or improvement.97 In patients with MG and myasthenic crisis, plasmapheresis and IVIG are effective short-term treatments and help prepare the symptomatic patient for surgery.98 Improvement in muscle strength usually becomes apparent in 2 to 3 days, but that improvement does not continue beyond several weeks unless the patient receives concurrent immunosuppressant agents. IVIG given at 1.2 to 2 g/kg over 2 to 5 days has been shown to result in a clinical response comparable with plasmapheresis. However, in a study of patients with myasthenic crisis, plasmapheresis increased the ability to extubate the patient and improved the patient’s functional status at 2 weeks. Immunosuppressant medications are not appropriate therapy in myasthenic crises because the therapeutic response to these agents is often delayed for weeks to months. Corticosteroids have been used in patients who were refractory to plasmapheresis or IVIG, but may cause a transient worsening of muscle weakness. Corticosteroids and cholinesterase inhibitors are best started several days after a clinical response to plasmapheresis is observed so as to avoid weakness due to corticosteroids and to avoid cholinergic crises. Acute respiratory failure in patients with MG is usually treated with invasive mechanical ventilation. Noninvasive mechanical ventilation is an

alternative ventilatory strategy in patients with severe myasthenic crises with early respiratory failure even in the presence of bulbar symptoms. In a retrospective study, NIV and invasive mechanical ventilation were the initial method of ventilatory support in 67% of episodes of acute respiratory failure.99 In the NIV group, 58% were successfully treated with NIV alone and 52% eventually required invasive mechanical ventilation. The use of NIV avoids the need for airway intubation, decreases the duration of mechanical ventilation, and decreases both ICU and hospital length of stay. The only predictor of failure of NIV to initially treat respiratory failure in MG is PaCO2 > 45 mm Hg. Ideally, NIV will be used early in acute respiratory failure, before the onset of hypercapnia. In patients who require invasive ventilatory support, aggressive respiratory management including the use of sighs, positive end-expiratory pressure, frequent suctioning, chest physiotherapy, turning in bed, and the use of antibiotics can decrease the prevalence of both atelectasis and bronchopneumonia.100 Spontaneous breathing trials can be initiated once the patient’s respiratory status improves. Evidence of such improvement includes PImax < –20 cm H2O, PEmax > 40 cm H2O, and FVC > 10 mL/kg. In a retrospective study of acute respiratory failure due to MG, extubation failure (defined as the need for reintubation, tracheostomy, or death on the ventilator) occurred in 44% of cases. Risk factors associated with extubation failures included male sex, history of previous myasthenic crises, atelectasis, and more than 10 days of mechanical ventilation. The FVC, PImax, and PEmax were worse in patients who failed extubation but were not statistically different compared with patients who were successfully extubated. Those patients who had lower pH, lower FVC, the presence of atelectasis, and the need for NIV support had a higher risk for reintubation.101 These data suggest that other factors—such as respiratory muscle fatigue, the presence of bulbar weakness, and the inability to handle upper airway secretions—are not measured by standard weaning parameters and should be considered before attempting extubation. Respiratory Recap Myasthenia Gravis

∎ Myasthenia gravis is an autoimmune disease presenting as fluctuating weakness of the ocular, facial, and neck muscles. The muscle weakness improves with anticholinesterase agents. ∎ In generalized MG, respiratory muscle weakness can lead to acute respiratory failure. ∎ Both myasthenic and cholinergic (due to excess of anticholinesterase medications) crises can lead to acute respiratory failure. ∎ Surgery can precipitate postoperative respiratory failure. ∎ Noninvasive ventilation can be helpful in the management of respiratory failure.

Lambert-Eaton Syndrome Lambert-Eaton syndrome (LEMS) is a rare myasthenic-like disorder resulting from impaired release of acetylcholine from presynaptic terminals. Antibodies against the voltage-gated calcium channel, a large transmembrane protein, interfere with the normal calcium flux necessary for the release of acetylcholine into the neuromuscular synapse. LEMS is commonly associated with small cell carcinoma of the lung, but has also been reported in patients with Hodgkin lymphoma, atypical carcinoid, and malignant thymoma. The prevalence of this syndrome in patients with small cell lung cancer is estimated to be 3%.102 It can occur throughout the course of the underlying disease, but can also serve as a marker of undiagnosed malignancy. In patients without malignancy, LEMS has been associated with autoimmune disorders such as type 1 diabetes mellitus and autoimmune thyroid disorders. Unlike in MG, limb and girdle muscles are predominantly involved in LEMS—more so than ocular and bulbar muscles. An improvement in muscle strength after a brief isometric contraction known as postexercise facilitation is a unique feature of LEMS that is not seen in MG. It can be observed physiologically as post-excitation facilitation—that is, as increased amplitude of the compound action potential on high-frequency repetitive nerve stimulation. Although respiratory failure is infrequent, respiratory muscle weakness is often detected on pulmonary function tests. Acute respiratory failure has been reported as the initial manifestation of LEMS and should be considered as a differential diagnosis in patients with neuromuscular weakness.100 The diagnosis of LEMS is confirmed by the presence of antibodies against the voltagegated calcium channel and electrodiagnostic studies.

Botulism Botulism is a rare disorder caused by a toxin produced by Clostridium botulinum. The toxin may be ingested via improperly cooked food, wound contamination by the organisms, or absorption of the toxin from the gastrointestinal tract, particularly in infants. Eight types of toxins are distinguished, with types A, B, and E causing human disease. Botulinum toxin binds with the calcium channel in the presynaptic terminals, impairing neuromuscular transmission of acetylcholine. Cases of botulism in adults are usually due to small outbreaks from ingestion of contaminated home-canned fruits and vegetables, fish, or aged meats. This disorder has also been reported among IV drug users and, rarely, following unlicensed use of botulinum toxin use for cosmetic reasons. Gastrointestinal symptoms predominate early in the course of the disease, followed by neurologic impairment including descending paralysis of the neck, trunk, and limb muscles. Botulism should be suspected in patients with bilateral cranial palsy or descending symmetrical paralysis, in the absence of fever. Patients may experience weakness of the respiratory muscles requiring ventilatory support, especially with exposure to botulinum type A toxins. Spirometry usually reveals a restrictive ventilatory defect. Acute respiratory failure is the most common cause of death in patients with botulism. Recovery from respiratory muscle weakness may take months, requiring prolonged ventilatory support. The average duration of ventilatory support for type A poisoning is 58 days, in contrast to 26 days for type B botulism.103 Exertional dyspnea and poor exercise tolerance may persist even when patients regain normal lung functions. Treatment includes ventilatory support in patients with respiratory failure, along with administration of antitoxin.

Inherited Myopathies Muscular dystrophies refer to a heterogeneous group of progressive, hereditary degenerative skeletal muscle diseases. The respiratory muscles, like any skeletal muscles, become progressively weaker with these conditions, eventually culminating in respiratory failure and death. In fact, respiratory complications are the most common cause of death in patients with these diseases.

Duchenne and Becker Muscular Dystrophies Both Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are progressive myopathies inherited as X-linked recessive traits. DMD is the most common muscular dystrophy, with an incidence of approximately 1 in 3300 male births and a prevalence rate of about 3 per 100,000. Becker muscular dystrophy is less common than DMD and usually has a milder clinical course. Both diseases are caused by mutation of the gene for skeletal protein dystrophin. Dystrophin gene mutations are caused by gene deletions in 65% of patients with DMD and 85% of patients with BMD. The dystrophin protein is thought to stabilize the membrane-bound dystrophin-associated glycoprotein complex and prevent it from degradation. The loss of this associated protein as a result of dystrophin deficiency leads to the degenerative changes observed in muscular dystrophy. Several potential therapeutic agents targeting the defective gene and its abnormal dystrophin protein are in active clinical trials. Exon skipping agents such as eteplirsen and drisapersen are gene product modifiers that act on RNA to correct mutations in the dystrophin gene. Several novel therapeutic agents targeting the downstream effect of the dystrophin gene mutation are in development as well. Patients are usually symptomatic early in life, with symptoms usually becoming evident at 2 to 3 years of age. Early presenting symptoms include gait disturbances and delayed motor development. Transient improvement may be seen between 3 and 6 years of age (honeymoon period) in DMD, followed by relentless deterioration and becoming

wheelchair bound by age 13 years. In contrast, patients with BMD have a milder clinical course and usually do not become wheelchair bound until age 16 years or older. Physical examinations show limb-girdle muscle weakness and pseudohypertrophy of the calf muscles. Muscle weakness is symmetric and selectively affects the proximal and lower limb muscles first, before appearing in the distal and upper-extremity muscle groups. When trying to stand from the floor, affected children often use hand support to push themselves to an upright position (Gower sign). Leg pain is a prominent symptom early in the disease. Cardiomyopathy is common in patients with these disorders and becomes clinically significant during the teenage years. In a variant of muscular dystrophy called X-linked dilated cardiomyopathy, heart failure occurs early on because the heart muscle is primarily involved. Cognitive impairments in areas of working memory and executive function have been reported. Intestinal hypomotility, presenting as pseudo-obstruction, is a recognized complication in DMD. This gastrointestinal manifestation is thought to be due to smooth muscle degeneration. The diagnosis of DMD is based on myopathic symptoms and signs, markedly increased creatine kinase values, myopathic changes on EMG, and muscle biopsy. A positive family history also is helpful in supporting the diagnosis. The diagnosis is confirmed by a mutation of the dystrophin gene in DNA from peripheral leukocytes or by the absence of or an abnormal dystrophin gene in muscle biopsy. Despite modern respiratory care and better understanding of the abnormal pulmonary mechanics of this disease, survival after the age of 25 is rare. The most common cause of death is progressive respiratory insufficiency and heart failure due to cardiomyopathy. In BMD, the onset of the disease usually occurs between the ages of 5 and 15 years and in some instances in the third to fourth decades of life. The pattern of muscle weakness resembles that seen in DMD but is markedly milder. Cardiac and cognitive impairments are uncommon, and most patients do not have gastrointestinal involvement. Patients with BMD usually remain ambulatory beyond 16 years and into early adulthood, and live beyond the age of 30 years. Death, as a result of respiratory failure and cardiomyopathy, usually occurs between 30 and 60 years of age. Pulmonary symptoms of DMD and BMD are often minimal early on

despite significant weakness of the respiratory muscles. Serial pulmonary function tests and selected ancillary procedures, such as chest radiography and polysomnography, can detect the severity of respiratory muscle weakness and the onset of secondary complications such as scoliosis, abnormal chest wall mechanics, atelectasis due to ineffective cough, and sleep-related breathing disorders. Measurements of FVC, PEmax, and PImax, when done correctly and in serial fashion, are simple and reproducible tests that can facilitate the assessment of respiratory muscle strength. Clinicians must remember, however, that FVC increases with growth during the first decade, before it plateaus and progressively decreases—a pattern that may mask early respiratory muscle dysfunction. After age 12 years, VC decreases by about 5% to 6% per year in patients with DMD and BMD. PImax is more useful during the formative years because it declines gradually despite body growth. In patients ages 10 to 18 years with DMD, there is a good correlation between PEF % predicted, FVC % predicted, and FEV1 % predicted. By comparison, there is greater intra-subject variability with PEmax and PImax. The yearly declines in PEF (–8.9%), FVC (–8.7%), and FEV1 (–10.2%) are greater compared to the declines in PImax (–4.5%) and PEmax (–2.8%). A significant decrease in PEF is associated with loss of upper limb function.104 Once the initial screening tests show respiratory muscle dysfunction, a more complete battery of pulmonary tests may be needed to further define respiratory muscle endurance, the extent of expiratory muscle weakness, selective weakness of specific respiratory muscle groups, and abnormalities in lung and chest wall mechanics. Once the FVC falls below 1 L, the median survival is 3.1 years, and the 5-year survival is only 8%. FEV1 < 40% is a sensitive predictor of sleep hypoventilation. Daytime hypercapnia occurs when FEV1 < 20%.105 Kyphoscoliosis is common and may contribute to a restrictive ventilatory defect. Maximum voluntary ventilation is useful to detect respiratory muscle fatigue, but should be avoided in severely weakened patients. Measurement of PEmax is important because involvement of the expiratory muscles (PEmax < 60 cm H2O) will lead to ineffective cough and inability to handle airway secretions. Because maximum inspiratory

pressure measures global inspiratory muscle strength, the clinician may miss the predominant involvement of the diaphragm muscle unless transdiaphragmatic pressure is measured using a balloon catheter in the esophagus and the stomach. This procedure is invasive, and many patients may not be able to tolerate it. Alternatively, weakness of the diaphragm can be inferred noninvasively by a >25% decrement in VC from the seated to supine position and by fluoroscopic visualization of diaphragmatic excursion (sniff test). These noninvasive tests are not always sensitive enough, however, especially in patients with mild diaphragm weakness. Although respiratory muscle weakness is progressive, hypercapnia is uncommon in the absence of complicating pulmonary infections. The maintenance of alveolar ventilation in early disease suggests that patients with DMD retain intact diaphragm function until late in the course of the disease. Once hypercapnia sets in, the course is rapidly progressive and prognosis is poor. Mean duration of survival after onset of hypercapnia is approximately 10 months.106 Hypoxemia due to ventilation-perfusion inequality is common in patients with moderate to severe disease. Because patients with muscular dystrophy primarily use the diaphragm to perform ventilation, nocturnal hypoventilation may be especially beneficial during REM sleep, when activity of the chest wall and neck muscles is diminished. Indeed, REM-induced hypoventilation has been documented even in patients with normal daytime gas exchange.107 Sleep-related hypoxemia may contribute to respiratory insufficiency and to the development of cor pulmonale. Hypoxemia is worst during REM sleep, when the accessory muscles do not contribute to ventilation. Supplemental oxygen may prolong the episodes of hypopnea and apnea, but does not appear to have clinically significant benefits. NIV has been used successfully in patients with sleepdisordered breathing and DMD.108,109 In patients with DMD who had pronounced nocturnal oxygen desaturation but normal daytime blood gas values, nocturnal NIV was successfully used to prevent nocturnal oxygen desaturation. Moreover, the progressive decline in lung function appeared to be attenuated with NIV for as long as 2 years in follow-up.108 Corticosteroids have been shown to improve muscle strength and increase the number of years of effective ambulation as well as to

prevent decline in FVC and PImax. In one study, prednisone given at a dose of either 0.75 mg/kg per day or 1.5 mg/kg per day resulted in increased muscle strength and reduced the rate of decline of muscle weakness.110 Improvement can usually be seen within 10 days of therapy and requires at least 0.75 mg/kg per day of prednisone. Maximal improvement is usually seen at 3 months and is sustained for about 3 years. Ultimately, the side effects associated with prednisone (e.g., weight gain, hypertension, behavioral changes, growth retardation, and cataracts) usually necessitate dose reduction of this medication to 0.35 mg/kg per day.111 A synthetic derivative of prednisone, deflazacort, has a better sideeffect profile compared with prednisone, especially regarding weight gain. Deflazacort and prednisone are equally effective in slowing the decline of muscle strength and improving muscle strength and functional performance.112 A meta-analysis of 15 studies reported that deflazacort improves strength and motor function, but its benefits over prednisone remain unclear.113 Oxandrolone, a synthetic anabolic steroid, has also been shown to have a beneficial effect comparable with prednisone. In a randomized controlled trial, oxandrolone significantly improved the mean change in quantitative muscle strength but not the average manual muscle strength when compared with placebo.114 Investigational treatment options include gene and stem cell therapy, aminoglycosides, creatine monohydrate, and cyclosporine. Idebenone, a short-chain benzoquinone, is a potent antioxidant and inhibitor of lipid peroxidation. In a phase 3 trial, idebenone attenuated the decline in PEF, FVC, and FEV1 compared to placebo.115 The gene mutation known as a stop codon is present in as many as 15% of patients with DMD. Aminoglycosides have been shown to suppress the stop codons by misreading of RNA, allowing insertion of different amino acids at the site of the stop codon.116 In the mdx mouse, treatment with gentamicin resulted in dystrophin expression at 10% to 20% of the level detected in normal muscle. All patients with DMD and BMD should be encouraged to maintain ambulation so as to retard the development of scoliosis. Surgical correction of severe scoliosis may partially correct the restrictive ventilatory defect, although studies show no significant improvement in

respiratory function in patients who undergo spinal fusion surgery. Table 44-5 presents guidelines for perioperative management of patients with DMD. NIV and assisted coughing techniques should be initiated before the contemplated procedure if FVC < 50% and peak cough flow < 270 L/min.117 Potential cardiac and gastrointestinal complications should be anticipated and treated appropriately. General physiotherapy is important in preventing contractures. TABLE 44-5 Guidelines for Perioperative Management of Patients with Duchenne Muscular Dystrophy Before Procedure

During Procedure

After Procedure

Consult anesthesiology, pulmonary, cardiology

Succinylcholine should be avoided

Consider extubation to NIV

Measure preoperative FVC, PImax, PEmax, CPF, SpO2; FVC < 50%: consider NIV; CPF < 270 L/min: consider manual and MIE training

Options for respiratory support include endotracheal intubation, laryngeal mask airway, and NIV

Use supplemental oxygen cautiously Monitor SpO2 and end-tidal CO2 Look for hypoventilation, atelectasis, airway secretions

Optimize nutritional status

Consider assisted ventilation if FVC < 50%, especially if FVC < 30%

Use manually assisted cough and MIE if PEmax < 60 cm H2O or CPF < 270 L/min

Discuss resuscitation parameters and advance directives, if applicable

Monitor SpO2 or end-tidal carbon dioxide intraoperatively

Adequate pain control; if sedation and hypoventilation occur, delay extubation for 24 to 48 hours or use NIV Treat constipation and consider prokinetic agents Initiate nutritional support if extubation delayed for more than 24 to 46 hours

CPF, cough peak flow; FVC, forced vital capacity; MIE, mechanical insufflation–exsufflation (cough assist); NIV, noninvasive ventilation; PEmax, maximum expiratory pressure; PImax, maximum inspiratory pressure; SpO2, oxygen saturation measured by pulse oximetry.

Patients with chronic NMD are at risk for respiratory muscle fatigue because weakened respiratory muscles are working against a high elastic load to maintain the same degree of alveolar ventilation. The effectiveness of respiratory muscle training varies, however, with some studies reporting substantial improvement whereas other studies show minimal or no significant improvement in respiratory muscle performance.118–120 Vigorous respiratory training could be hazardous in patients with advanced disease, as it may increase the ventilatory burden on already weakened respiratory muscles. Some reports indicate that patients with DMD may have defective nitric oxide release during exercise.121,122 Thus, respiratory muscle strength training is not recommended in this population. Proper nutrition is important in the maintenance of respiratory muscle function: VC declines as nutritional status deteriorates. In addition, PEmax and PImax correlate with body mass in both normal and malnourished persons. High-protein, low-calorie diets aiming to achieve the patient’s ideal weight may be beneficial. Nocturnal NIV in patients with DMD has been reported to improve survival and quality of sleep, decrease daytime sleepiness, improve wellbeing and independence, improve gas exchange, and attenuate the rate of decline of lung function compared with nonventilated control patients.123–126 Assisted ventilation is required once patients show signs of respiratory insufficiency or have symptoms of sleep-related breathing disorders. Once FVC falls to between 300 to 950 mL, or less than 50% of predicted values, assisted ventilation is often required. Chronic hypercapnic respiratory failure usually develops when the FVC is between 500 and 700 mL. NIV prolongs survival and attenuates the decline in FVC and MVV in patients with advanced DMD. Successful long-term assisted ventilation has been reported in DMD. NIV may be used initially for chronic alveolar ventilation, but all patients will eventually require invasive ventilation. Tracheostomy is eventually needed to provide access to the airway secretions in patients who are too weak to cough. Respiratory Recap Duchenne Muscular Dystrophy

∎ DMD is a sex-linked recessive disorder associated with progressive myopathy, culminating in respiratory failure. Becker muscular dystrophy is a milder form of the disease. ∎ To follow the progression of muscle weakness in DMD, measure serial vital capacity and maximum mouth pressures. ∎ Cardiomyopathy is common and can precipitate respiratory failure. ∎ Development of kyphoscoliosis can contribute to ventilatory pump failure. ∎ NIV can be used initially, but many patients ultimately require tracheotomy. ∎ Corticosteroid therapy may improve muscle strength and functional capacity for a few years.

Myotonic Dystrophy Myotonic dystrophy type 1 (MD type 1) is the most common form of hereditary muscular dystrophy in adults, with an estimated incidence of 1 in 8000. Inherited in an autosomal dominant fashion, this disease can present in two phenotypic forms based on the genetic abnormality. MD type 1 is known as Steinert’s disease, and MD type 2 is known as proximal myotonic dystrophy. MD type 1 is due to an amplified trinucleotide CTG repeat in the 3' untranslated region of the dystropia myotonica protein kinase gene on chromosome 19q13. MD type 2 is caused by a CCTG expansion located within intron 1 of the cellular nucleic acid binding protein gene on chromosome 3q21. In normal individuals, the two alleles contain between 5 to 50 copies of the CTG repeat. In patients with MD type 1, there are 50 to 80 copies of the CTG repeat in mildly affected or asymptomatic patients; symptomatic subjects have between 80 to 2000 or more copies. With MD type 2, the repeat DNA expansion does not correlate with the age of onset and disease severity. Both types of myotonic dystrophy lead to myotonia, cataracts, and cardiac conduction defects, although MD type 2 is usually a milder disease. The similarity in their clinical presentations despite fundamental differences in the underlying genetic defect suggests that the expanded repeats containing RNA form ribonucleic foci that disrupt the activities of the RNA binding proteins.127 Symptoms usually present during adolescence and early adulthood, although the syndrome may be recognized as early as infancy. The cardinal symptoms of myotonic dystrophy are myotonia (delayed

relaxation after contraction), weakness and wasting affecting facial muscles and distal limb muscles, frontal balding in males, cataract, cardiomyopathy with conduction block, multiple endocrinopathies (e.g., hyperinsulinism, diabetes, adrenal insufficiency, infertility), hypersomnia, low intelligence, and dementia. Chronic respiratory failure is common in patients with myotonic dystrophy even in the presence of only mild limb muscle weakness. This is due to the presence of several factors other than respiratory muscle weakness—such as increased respiratory elastance, low central ventilatory drive, and sleep-related breathing disorder—that act in concert to impair lung function. Moreover, myotonia of the respiratory muscles can contribute to increased work of breathing by increasing the impedance to breathing. Weakness of the expiratory muscles is much more severe compared with the effects on the inspiratory muscles in these patients. Weakness of the inspiratory muscles becomes severe once proximal muscle weakness becomes apparent, heralding the onset of alveolar hypoventilation. Early studies showed a high incidence of hypercapnia and blunted ventilatory response to CO2, suggesting abnormal central respiratory drive is a factor in myotonic dystrophy. Subsequent studies reported that these patients have either a normal or high central ventilatory drive. The abnormal ventilatory response to both hypoxia and hypercarbia has been attributed to respiratory muscle weakness and fatigue. In addition, these patients may have a chaotic breathing pattern due to impaired afferent input from the respiratory muscles. Daytime hypersomnolence, possibly due to a low central ventilatory drive or sleep apnea, may contribute to the high prevalence of chronic hypercapnia in these patients.128 Patients with myotonic dystrophy are particularly susceptible to general anesthesia and respiratory depressants, so clinicians should avoid prescribing general anesthesia and muscle relaxants for them. If surgery is required, postoperative respiratory monitoring is required. The presence of pharyngeal and laryngeal dysfunction manifesting as nasal speech increases the risks of aspiration. Sleep-related breathing disorders, both central and obstructive sleep apnea, are common in myotonic dystrophy. Nocturnal nasal positive pressure ventilation should be initiated once hypercapnia (PaCO2 > 50 mm Hg) and hypoxemia (SpO2 < 85%) occur.

Acid Maltase Deficiency Enzymatic defects in the metabolism of carbohydrates (glycogen) lead to an abnormal accumulation of glycogen in the liver, kidney, and cardiac and skeletal muscles. Acid maltase deficiency (Pompe disease) is a type II glycogen storage disease that arises because of a deficiency of the lysosomal enzyme responsible for the hydrolysis of both the alpha 1– 4 and alpha 1–6 linkages of glycogen. This rare (1 in 40,000 births), inherited, and often fatal disorder disables the heart and muscles. It presents in three clinical forms: infantile, childhood, and adult. In adultonset disease, onset usually occurs after age 20 years. The syndrome typically presents with truncal and proximal limb weakness. Respiratory muscle weakness invariably leads to respiratory failure and REMassociated breathing disturbances. Severe weakness of the diaphragm, out of proportion to limb muscle weakness, may be the predominant clinical manifestation of the disease, which results in respiratory failure. Patients with Pompe disease are often misdiagnosed because of the presence of nonspecific symptoms of fatigue, hypersomnolence, morning headaches, and orthopnea. The diagnosis of diaphragm weakness is suspected when paradoxical motion of the abdomen on inspiration is evident, leading to additional neurologic evaluation.129 Autopsy studies have shown predominant involvement of the proximal respiratory muscles, reflecting predominance of type 1 muscle fibers, which are less efficient in the synthesis and storage of glycogen compared with type 2 muscle fibers. Diagnostic studies reveal elevated serum muscle enzyme levels, myopathic changes on EMG, and vacuoles with glycogen content on muscle biopsy. The diagnosis is confirmed by reduced acid maltase content in muscle and urine assays. In patients with Pompe disease, inspiratory muscle training and a high-protein diet may be beneficial.130,131 Enzyme replacement therapy (alglucosidase alfa) has been shown to decrease heart size; maintain normal heart function; improve muscle function, tone, and strength; and reduce glycogen accumulation.

Facioscapulohumeral Muscular Dystrophy Facioscapulohumeral muscular dystrophy (FSH) is an autosomal

dominant dystrophy that primarily affects the face and the proximal portion of the upper extremities. The defective gene has been localized to chromosome 4q35. In normal subjects, the number of D4Z4 repeats in chromosome 4q35 ranges from 11 to more than 100. In contrast, most patients with FSH have 1 to 10 residual repeat units within the subtelomere of chromosome 4q. This forms the basis of the genetic testing, which is positive in 95% to 98% of patients with typical FSH. It has been hypothesized that deletion of D4Z4 repeat units in chromosome 4q35 leads to overexpression of one or more disease genes. In the infantile form of FSH, the disease manifests very early in life and is rapidly progressive; patients are usually confined to wheelchairs by the age of 9 to 10 years. In contrast, the classic form of FSH is slowly progressive, with long periods of disease inactivity. This disease usually affects young adults between the second and third decades of life. The initial manifestations of FSH usually consist of difficulty in raising the arms above the head and winging of the scapula. Facial weakness is manifested by the inability to close the eyes, purse the lips, and whistle. In 20% of patients with FSH, the disease also affects pelvic girdle and trunk muscles, which may impair respiratory function. Spirometry often shows decreased FVC, but facial weakness makes the test unreliable due to poor lip seal.

Limb-Girdle Muscular Dystrophy Limb-girdle muscular dystrophy comprises a heterogeneous group of muscle dystrophies that are mainly characterized by weakness of the shoulder and pelvic girdles, with sparing of the distal, facial, and extraocular muscles. The mode of inheritance varies, with the recessive forms being the most common. Similar to other congenital myopathies, symptoms usually become evident during childhood or early adult life. Late-onset disease usually has a benign course. In patients with this type of muscle dystrophy, creatine kinase is usually moderately elevated and EMG shows myopathic changes. Muscle biopsy reveals dystrophic changes with degeneration and regeneration of the muscle fibers, fiber splitting, internal nuclei, fibrosis, and moth-eaten and whorled fibers. Hypercapnic respiratory failure is uncommon even with moderate respiratory muscle weakness. Bilateral

paresis of the diaphragm may lead to ventilatory failure. Cardiac involvement is rare.

Mitochondrial Myopathy Mitochondrial myopathy, one of the manifestations of hereditary mitochondrial disorders, occurs due to a point mutation in mitochondrial DNA (gene mutation at 3250). This group of mitochondrial disorders can also affect other organ systems, particularly the brain. Mitochondrial disorders that manifest polymyopathy as part of the syndrome include myoneural–gastrointestinal encephalopathy; myoclonic epilepsy with ragged red fibers (MERRF); and mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS). Although the disease may present initially in childhood, onset during adulthood has also been described. The usual clinical manifestations consist of symmetric proximal muscle weakness that occurs in isolation or in association with central nervous system dysfunction and metabolic derangements. Acute respiratory failure as the initial presentation of the disorder has also been reported.132 Muscle biopsy is often required to confirm the diagnosis. Modified trichrome stains show marked enlargement of the mitochondria with a reddish tinge, the so-called ragged red fibers. No specific treatment is available for mitochondrial myopathy. Clinicians should avoid sedative drugs in patients with this disease.

Acquired Inflammatory Myopathies Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect almost all organ systems. The pulmonary complications of SLE can be classified as pleuritis and pleural effusions, acute lupus pneumonitis, interstitial lung disease, and respiratory muscle weakness. Respiratory muscle weakness and diaphragm muscle dysfunction may occur without significant limb weakness. Indeed, as many as 25% of patients with SLE have significant diaphragm weakness even in the absence of generalized myopathy. This diaphragm weakness can be apparent on the chest radiograph, which shows bilateral diaphragm elevation, which Hoffbrand and Beck called “the shrinking lung syndrome.”133

Steroid Myopathy Steroid myopathy results from the prolonged use of corticosteroids, sometimes over a period as short as 2 weeks of therapy. Myopathy can occur with any glucocorticosteroid preparation but is unusual in patients treated with less than 10 mg/day of prednisone or its equivalent. Concomitant use of high-dose corticosteroids and neuromuscular blocking agents in the ICU setting increases the risk of the development of critical illness myopathy. Glucocorticoids induce myopathy largely through their direct catabolic effects and interference with insulin-like growth factor-1 signaling, which leads to increased myocyte apoptosis. This condition usually manifests subacutely as proximal limb and girdle muscle weakness. Lower-extremity muscles tend to be involved earlier and much more severely than the upper-extremity proximal muscle groups. Thus, affected patients have difficulty climbing stairs, followed by difficulty combing their hair and reaching overhead for an object. Unlike in inflammatory myopathies, muscle enzyme levels are usually normal in steroid myopathy. EMG is either normal or reveals only slight myopathic changes. Muscle biopsy usually shows loss of type IIa muscle fibers, but no evidence of inflammation or fiber necrosis.

There is a poor correlation between the total dose of steroids and the severity of muscle weakness. A gradual improvement in muscle strength is usually observed with discontinuation or significant reduction in corticosteroid dosage in 3 to 4 weeks.

Treatment of Neuromuscular Dysfunction The proper care of these complicated patients with NMD often requires a multidisciplinary team of healthcare workers consisting of pulmonary specialists, respiratory therapists, pulmonary trained nurses, physiatrists, physical therapists, nutritionists, social workers, and clinical psychologists. Depending on the acuity of care required in an individual case, patients can be initially treated in an ICU setting until the resolution of their acute illness and then transferred to a respiratory rehabilitation unit specializing in the care of these patients. Frequent family interaction with the healthcare team can facilitate the transition of care from the hospital to home. It is helpful to admit patients with stable chronic respiratory failure to a noninvasive respiratory rehabilitation unit for a few days to familiarize them with the different types of noninvasive ventilator support available in a relaxed and supportive environment. The goals of therapy in the treatment of patients with chronic NMD are similar to those for other groups of patients with chronic lung disease: to maintain lung function and to restore and maintain an independent and functional lifestyle for as long as possible. Some patients with advanced disease will not be able to achieve these goals. Nevertheless, a rapid decline in lung function may be avoided by following judicious pulmonary rehabilitation practices such as use of respiratory aid devices to facilitate clearance of airway secretions; early use of noninvasive ventilation to augment alveolar ventilation, especially during periods of acute decline; and timely treatment of respiratory infections with appropriate antibiotics. Maintenance of proper nutrition is of utmost importance. Both obesity and undernutrition can further contribute to respiratory muscle dysfunction. The decreased chest wall compliance observed in obese patients will lead to an increased work of breathing and may induce respiratory muscle fatigue in already weakened respiratory muscles. Conversely, undernutrition may decrease respiratory muscle strength in a variety of chronic lung diseases. Respiratory Recap Treatment of Neuromuscular Dysfunction

∎ Respiratory muscle training may be helpful. ∎ Assisted coughing techniques are useful in clearance of airway secretions. ∎ Glossopharyngeal breathing (frog breathing) allows short periods of spontaneous ventilation in ventilator-dependent patients. ∎ Noninvasive ventilation includes positive and negative pressure devices, rocking beds, and pneumobelts. ∎ Diaphragmatic pacing is an option in ventilator-dependent patients with high cervical cord injury.

Respiratory Muscle Training Respiratory muscle training improves strength and ventilatory endurance in both normal subjects and patients with pulmonary diseases. The clinical benefits of regular exercise training focus specifically on increased ventilatory capacity and better airway clearance in patients with chronic NMD. Inspiratory muscle training may improve respiratory muscle endurance and strength in patients with muscular dystrophy.134 Concerns have been raised about the potential detrimental effects of respiratory muscle training in patients with advanced neuromuscular weakness. Breathing through resistive loads may lead to muscle fiber damage and fatigue already weakened respiratory muscles. Moreover, no study has correlated any improvement in respiratory mechanics with an improvement in clinical outcome. Inspiratory threshold devices are safe and may improve muscle strength and endurance, but their effectiveness in decreasing respiratory morbidities such as infection, shortening hospitalization stays, and improving quality of life has yet to be proved.135 Thus, the beneficial effects of respiratory muscle training remain unresolved.

Assisted Coughing Effective mucus clearance depends on the mucociliary escalator and cough. Cough is usually the limiting function in patients with a neuromuscular dysfunction. A weakness of inspiratory muscles such as the diaphragm will limit inspiratory volume. By contrast, a weakness in abdominal muscles will limit the ability to compress gas in the lungs. When the peak cough flow is less than 160 L/min (Figure 44-10), the

patient needs assistance in clearing secretions. Modalities that assist the patient with an ineffective cough include lung volume recruitment, quad cough, insufflator–exsufflator cough assist, and mechanical aspiration.

FIGURE 44-10 Peak cough flow meter with an air-cushion face mask.

To improve spontaneous cough efforts in patients with weak inspiratory muscle strength, either manual or mechanical insufflation may be performed. Manual hyperinflation with a resuscitator bag equipped with a one-way valve and mouthpiece can facilitate breath stacking (Figure 44-11). A series of breath-stacking maneuvers is applied until the lungs are maximally insufflated. Insufflation can also be administered mechanically using volume control ventilation with a mouthpiece. The stored elastic recoil energy of the patient’s lungs may produce a peak cough flow sufficient to clear secretions.

FIGURE 44-11 Resuscitator bag, one-way valve, flexible tube, and mouthpiece for manual hyperinflation.

The mechanical insufflator–exsufflator (MIE) cough assist inflates the lungs with a positive pressure and then produces a negative pressure to create a peak cough flow great enough to clear secretions. Selection of

positive and negative pressures—usually between 10 and 60 cm H2O— depends on patient tolerance and the effectiveness of the treatments. Inhalation and exhalation times of 1 to 3 seconds and a pause of 0 to 5 seconds may be selected. The ability of the patient to tolerate the settings and the effectiveness of the therapy will dictate the best settings. Most patients need an oronasal mask as the patient interface, but the cough assist can also be attached to a tracheostomy tube. Applying high insufflation pressures during MIE with mask in patients with ALS can be counterproductive.136 During insufflation, adduction of the patient’s true vocal folds, aryepiglottic fold adduction, and backward movement of the base of the tongue can all occur. Thus, the external pressures generated with MIE, especially during insufflation, can promote airway adduction at both the pharyngeal and laryngeal levels, thereby obstructing flow and disrupting the intended effects of the treatment. The quad cough is used to strengthen the patient’s cough efforts. The clinician places the thumb of each hand below the xiphoid process, with all fingers placed below the ribs. The patient then takes a deep inhalation and coughs on exhalation; the clinician pushes in and up as the patient coughs. Quad cough can be combined with hyperinflation or the cough assist (MIE). If the patient has excessive airway secretions, airway clearance therapies such as postural drainage, high-frequency chest wall compression, positive expiratory pressure (PEP), and oscillatory PEP can be used. However, the effectiveness of these therapies is often limited for patients with neuromuscular dysfunction. Inhaled bronchodilators also have limited value in patients with NMD unless they also have a pulmonary disease such as asthma. Tracheal suction can prove useful in some patients with a tracheostomy tube, but nasotracheal suction is not usually indicated. In patients with bulbar disease and poor swallowing function, oral suction is helpful.

Glossopharyngeal Assistance Glossopharyngeal breathing, also known as frog breathing, is a technique involving the use of oropharyngeal muscles to inject air into the trachea, thereby augmenting ventilation to provide short periods of

spontaneous ventilation, improve effective cough, and increase the volume of the voice. With this technique, the patient gulps in air by lowering and raising the tongue against the palate in a piston-like fashion, thereby injecting air into the trachea. With practice, patients may be able to gulp in 50 to 150 mL of air every half second. With six to eight successive gulps, a tidal volume of approximately 500 to 600 mL may be achieved and sustained for several hours, liberating the patient from ventilatory support. Although some patients have difficulty in learning and mastering the technique, patients with spinal cord injuries, postpoliomyelitis syndrome, and other NMDs have successfully used this technique. Stop and Think You are asked to assist in the care of a patient with neuromuscular disease who is having difficulty clearing airway secretions. What would you recommend?

Mechanical Ventilation Although ventilatory insufficiency leading to chronic respiratory failure is a common sequela of progressive NMD, acute respiratory failure is commonly seen after aspiration pneumonia, lower respiratory tract infections, or other acute illnesses that place an additional burden on already compromised ventilatory reserve. Pneumonia is the most common cause of increased morbidity and mortality in patients with advanced chronic NMD. Patients with an acute-onset NMD, such as Guillain-Barré syndrome, or exacerbation of a known NMD, such as myasthenic crisis, can present with acute respiratory failure. These patients are often transferred to the ICU for better respiratory monitoring. Once impending respiratory failure is recognized, mechanical ventilation should be used early to support spontaneous breathing until the care team can identify and treat the acute precipitating event. Table 44-6 lists the indications for mechanical ventilation. Bedside assessment of respiratory and bulbar functions can be monitored safely and serially in the ICU. Some of the early signs of impending respiratory failure include difficulty in speaking long sentences, moderate to severe orthopnea, nasal flaring, anxiety, and restlessness. Serial measurement

of the respiratory muscle function can inform early signs of respiratory failure. A useful mnemonic in considering intubation and the need for mechanical ventilatory support is the 20/30/40 rule: FVC < 20 mL/kg (normal 40–75 mL/kg); PImax > –30 cm H2O (normal male < –100 cm H2O; normal female < –70 cm H2O); and PEmax < 40 cm H2O (normal male > 80 cm H2O; normal female > 80 cm H2O). An effective cough requires FVC > 15 mL/kg and enough expiratory muscle strength to generate a cough peak flow > 160 L/min. Assessment of bulbar function is also important, as the inability to handle secretions will warrant early intubation and indicate whether the patient will likely tolerate NIV. TABLE 44-6 Indications for Mechanical Ventilation in Patients with Neuromuscular Disorders Disorder

Indications

Acute respiratory failure

Severe dyspnea Marked accessory muscle use Inability to handle secretions Unstable hemodynamic status Hypoxemia refractory to supplemental O2 Acute respiratory acidosis

Chronic respiratory failure



Nocturnal hypoventilation

Morning headache Lethargy Nightmares Enuresis

Nocturnal oxygen desaturation Cor pulmonale

SpO2 < 88% despite supplemental O2 Due to hypoventilation with PaCO2 > 45 mm Hg, pH < 7.32

In a Cochrane review, the authors were unable to find any randomized controlled trial comparing the efficacy of invasive ventilation versus NIV in patients with acute respiratory failure due to acute or chronic NMD.137 Thus, the care team must tailor the type of ventilatory support based on the condition of the individual patient. Invasive

mechanical ventilation is often necessary in patients with severe dyspnea, acute hypercapnia respiratory acidosis, moderate to severe hypoxemia, copious secretions, and hemodynamic instability. In contrast, NIV may be used to augment minute ventilation in patients who present with acute hypercapnic respiratory failure and who are alert and cooperative, with intact upper airway function and minimal airway secretions.1 For safety, the patient receiving NIV should be able to tolerate spontaneous breathing with supplemental oxygen for a short interval. Table 44-7 compares invasive ventilation and NIV in patients with NMD. TABLE 44-7 Clinical Factors Favoring Invasive Versus Noninvasive Mechanical Ventilation in Patients with Neuromuscular Disease Invasive Ventilation (Endotracheal Intubation)

Noninvasive Ventilation

Copious secretions Poor airway control Inability to tolerate or failure of noninvasive ventilation Impaired cognition Unstable hemodynamics

Awake, cooperative patient Good airway control Minimal secretions Hemodynamic stability

In patients who present with chronic respiratory failure or acute or chronic respiratory failure due to progression of their underlying NMD, NIV is effective in reversing hypercapnia and hypoxemia and is the treatment of choice because of patient comfort, effectiveness, and portability. Moreover, NIV decreases the incidence of pneumonia and reduces hospitalization rates of patients with NMD. In these patients, the manifestation of chronic respiratory insufficiency may be subtle, with the onset of dyspnea occurring gradually over days to weeks. Common complaints include lethargy, fatigue, daytime sleepiness, morning headache, and occasionally nightmares and enuresis. Such patients often have nocturnal hypercapnia with normal arterial gas values during daytime. Nocturnal oximetry or polysomnogram may be indicated to detect the presence of nocturnal oxygen desaturation and hypercapnia, which may contribute to daytime symptoms. The presence of nocturnal

hypoventilation usually leads to chronic hypercapnia and progressive symptoms of respiratory failure within 2 years. In a randomized controlled trial of patients with nocturnal hypercapnia and daytime normocapnia, nocturnal NIV decreased the severity of hypercapnia and improved arterial oxygen saturation. In patients randomized to the control group, 9 of 10 required NIV for daytime hypercapnia after 8.3 months.138 NIV can be divided into noninvasive positive pressure ventilation and noninvasive negative pressure ventilation. Table 44-8 lists the benefits and limitations of both forms of NIV. Noninvasive positive pressure ventilation is preferred over negative pressure ventilation because of its greater ease of use, portability, and maintenance of upper airway patency during sleep. In addition, noninvasive positive pressure better maintains alveolar ventilation and airway stability during sleep. Different types of masks may be used (e.g., nasal, oronasal, full face mask) depending on patient comfort and preference. In patients with significant mouth leaks, the use of a chin strap or changing to an oronasal or total face mask will often solve the problem. In chronic NIV, facial ulcers can rarely develop due to contact pressure from a particular mask interface. In this situation, rotating interfaces may promote healing of facial ulcers and prevent their recurrence. Alternatively, mouthpiece interfaces—either a generic mouthpiece with a plastic lip seal or a mouthpiece custom-fitted by orthodontics—have been used to administer ventilatory support in some patients.139 TABLE 44-8 Advantages and Disadvantages of Positive and Negative Pressure Ventilation Used in Patients with Neuromuscular Disease Type

Advantages

Disadvantages

Negative pressure ventilators (tank, Pulmowrap, cuirass)

Dependable Airway cannulation not required Minimal hemodynamic effect Maintenance of speech

Cumbersome Predispose patients to obstructive apnea Limit nursing care Controlled ventilation

Positive pressure by mask or mouthpiece

Avoids upper airway obstruction

Aerophagia Pressure sores

Pressure preset, compensates for leaks Patient-initiated machine breaths

Leaks Problems with interface

A wide variety of positive pressure ventilators may be used to deliver NIV. In the intensive care setting, use of a standard ICU ventilator allows either continuous mandatory ventilation or pressure support mode. Some features available in standard ventilators that are useful in the acute care setting include the ability to monitor the patient’s respiratory pattern and the delivery of supplemental oxygen. In patients with stable chronic respiratory failure, portable bilevel ventilators are widely used. The initial ventilator settings should be set low and slowly increased to achieve an increase in tidal volume of 30% to 50% and/or a decrease in PaCO2 of 5 to 10 mm Hg. The expiratory pressure during bilevel ventilation is usually set at 4 cm H2O to minimize rebreathing and maintain functional residual capacity. Supplemental oxygen can be titrated into the circuit of the bilevel ventilator, but is rarely necessary in patients with NMD. The duration of ventilatory assistance depends on the severity of respiratory failure and patient tolerance. In the acute setting, ventilatory assistance of 20 hours or more may be needed. In the chronic setting, patients may use NIV during the daytime for a few hours, followed by nocturnal use of 6 to 8 hours once they become accustomed to the NIV settings. A Cochrane review that included eight randomized or quasirandomized controlled studies on the efficacy of nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders concluded that NIV resulted in short-term improvement of symptoms of chronic hypoventilation, daytime hypercapnia, and nocturnal mean oxygen saturation compared with no ventilation. In the three studies that reported one-year mortality rates, the estimated risk of death following nocturnal ventilation was significantly reduced. The survival advantage of NIV was shown only in patients with ALS.42 In a meta-analysis of 10 studies of patients with neuromuscular and chest wall diseases, the risk ratio for mortality in four trials was 0.62 (95% confidence interval [CI], 0.42–0.91), favoring nocturnal NIV compared to

spontaneous breathing.124 In two trials that assessed unplanned hospitalizations, the pooled risk ratio was 0.25 (95% CI, 0.08–0.82), suggesting a protective effect of nocturnal invasive ventilation. Data from two trials suggested that volume-controlled ventilation may lead to shorter periods of hypoxemia and a lower apnea/hypopnea index. The meta-analysis authors concluded that, although the current evidence on the therapeutic benefit of nocturnal mechanical ventilation is of very low quality and suffers from the heterogeneity of the study subjects, the short-term benefits of improved survival and reduced hospitalization are consistent across studies, especially in patients with motor neuron disease and DMD. Based on the current evidence, it may be difficult to withhold NIV therapy in patients with chronic hypoventilation due to neuromuscular weakness. Negative pressure ventilators intermittently apply subatmospheric pressures to the thorax and abdomen to increase transpulmonary pressure and inflate the lungs. The efficacy of negative pressure ventilation is determined by thoracic and abdominal compliance and by the surface area over which the negative pressure is applied. Tank ventilators are the most efficient form of negative pressure ventilation because of the larger amount of body surface area covered compared with cuirass ventilators, which cover only the upper torso. Tank ventilators are reliable, but are seldom used today because they are large and cumbersome, have the potential to induce claustrophobia, and interfere with nursing care. Chest cuirass ventilators are more portable than tank ventilators but must be used in the recumbent position to be effective. A limitation to all forms of negative pressure ventilators is that they may induce obstructive sleep apnea due to upper airway collapse during a mechanically delivered breath. In patients with mild to moderate ventilatory failure, rocking beds and pneumobelts may be used, depending on patient preference, comfort, and the amount of ventilatory support required by the individual patient. These devices act as abdominal displacement devices that augment diaphragmatic motion by displacing abdominal viscera against gravity. The rocking bed consists of a mattress on a motorized platform that rocks in an arc of 40 degrees with the patient recumbent. As the bed moves with the head in a dependent position, gravity induces the abdominal contents and diaphragm to move cranially, assisting with exhalation. In

the next cycle, as the bed tilts upward, gravity acts to move the diaphragm and abdominal contents in a caudad direction, assisting inspiration. The bed rocks between 12 and 24 times per minute and may be adjusted to optimize patient comfort so as to achieve the desired minute ventilation. The pneumobelt is an inflatable bladder worn over the anterior abdomen and connected to a positive ventilator that intermittently inflates it. When the patient is seated upright, bladder inflation increases intraabdominal pressure, forcing the diaphragm cephalad and thereby inducing active exhalation. When the bladder deflates, gravity moves the abdominal contents and diaphragm caudally, thereby facilitating passive inspiration. Both rocking beds and pneumobelts are limited by the constraints they place on patients and posture and in terms of the amount of ventilatory assistance they provide. The rocking bed is bulky and stationary. Similarly, the pneumobelt requires that the patient use it in the upright posture, and some patients complain of pain and discomfort when high bladder inflation pressures are required to sufficiently augment ventilation. Impressive improvements in daytime gas exchange can be achieved even when NIV is used only at night or intermittently throughout the 24hour period. Moreover, patients can realize significant improvements in their symptoms and functional capacity. The exact mechanisms responsible for the improvement of daytime gas exchange in patients with NMD using chronic intermittent noninvasive ventilation are unknown. Some of the proposed mechanisms are that intermittent ventilatory assistance rests already fatigued respiratory muscles; the PaCO2 central threshold is reset by preventing nocturnal alveolar hypoventilation; ventilation-perfusion matching is improved; and the higher lung volume achieved during assisted ventilation improves lung and chest wall compliance, which then decreases the work of breathing.

Diaphragmatic Pacing Diaphragmatic pacing consists of a radio frequency transmitter and an antenna that discharges signals to a receiver to transmit electrical

impulses to an electrode placed over the phrenic nerve, or directly on the diaphragm in some cases. Both the electrodes and the receiver are surgically implanted. Electrode implantation around the phrenic nerves can be divided via a cervical and thoracic approach; however, the thoracic approach is preferred to ensure stimulation of all phrenic nerve roots while avoiding the brachial plexus. The subcutaneous receiver is usually positioned in the lower anterolateral rib cage to allow it to be superficial, but placed in an area where soft tissue movement is limited. The patients who appear to benefit most from this technology are ventilator-dependent patients following high cervical cord injury. In these cases, the central nervous system injury must be above the second or third cervical level, above the origin of the phrenic nerve root. Approximately one-third of patients with high cervical spinal cord injury may be suitable candidates for this type of treatment. Other potential candidates for diaphragmatic pacing include patients with central alveolar hypoventilation syndrome, and selected patients with brain stem tumors or infarctions that have affected central respiratory regulation. In addition, candidates should have normal cognitive function, complete respiratory muscle paralysis without recovery for 3 months, and viable, functional phrenic nerves. Indeed, bilateral intact phrenic nerve function is key to successful application of diaphragmatic pacing. Contraindications to diaphragmatic pacing include failure of the diaphragm to contract with percutaneous stimulation of the phrenic nerves, coma, and severe primary pulmonary disease. A period of diaphragm conditioning is necessary in patients who have had no diaphragm function for more than 6 months. Successful implantation and conditioning of the diaphragm allows the patients to be independent from ventilator support for prolonged periods of time and enables them to regain speech and olfaction.140,141 In patients with ventilatory failure due to high spinal cord injury, brain stem injury, and congenital central alveolar hypoventilation, long-term diaphragm pacing on a full-time basis is well tolerated in carefully selected patients. Direct diaphragm stimulation by a device inserted via laparoscopic technique can successfully liberate these patients from the ventilator for at least 4 hours each day in 96% of cases.140 For patients with ALS, however, diaphragmatic pacing is associated with increased mortality and is currently not recommended. The widespread use of

diaphragmatic pacing is limited by its high cost, the potential for sudden failure of the hardware, the development of upper airway obstruction after tracheotomy closure, and the induction of diaphragm fatigue.142

Key Points The various types of NMD impair the pump function of the respiratory muscles, leading to chronic respiratory failure or failure to liberate from mechanical ventilation. Severe respiratory muscle weakness may occur in the absence of clinical symptoms. Measurements of static respiratory muscle strength and vital capacity help predict impending respiratory failure. Sleep-related breathing disorders and nocturnal oxygen desaturation may occur and often precede changes in daytime gas exchange abnormalities. A strong clinical suspicion is often required for the proper diagnosis and treatment of NMD. Upper motor neuron lesions include stroke, spinal cord injury, Parkinson disease, and multiple sclerosis. Lower motor neuron lesions include amyotrophic lateral sclerosis, poliomyelitis, and postpoliomyelitis muscular dystrophy. Disorders of peripheral nerves include phrenic nerve injury, GuillainBarré syndrome, and critical illness polyneuropathy. Disorders of the neuromuscular junction include myasthenia gravis, Lambert-Eaton syndrome, and botulism. Inherited myopathies include Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, acid maltase deficiency, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, and mitochondrial myopathy. Acquired inflammatory myopathies include systemic lupus erythematosus, acute ICU steroid myopathy, and chronic steroid myopathy. NIV is the preferred mode of ventilatory assistance in patients with respiratory insufficiency who have intact bulbar function.

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CHAPTER

45 Sleep-Disordered Breathing Bashir A. Chaudhary Shelley C. Mishoe

© Andriy Rabchun/Shutterstock

OUTLINE Descriptions and Common Terms Screening for Sleep-Disordered Breathing Obstructive Sleep Apnea Central Sleep Apnea Restless Legs Syndrome

OBJECTIVES 1. 2. 3. 4. 5. 6. 7. 8.

Define obstructive sleep apnea (OSA). Compare OSA, central sleep apnea, and mixed apnea. Discuss the prevalence and pathogenesis of OSA. Describe the clinical features of OSA. Describe the systemic effects of OSA. Compare the advantages and disadvantages of various treatment strategies for OSA. Define central sleep apnea (CSA). Describe the conditions that encompass CSA, including idiopathic CSA, Cheyne-Stokes breathing, high altitude–induced periodic breathing, narcotic-induced central apnea, and obesity hypoventilation syndrome. 9. Describe the features and treatments for restless legs syndrome.

10. Discuss the common approaches for diagnosis and treatment of sleep disordered breathing in adults and children.

KEY TERMS adaptive servo-ventilation (ASV) apnea arousals bilevel positive airway pressure (BPAP) central apnea Cheyne-Stokes breathing complex sleep apnea syndrome continuous positive airway pressure (CPAP) hypersomnolence hypopnea mixed apnea obesity hypoventilation syndrome (OHS) obstructive apnea oral appliance positive airway pressure (PAP) polysomnography restless legs syndrome (RLS) sleep apnea uvulopalatopharyngoplasty (UPPP)

Introduction Sleep is an essential biological function that serves many purposes, ranging from regulation of metabolism and the immune system to memory consolidation. Research at the molecular level suggests that sleep’s basic purpose is to clear the brain of toxic metabolic by-products.1 Without adequate sleep, health is jeopardized due to safety risks from unexpectedly falling asleep and physiologic effects on the body that can lead to serious complications affecting the cardiac, pulmonary, psychological, sexual, endocrine, central nervous, renal, vascular, and ophthalmic systems. This chapter describes the most common sleep disorders, including obstructive sleep apnea, central sleep apnea, upper airway resistance syndrome, high-altitude periodic apnea, obesity hypoventilation syndrome, and restless leg syndrome. For central and obstructive sleep apneas, the chapter covers their prevalence and pathogenesis as well as their effects on the different systems of the body. Obstructive sleep apnea is characterized by chest and abdominal efforts to breathe during periods of airflow cessation. Central apnea is characterized by cessation of both the effort to breathe and airflow. Mixed apnea has characteristics of both types of apneas with central apnea at the beginning of the episode followed by obstructive apnea. Upper airway resistance syndrome (UARS) is a milder sleep-related breathing problem. In UARS, the sleep study does not show apneas, but the patient experiences an increased number of arousals related to increase in respiratory effort. This chapter discusses the advantages and disadvantages of various treatment strategies and describes how treatment can improve health and prolong life. Stop and Think Why do respiratory therapists need an understanding of sleep-disordered breathing?

Descriptions and Common Terms In the 1800s, symptoms suggestive of sleep apnea were well described in Charles Dickens’s novel The Pickwick Papers. Indeed, in 1906, William Osler, in his book The Principles and Practice of Medicine, referred to obese patients with uncontrollable sleepiness as Pickwickians, “like the fat boy Joe in Pickwick Papers.” The recognition of episodic cessation of breathing during sleep in drowsy patients heralded the modern era of sleep medicine. Sleep apnea is a chronic disorder characterized by daytime hypersomnolence, snoring, disrupted sleep, hypoxemia, and repeated episodes of hypopnea or apnea, or both, during sleep.2 Table 45-1 lists some of the common terms used for describing sleep-related breathing problems. TABLE 45-1 Definitions for Describing Sleep-Related Breathing Problems Term

Definition

Apnea Obstructive apnea Central apnea Mixed apnea

Cessation of airflow for at least 10 seconds Continuation of chest and abdominal effort during apnea Cessation of both airflow and the respiratory effort Both central and obstructive apnea characteristics

Hypopnea

Reduction of airflow by 30%, with oxygen desaturation of at least 4%

Apnea index

Number of apneas per hour of sleep

Hypopnea index

Number of hypopneas per hour of sleep

Apnea–hypopnea index (AHI)

Number of apneas and hypopneas per hour of sleep

Respiratory disturbance index

Apneas, hypopneas, and respiratory arousals per hour of sleep

Respiratory Effort-Related Arousals (RERA) index

Number of respiratory effort–related arousals per hour of sleep

During the past 50 years, the published literature has explored various aspects of sleep apnea in depth.2 Notably, two longitudinal studies have provided a wealth of information about the long-term effects of sleep apnea. The Wisconsin Sleep Cohort Study is an epidemiologic study of sleep apnea and other sleep problems, based on a random sample of 1522 Wisconsin state employees, that began in 1989.3 In 1994, the National Heart, Lung and Blood Institute initiated the Sleep Heart Health Study as a multicenter prospective cohort study to assess the contribution of sleep apnea to hypertension and cardiovascular disease.4

Types of Sleep-Disordered Breathing Three types of sleep apnea are recognized: obstructive apnea, central apnea, and mixed apnea. During normal sleep, chest and abdominal movements occur in synchrony and airflow is normal (Figure 45-1). Obstructive apnea is characterized by continued chest and abdominal efforts to breathe during periods of airflow cessation (Figure 45-2). When the obstruction is not complete and airflow does not cease, but diminishes to 30% or less of the average rate, these episodes are known as hypopneas (Figure 45-3). Central apnea is characterized by cessation of both the effort to breathe and airflow (Figure 45-4). Mixed apnea has characteristics of both types of apnea: central in the beginning and obstructive at the end (Figure 45-5). Mixed apnea often is combined with obstructive apnea, as they share a similar pathogenesis and clinical manifestations. The usual description of sleep apnea refers to patients with obstructive sleep apnea (OSA).

FIGURE 45-1 Normal breathing pattern. Upper tracing: airflow. Middle tracing: chest movements. Lower tracing: abdominal movements.

FIGURE 45-2 Obstructive apnea. First tracing: airflow. Second tracing: chest movements. Third tracing: abdominal movement. Fourth tracing: oxygen saturation.

Description

FIGURE 45-3 Hypopnea. First tracing: airflow. Second tracing: chest movements. Third tracing: abdominal movements. Fourth tracing: oxygen saturation.

Description

FIGURE 45-4 Central sleep apneas. First tracing: airflow. Second tracing: chest movements. Third tracing: abdominal movement. Forth tracing: oxygen saturation.

Description

FIGURE 45-5 Mixed apnea. First tracing: airflow. Second tracing: chest movements. Third tracing: abdominal movements. Fourth tracing: oxygen saturation.

Description Central sleep apnea is an uncommon disorder that causes mild sleeprelated symptoms and usually occurs in patients with cardiac or neurologic problems.5 Patients have clinical symptoms similar to OSA. Some patients who are treated for OSA develop central apneas during therapy, referred to as complex sleep apnea syndrome. When episodes of central, mixed, or obstructive apnea exceed those that occur normally, sleep-disordered breathing may be diagnosed by polysomnography. In the past, the presence of 30 apneas during a 6- to 8-hour polysomnogram and/or an apnea index of 5 was used to define sleep apnea.2 The apnea index (AI) is the frequency of apneas per hour of sleep. With the recognition that hypopnea can produce clinical symptoms similar to those of apneas, researchers suggested a combination of apnea and hypopnea as the definition of sleep hypopnea using the apnea–hypopnea index (AHI).6 Although the AHI can indicate sleep apnea, it is not the best index to assess the severity of sleep apnea, as the total duration of apnea and hypopnea events and the

average desaturation events in patients with similar AHIs can vary dramatically. Composite severity indices using a variety of physiologic and quality of life measures are better outcome assessments for determining the severity and management of sleep apnea.7–11 The presence of daytime hypercapnia and hypoxemia defines hypercapnic and hypoxemic respiratory failure. Sleepy obese patients with respiratory failure were diagnosed as having Pickwickian syndrome before practitioners had an understanding that the underlying cause of their symptoms was sleep-disordered breathing. A milder sleep-related breathing problem is upper airway resistance syndrome (UARS). In UARS, the sleep study does not show apneas, but the patient experiences an increased number of arousals related to increased respiratory effort. These arousals are identified by an electroencephalogram (EEG) pattern similar to awakening, but lasting less than 15 seconds—that is, by respiratory effort–related arousals (RERAs). Such patients have upper airway narrowing but can maintain airflow in the normal range with increased respiratory effort. The increased effort required to keep breathing in the normal range results in repeated nocturnal arousals. Consequently, patients exhibit symptoms similar to those associated with OSA. Respiratory Recap Types of Sleep-Disordered Breathing ∎ Obstructive sleep apnea: greater than normal episodes of absent or diminished breathing, but continued chest and abdominal movements during sleep, causing pathophysiologic changes while awake ∎ Central sleep apnea: episodes of cessation of airflow and chest/abdominal movements during sleep, greater than expected ∎ Mixed sleep apnea: episodes of both types of apnea, central in the beginning and obstructive at the end ∎ Complex sleep apnea: central sleep apnea as a result of treating OSA ∎ Upper airway resistance breathing: a milder sleep disorder characterized by an increased number of respiratory effort–related arousals due to increased upper airway resistance, but with normal numbers of apneas and hypopneas

Prevalence

Sleep apnea is a very common disorder; it affects approximately 12% of the general population and is more common in men.3,12–14 The estimated cost burden of undiagnosed OSA among U.S. adults is very high— approximately $149.6 billion—due to lost productivity and absenteeism; increased risk of costly comorbidities such as hypertension, heart disease, diabetes, and depression; motor vehicle accidents; and workplace accidents.14 The estimated costs of diagnosis and treatment would be less than one-third of the projected cost savings. Table 45-2 shows some of the common risk factors for the presence of sleep apnea. Notably, the prevalence of sleep apnea increases with both age and obesity. People older than 65 years are about three times more likely to have sleep apnea compared with middle-aged persons. A nationally representative sample of Medicare beneficiaries suggests that a large percentage of older Americans are not evaluated for OSA: 56% of those evaluated were at risk of OSA, and of those who received polysomnography studies, 94% were diagnosed with OSA.15 TABLE 45-2 Common Risk Factors Associated with Sleep Apnea Obesity

Most patients are obese (body mass index > 30 kg/m2)

Age

Progressive increase in incidence with age

Gender

Twice as common in men

Snoring

Almost all sleep apnea patients snore

Sleepiness

Very common in sleep apnea

Alcohol use

Increases the number of apneas

Hypertension

Three times more common in hypertensive patients

Congestive heart failure (CHF)

More than half of patients with CHF have sleep apnea

Stroke

More than two-thirds of patients with acute stroke have sleep apnea

Hypothyroidism, acromegaly

High incidence of sleep apnea

Medications

Sedatives and narcotics increase the number of apneas

Upper airway abnormalities

Higher incidence in persons with upper airway narrowing

Family history

Two to four times higher risk among family members regardless of other factors such as obesity, age, or gender

Most patients clinically diagnosed to have sleep apnea are obese, and the prevalence of sleep apnea progressively increases with increasing severity of obesity. A person with a body mass index (BMI) of 30 kg/m2 has more than a 30% chance of having sleep apnea, whereas a BMI of 40 kg/m2 increases the chance of having sleep apnea to 50%.16 Adults, children, and youth who have a large neck circumference have a greater likelihood of sleep apnea, but require further testing to confirm the diagnosis. A male with a neck circumference greater than 41 cm (16.1 inches) is 1.68 times more likely to have OSA.17 Children and youth with a neck circumference greater than the 95th percentile have significantly increased risk for OSA.18 Approximately one-third of all patients with hypertension have sleep apnea. The prevalence rises to more than 50% in patients with hypothyroidism and acromegaly. Persons with anatomic upper airway abnormalities also have a high prevalence of the disease. The prevalence of sleep apnea in many Asian populations is similar to that in the United States, even though obesity is uncommon among Asians, especially persons of Chinese ethnicity.19 When severe obesity is present, Asians have significantly greater prevalence and severity of OSA than white Europeans with severe obesity,20 although the prevalence varies with ethnicity.21 This propensity for sleep apnea may be related to craniofacial characteristics of Asian populations. There is a two to four times higher risk of sleep apnea among the family members of sleep apnea patients, independent of the effects of obesity, gender, and age. The risk of sleep apnea increases with the number of affected family members.

Stop and Think You are caring for a patient with a BMI of 35 kg/m2. How would you screen this patient for OSA?

Screening for Sleep-Disordered Breathing Many screening questionnaires have been developed to clinically identify patients who have sleepiness and might have sleep apnea. These questionnaires are based on patient-reported symptoms, demographics, physical examination, and the presence of comorbid conditions. Respiratory Recap Prevalence of Sleep Apnea ∎ People older than 65 years are three times more likely to develop sleep apnea than middle-aged persons. ∎ The risk of sleep apnea is two to four times higher among family members of sleep apnea patients regardless of age, weight, or gender. ∎ Approximately one-third of patients with hypertension have sleep apnea. ∎ Sleep apnea affects approximately 12% of the population. ∎ The cost burden of undiagnosed sleep apnea is very high.

Sleepiness is usually assessed by the Epworth Sleepiness Scale (ESS), in which the patient is asked to rate the likelihood of falling asleep from 0 (no chance of dozing off) to 3 (high chance of dozing off) in eight situations (sitting and reading, watching TV, sitting inactive in a public place, as a passenger in a car for an hour, lying down in the afternoon, sitting and talking to someone, sitting quietly after lunch, and in a car while stopped in traffic).22–24 An ESS score of 10 or more is suggestive of significant daytime sleepiness.22 Objective assessment of daytime sleepiness can be obtained by the Multiple Sleep Latency Test (MSLT), in which a patient is given an opportunity to nap for 20 minutes.24 This is repeated every 2 hours four more times, and the time it takes to fall asleep during these five naps is calculated. The mean sleep latency in the general population is more than 8 minutes, but is less than 8 minutes in patients with sleepiness. This test is not needed for routine care of sleep apnea patients, and determining whether someone has excessive sleepiness or narcolepsy should not be based solely on the MSLT results.25 Many screening questionnaires have been developed to clinically

identify patients who might have sleep apnea.26,27 The most commonly used tool to screen for possible obstructive sleep apnea is the STOPBANG questionnaire.28 Scoring is based on yes-or-no answers for eight questions: presence of snoring, tiredness, observed apneas, elevated blood pressure, body mass index ≥ 35 kg/m2, age greater than 50 years, neck size ≥ 40 cm, and male gender. Three or more “yes” answers are suggestive of increased risk for having sleep apnea. Higher scores increase not only the likelihood of the presence of sleep apnea, but also the likelihood that the sleep apnea will be characterized as severe. For example, use of this tool in sleep clinics shows that a STOP-BANG score of 8 suggests the probability of having severe sleep apnea in more than 80% of patients.29 Based on the screening results, a complete sleep study may be performed to confirm a diagnosis. Thus, the Epworth Sleepiness Scale and the STOP-BANG Questionnaire are useful screening tools that can uncover potential sleep disorders, which require further testing using polysomnography for a complete sleep study.

Obstructive Sleep Apnea Pathogenesis Hypopnea and apnea result from the narrowing and occlusion of the upper airway.30,31 The upper airway from the back of the nasal septum to the epiglottis has minimal bony support and can collapse easily. Normally this region is maintained open by a balance of the forces that tend to dilate and the forces that tend to narrow this area. Forces that tend to dilate this area include the tonic and phasic activity of the genioglossus (tongue) and upper airway muscles. The tonic activity is present throughout the respiratory cycle, whereas the phasic activity is present during inspiration. Conversely, inspiration creates negative pressure inside the airway—and negative pressure inside a collapsible tube can reduce the size of the tube. Thus, increased inspiratory effort opens the intrathoracic airway but reduces the luminal area of the upper airway. This effect is similar to sucking though a collapsible straw: The harder one sucks at the straw, the narrower the lumen of the straw becomes. Airflow linearly decreases as the pressure in the upper airway becomes negative. When the negative pressure exceeds a critical pressure (e.g., – 10 cm H2O in normal persons), airway occlusion occurs. During sleep, as the tone of the pharyngeal dilator muscles decreases, the soft palate and the tongue move backward, causing narrowing of the oropharynx. Maximum narrowing occurs during rapid eye movement (REM) sleep, when the muscle tone is further reduced, as well as in the supine posture, where gravity has the greatest effect. Consequently, occasional apnea and hypopnea can occur during REM sleep and in supine posture, even in normal individuals. The site of occlusion varies: It may occur at multiple sites, but most commonly occurs at the velopharynx and in the retroglossal area. The velopharynx consists of the velum (soft palate), the lateral pharyngeal walls (side walls of the throat and the posterior pharyngeal wall), and the back wall of the throat. The velum rests against the back of the tongue during normal nasal breathing. During inhalation, air can flow through the nose and pharynx to the lungs without obstruction. By contrast, velopharyngeal closure occurs during speech, swallowing, gagging, vomiting, sucking,

blowing, and whistling. Velopharyngeal closure during sleep is a major contributing cause of obstructive sleep apnea. Four interdependent factors play a role in upper airway occlusion during sleep: narrowing of the pharyngeal cavity, decreased activity of the pharyngeal dilator muscles, increased respiratory effort (i.e., more negative intraluminal pressure), and increased compliance (collapsibility) of the pharyngeal airway. The presence of fat in the neck and tongue causes enlargement of the tongue, along with narrowing of the upper airway. Many abnormalities can cause narrowing of the upper airway (Table 45-3). Alcohol, sedatives, and opioids reduce upper airway muscle activity, predisposing patients to apnea.32,33 The decreased muscle tone induced by these substances results in narrowing of the airway and reduced airflow, triggering an increased respiratory effort to try to restore the airflow. Narrowing above the site of occlusion (i.e., upstream resistance) causes more negative intraluminal pressure, leading to even more narrowing. In a vicious cycle, the harder the patient tries to breathe, the more the airways become obstructed. Deposition of fat also makes the upper airway more compliant, such that a small increase in negative pressure can pull the upper airway muscles together. Thus, in obese patients with sleep apnea, occlusion occurs with less negative pressure and, at times, even with positive airway pressure. TABLE 45-3 Common Upper Airway Abnormalities Associated with Obstructive Sleep Apnea Nose

Enlarged turbinates, deviated septum, polyps, nasal valve dysfunction

Nasopharynx

Enlarged adenoids, tumors, pharyngeal flap

Oropharynx

Enlargement of uvula and soft palate, tonsillar hypertrophy, tumor, macroglossia

Larynx

Vocal cord paralysis, epiglottic edema

Jaw

Micrognathia, retrognathia

Respiratory Recap Pathogenesis of Obstructive Sleep Apnea The pathogenesis of OSA is related to upper airway anatomy characteristics, pharyngeal tone during sleep, airway pressure changes during inspiration, and inspiratory efforts associated with airway narrowing or occlusion.

Clinical Features Apneas cause hypoxemia and hypercapnia, which are terminated by arousals. Most of the clinical manifestations of sleep apnea result from repeated arousals and hypoxemia. Snoring, daytime hypersomnolence, and disturbed sleep are the usual reasons patients seek medical attention. Many times, patients are unaware of their problems and are brought for evaluation because their spouses are bothered by the snoring and disturbed sleep. Box 45-1 lists the usual symptoms associated with OSA. A wide spectrum of clinical manifestations exists, ranging from mild nocturnal snoring and daytime tiredness to acute or chronic hypoxemic and hypercapnic respiratory failure (Table 45-4). TABLE 45-4 Clinical Spectrum of Sleep Apnea

AHI, apnea–hypopnea index.

BOX 45-1 Symptoms of Sleep Apnea Daytime Symptoms

Sleepiness Non-refreshing sleep Morning headaches Intellectual dysfunction Personality changes

Nighttime Symptoms Snoring Apneic, choking, gasping awakenings Restless sleep Nocturia Dry mouth Drooling Diaphoresis Erectile dysfunction

Snoring, which is caused by the oscillation of pharyngeal soft tissues, is the most common symptom among patients with OSA. It is usually loud enough to be heard from outside the room. The loudness of snoring is often a predictor of the severity of sleep apnea. The snoring may be continuous, but usually demonstrates an intermittent pattern. Habitual snoring is common in the general population, with approximately 48% of men and 34% of women having it.34 Snoring is present in almost all patients seen in sleep clinics. Occasionally a patient with sleep apnea may deny snoring, but either he or she is sleeping alone or the bed partner does not corroborate the denial. The snoring is often described as resembling the noise coming from a freight train. It disturbs the bed partner’s sleep and frequently leads to sleeping in separate beds or rooms. Daytime hypersomnolence is one of the main reasons for seeking evaluation. Falling asleep during periods of relative inactivity, such as watching television, driving, and attending meetings, is common. In advanced cases, the patient may fall asleep even when engaged in an activity (e.g., talking, walking, and eating). Many patients seen in sleep clinics complain of daytime tiredness and general decreased performance. In sleep studies performed in the general population, regardless of the presence of symptoms, sleepiness is present in approximately 50% of subjects who receive a diagnosis of sleep apnea.35 Sleepiness is also common in sleep apnea patients with congestive heart failure. Some patients complain of daytime tiredness instead of

sleepiness: “I am tired of being tired” is a common complaint. Both repeated nocturnal awakenings (i.e., sleep fragmentation) and hypoxemia have been implicated as the cause of daytime somnolence, but sleep fragmentation appears to be the main determinant.11 The sleep pattern of patients with OSA is characterized by frequent tossing and turning. Patients wake up repeatedly from their sleep because of choking, shortness of breath, or dry mouth, or for no apparent reason. Some patients’ primary complaint may be the inability to achieve a good night’s sleep. Nocturnal sweating, probably related to increased breathing effort, is common. Hallucinations may occur because of awakening from REM sleep. Patients do not feel fresh when they wake up in the morning. Morning headaches, personality changes, and decreased hearing acuity are common.

Complications of Obstructive Sleep Apnea Blood gas abnormalities, repeated arousals, and increased negative intrathoracic pressure are the main mechanisms responsible for a myriad of complications occurring in patients with severe sleep apnea. Many biochemical abnormalities may play a role in the pathogenesis of these complications. Hypoxemia occurs with apneic episodes and, with increasing severity of the disease, may become sustained and occur during the daytime. The chronic hypoxemia is the main determinant of most sleep apnea–related complications. Hypoxemia causes tissue ischemia, induces pulmonary artery constriction leading to pulmonary hypertension, and causes increased sympathetic discharge (catecholamines). Long-standing pulmonary hypertension may result in right-sided heart failure, or cor pulmonale. Transient hypercapnia also occurs with apneas and can become sustained and chronic. If left untreated, this can lead to chronic respiratory failure. Repeated arousals from sleep lead to higher catecholamine release during the night. The increased respiratory effort needed to overcome upper airway narrowing causes increased negative pressure in the chest cavity, which affects the heart in two ways: It makes it easier for blood to come back to the right side of the heart, but makes it more difficult for the left heart to pump blood into the aorta. Because of

the increased negative pressure around it (i.e., the heart is being pulled to the outside), the heart has to work harder (produce more positive pressure) to pump the blood out. Ultimately, this increased cardiac workload may lead to left-sided heart failure. Patients with OSA have increased blood levels of C-reactive protein (CRP), a marker of inflammation.36 An elevated CRP level causes blunting of endothelium-dependent vasodilation and correlates with an increased risk of developing cardiovascular disease. Similarly, levels of fibrinogen, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), homocysteine, and other biomarkers of inflammation are increased, whereas levels of protective peptides such as adropin are decreased.37 Leptin is a protein secreted mainly by fat cells that regulates metabolic activity and other physiologic functions. It is modulated by many factors, including fasting, sleep, gender, and circadian rhythm, and is thought to function as an appetite suppressant. Serum leptin levels are often high in patients with OSA, suggesting there is resistance to this protein; leptin levels often decrease with successful treatment of OSA by positive airway pressure (PAP) therapy.38 Increased leptin levels are also linked to cardiovascular disease.39 The circulating nitric oxide level is decreased with OSA, but improves with therapy.40 Leptin, nitric oxide, and related metabolic by-products can be monitored as biomarkers of treatment efficacy for sleep apnea.39,40 Almost all parts of the body are affected by the presence of sleep apnea. Complications are common and become more frequent as the severity of disease increases. Some of the common complications of OSA are discussed in the following subsections according to their effects on various systems of the body.

Central Nervous System Cognitive dysfunction and sleepiness are common in patients with OSA. Neuropsychological measures of overall performance are moderately impaired, and cognitive abilities have an inverse correlation with oxygen desaturation and apnea. Patients may have problems related to attention, concentration, memory, and vigilance. Some become irritable and experience difficulty with social interactions. Sleepiness at work is associated with reduced efficiency. Sleepiness

in patients who operate heavy equipment or drive for work, such as longhaul truck drivers and bus drivers, may be particularly hazardous. The rate of automobile accidents in patients with sleep apnea is significantly higher than in the general population,41 but declines as patients are successfully treated.42 Most children with lack of adequate sleep resist sleepiness and are restless during the day. These patients may be labeled as having attention-deficit/hyperactivity disorder (ADHD). Children and adults with ADHD who snore need to be evaluated for possible sleep apnea.43 Nevertheless, the absence of snoring does not exclude the possibility of sleep apnea.44 A neuroimaging study showed that patients with severe, untreated sleep apnea had a significant reduction in white matter fiber integrity in multiple brain areas, which was associated with impairments to cognition, mood, and daytime alertness. After one year of continuous positive airway pressure (CPAP) therapy, the patients demonstrated significant reversal of brain injury.45

Cardiovascular Sleep apnea has been implicated in many cardiovascular abnormalities.46 Cardiac arrhythmias and both right and left ventricular dysfunction ultimately leading to congestive heart failure can occur in patients with OSA. The heart rate slows during an apneic episode and speeds up when the apnea is terminated. Nocturnal bradycardia (30 to 50 beats per minute) during apneic episodes, followed by tachycardia (90 to 120 beats per minute) at the resolution of apnea, is the most common pattern of arrhythmias.47 Other cardiac arrhythmias are seen in approximately 20% of patients undergoing polysomnography. These arrhythmias occur more frequently in patients with hypoxemia and include premature atrial and ventricular contractions, atrial and ventricular tachycardia, sinus pauses, and heart block. The incidence of OSA in patients with atrial fibrillation is high, and the recurrence rate of fibrillation after cardioversion remains high if the OSA remains untreated.47 Both right and left ventricular hypertrophy and congestive cardiac failure can develop secondary to OSA. Additionally, the incidence of both central and obstructive sleep apnea is very common in patients with congestive heart failure.48

Hypertension occurs in about 50% of patients with sleep apnea; conversely, the prevalence of sleep apnea in the hypertensive population is estimated at 30%. Although the prevalence of hypertension progressively increases with the severity of sleep apnea, even mild sleep apnea is associated with a greater prevalence of hypertension.49 The prevalence of hypertension is nearly two to three times higher in sleepy patients compared with nonsleepy patients.34 Almost all male patients and two-thirds of female patients with refractory hypertension (defined as continued elevation of blood pressure despite taking three or more antihypertensive medications) have OSA.50,51 The likelihood of developing hypertension over time progressively increases with the severity of OSA. Although both hypertension and sleep apnea occur more commonly in middle-aged obese men, sleep apnea is an independent risk factor for hypertension. Successful therapy for sleep apnea may lead to improvement in hypertension. Patients with OSA have an increased incidence of angina, myocardial infarction, and congestive heart failure.46 Like hypertension, smoking, and obesity, OSA is considered an independent risk factor for myocardial infarction. The prevalence of OSA is higher in patients with cardiovascular disorders than in the general population. Moderate to severe OSA significantly increases cardiovascular risk— in particular, stroke risk.52 A strong association exists between sleep apnea and cerebral vascular accidents: Patients with OSA are two to three times more likely to develop stroke compared with controls.52 Because OSA is a risk factor for hypertension, which is itself one of the strongest risk factors for stroke, it is not surprising that the risk of stroke is increased in patients with this type of sleep apnea. The risk of stroke in patients with sleep apnea is higher even in the absence of hypertension. The prevalence of OSA in patients with stroke is very high.

Pulmonary Pulmonary hypertension during apneic episodes is common. In patients with severe hypoxemia, extremely high levels of pulmonary hypertension may be observed.52 Sustained pulmonary hypertension during the day is found in about 20% of patients with OSA, primarily in those with hypoxemia and hypercapnia during the day and severe oxygen

desaturation during the night.53 Occasionally, acute pulmonary edema may be the presenting feature of the disease in patients with severe sleep apnea.54 A paradoxical shift of the interventricular septum can occur because of increased right ventricular pressure.

Endocrine The prevalence of type 2 diabetes is higher in patients with OSA; likewise, the prevalence of OSA is higher in patients with type 2 diabetes.55 Although obesity is a common risk factor for both diseases, OSA is an independent risk factor for the development of insulin resistance, having a causal impact on insulin and glucose homeostasis.56 Patients with OSA and diabetes who receive CPAP therapy often demonstrate improvements in insulin resistance.56

Renal Proteinuria often occurs in obese patients, but it appears that sleep apnea may be an even stronger determinant of its frequency and severity.57 Proteinuria may be significant enough to be in the nephrotic range, but usually can be reversed with adequate therapy for sleep apnea.58 This condition usually arises in patients with severe sleep apnea and appears to be related to the degree of hypoxemia.59–61

Gastrointestinal Gastroesophageal reflux symptoms are present in more than 50% of patients with OSA. Patients with reflux disease have a higher prevalence of snoring and sleep apnea. The paradoxical breathing pattern (chest and abdomen moving in opposite directions) during apneic episodes predisposes patients to develop reflux. The increased negative intrathoracic pressure during an apneic episode encourages the movement of gastric acid into the esophagus. At the same time, abdominal pressure is increased due to the inward movement of the abdominal muscles causing the same effect. PAP therapy leads to improvement in reflux symptoms.62

Ophthalmic The eyes are particularly susceptible to both mechanical and vascular sequelae of OSA, as this sleep disorder contributes to a variety of ophthalmic conditions.63 Optic disc swelling, teardrop retinal hemorrhages, normotensive glaucoma, ischemic optic neuropathy, floppy eye syndrome, central serous retinopathy (CSR), retinal vein occlusion (RVO), and increased intracranial pressure associated with disc edema (pseudo tumor cerebri) have all been reported in patients with OSA.63,64 Attention to ocular symptoms in patients with sleep apnea is important to prevent complications that can threaten vision. RVO is the most threatening condition for vision loss, second to the leading cause of vision loss, diabetic retinopathy.

Psychiatric Sleep disturbances are frequently seen in patients with depression, and depression is common in patients with sleep apnea. Moreover, patients with both depression and hypertension have a high prevalence of sleep apnea. CPAP therapy can improve symptoms of depression in many patients with sleep apnea and depression.65,66

Sexual There is a link between sleep and sexual dysfunction that goes beyond the shared influence of other mental health factors.67 Sexual dysfunctions in both men and women have been reported and are often underrecognized in patients with OSA.68 Erectile dysfunction is common in men with severe OSA, particularly those with hypoxemia. CPAP therapy is associated with improvement in erectile dysfunction.68 Respiratory Recap Complications of Sleep-Disordered Breathing ∎ Sleep-disordered breathing causes a variety of serious complications affecting the cardiac, pulmonary, psychological, sexual, endocrine, central nervous, renal, vascular, and ophthalmic systems. ∎ Cognitive dysfunction and sleepiness are common in patients with OSA. The rate of automobile accidents in patients with sleep apnea is about three times higher than that in

the general population. Patients may also experience problems related to attention, concentration, memory, and vigilance.

Diagnosis of Obstructive Sleep Apnea Many clinical findings, such as degree of obesity, neck circumference, snoring, nocturnal choking, hypertension, age, sleepiness during driving, and the presence of upper airway abnormalities, have been identified as predictors of the presence of OSA. A flow-volume loop usually shows the presence of upper airway obstruction or a sawtooth pattern, or both.69 Holter monitoring can reveal characteristic arrhythmias present predominantly during sleep. None of these findings, however, is strong enough to obviate the need for polysomnography for a definite diagnosis. Nocturnal pulse oximetry showing repeated episodes of oxygen desaturation is strongly suggestive of sleep apnea.70 In many countries, an oxygen desaturation of 4% is considered equivalent to an apneic episode. Instead of using the AHI, an oxygen desaturation index (ODI) is reported. In most patients with sleep apnea and hypoxemia, the AHI and the ODI are highly correlated. Hypoxemia may not be present in patients with mild sleep apnea, however. Overnight polysomnography, with recording of the electroencephalogram, electro-oculogram, electromyogram, electrocardiogram, oronasal airflow, chest and abdominal movements, and oxygen saturation, remains the standard diagnostic test for sleep apnea. Polysomnography reveals the frequency, type, and duration of apnea and hypopnea; the presence of cardiac arrhythmias; and the quality and quantity of sleep. In addition, the presence of repeated arousals and episodes of nocturnal myoclonus that can produce hypersomnolence can be identified. The American Academy of Sleep Medicine has published guidelines for scoring of sleep and sleep-related breathing problems.71 Usually single-night polysomnography is a sufficiently sensitive test to determine or exclude clinically significant sleep apnea. Sometimes, however, the first polysomnogram may be falsely negative. Factors that may cause a false-negative polysomnogram include a technically poor study, an inadequate amount of sleep, reduced REM sleep, sleeping in a

lateral posture, recent weight loss, or recent therapy for suspected sleep apnea. Home unattended portable monitoring and auto-titration of CPAP has been shown to be an effective means of making the diagnosis in a subset of patients with moderate to severe obstructive sleep apnea.70 Additionally, a single unattended titration night can be sufficient to determine the therapeutic pressure needed to treat sleep apnea. Home monitoring and auto-titration of CPAP is becoming more common as a first approach when sleep apnea is suspected. The use of consumergrade wearable devices for the early detection of sleep apnea is being explored and could prove promising, though it is not a substitute for polysomnography.72

Treatment of Obstructive Sleep Apnea During the 1970s, tracheostomy was considered the standard treatment for very sick patients with OSA. Today, most patients, including those with acute or chronic respiratory failure, can be adequately treated with PAP therapy if they adhere to regular use during sleep. Oral appliances also are considered first-line therapy for mild sleep apnea. Surgical therapy can be used if the patient has significant correctable anatomic abnormalities. Other helpful strategies include weight loss, sleeping in a nonsupine posture, and avoiding aggravating factors such as alcohol, smoking, sedatives, and narcotics. In addition, treatment of diseases contributing to sleep apnea, such as hypothyroidism, can improve sleep apnea symptoms.

Weight Loss Fat deposition in the neck and pharyngeal tissue contributes to the anatomic and physiologic narrowing of the upper airway. In turn, weight loss can reduce the number of apneas and improve both nocturnal oxygen desaturation and the quality of sleep. Generally, for every 1% decrease in total body weight, there is a 3% decrease in the AHI.73,74 Usually, a 10% to 20% weight loss is needed to significantly affect clinical symptoms. In some patients, however, even a modest amount of weight loss may have a significant effect on the severity of sleep apnea. Regular follow-up with dietary counseling and nutritional consultation is helpful.

Weight reduction surgery or medications can also be considered in patients with significant weight-related problems.

Posture Sleeping on the back is consistently associated with more severe OSA indices in adults, though this relationship is weaker in children.75 Sleeping on the side improves apnea and hypopnea and, in some patients, may totally control the problem.76 Sleeping with a tennis ball sewn in the back of the shirt or a lateral wedge pillow can help reduce time spent sleeping on the back. Homemade or commercially available positional sleeping devices have shown to be effective in some patients.77 Most spouses are aware of the improvement that occurs with nonsupine positioning, and many use “elbow therapy” to ensure the patient sleeps on the side. Sleeping with the head and upper body elevated 30 to 60 degrees can also decrease the severity of sleep apnea.78 Patients with severe obesity show little improvement in frequency or duration of sleep apnea based on changing sleep position.75

Positive Airway Pressure Therapy Positive airway pressure for treating OSA was first described in 198179 and has since become the most commonly used therapy for sleep apnea.80–82 PAP acts as a pneumatic splint in the upper airway, counteracting the negative inspiratory pressure and preventing airway collapse (Figure 45-6). The size of the upper airway progressively increases with increasing PAP. Thus, this approach is now considered the first-line therapy for sleep apnea and can be successfully used in most patients.

FIGURE 45-6 (A) Normal upper airway. (B) Upper airway obstruction. (C) Upper airway obstruction relieved with the addition of continuous positive airway pressure (CPAP) circuit for acute respiratory failure.

Description PAP can be applied using several techniques. The most common method is to apply preselected constant pressure during sleep from an airflow generator. With continuous positive airway pressure (CPAP) therapy, the same pressure level is maintained during both inspiration and expiration. Many patients are uncomfortable during exhalation when they breathe against the airflow. Most CPAP machines provide pressures ranging from 4 to 20 cm H2O, with the CPAP pressure range for treating OSA usually ranging between 8 and 10 cm H2O. Bilevel positive airway pressure (BPAP) provides two pressure levels: a higher pressure during inspiration and a lower pressure during exhalation. The pressure difference between the inspiratory positive airway pressure (IPAP) and the expiratory positive airway pressure (EPAP) is usually about 4 cm H2O. Because of the lower expiratory pressure during BPAP, exhalation may be more comfortable than with CPAP. It was anticipated that the adherence would be better with BPAP than with CPAP, but that has not turned out to be the case. BPAP is most commonly used when the pressure level during expiration is high (mostly above 15 cm H2O), to the point that the patient cannot tolerate CPAP therapy. BPAP machines are more expensive than CPAP machines. Auto-titrating CPAP machines detect airway narrowing and progressively adjust the pressure until airflow becomes normal again. These devices are used for the diagnosis and therapy of obstructive

sleep apnea and to predict the pressure needed for CPAP therapy.70 The mean pressure with auto-titrating machines is lower than that with CPAP machines because the pressure goes to the maximum only when needed. Although these machines do not improve adherence with CPAP therapy, they have the potential to decrease the need for CPAP titration studies. One drawback with auto-titrating machines is that these machines can overcompensate if leakage around the mask occurs or if the patient keeps the mouth open. This overcompensation can unnecessarily increase the airway pressure, which has the potential to cause even more air leakage and can also disturb sleep. Conversely, the patient may be undertreated because of the time delay in reaching the optimal pressure needed to correct apneas. Because some auto-titrating machines rely on detection of reduced inspiratory airflow, these devices may not be able to treat patients with central apneas. Also, they may not be appropriate for patients with OSA who develop central apnea during CPAP therapy (complex sleep apnea). Auto-titrating CPAP machines are more expensive than conventional CPAP machines. One useful feature of CPAP machines is a ramp, in which the pressure starts at a low level and gradually increases to the prescribed level. A ramp helps some patients better tolerate this therapy. The newer CPAP machines have the capability of reducing pressure (expiratory pressure relief and C-Flex modes) briefly by 1 to 4 cm H2O at the beginning of exhalation, which may improve patient comfort and adherence. Many different interfaces are available for CPAP. Oronasal masks, which cover both the nose and the mouth, are useful for patients who keep their mouth open during PAP therapy. Nasal masks are smaller and cover only the nose. Oral masks deliver air through the mouth and generally are less-tolerated than other masks. Nasal pillows or prongs are used to deliver air directly into the nose. These pillows avoid skincontact abrasions, but may cause irritation of the nares. Hybrid masks combine oral masks with nasal pillows. Nasal pillows or nasal masks are preferred because of reduced claustrophobia. In some patients, oronasal masks may not alleviate apneas because of the air going through the mouth and pushing the tongue against the pharyngeal wall. Higher CPAP pressures may be needed to control apneas in such a case.

The most immediate effect of CPAP usage is elimination of snoring. Spouses sleep much better, nighttime awakenings and visits to the bathroom are decreased, patients feel rested upon awakening, and the frequency of morning headaches is decreased. In addition, a significant number of patients report reduction or elimination of daytime sleepiness and tiredness. Improvement in sleep-related complications (driving, functioning at work) may occur, as well as improvement in cognitive functions. Long-term CPAP usage is associated with improvement in many of the complications of sleep apnea. A small but significant reduction in hypertension occurs, including patients with resistant hypertension. CPAP therapy prior to surgery significantly reduces postoperative cardiovascular complications.83 The side effects of CPAP therapy are caused either by the interface or the air pressure and flow (Table 45-5). Newer PAP machines produce only a minimal humming noise. Noise at the face is largely attributable to leakage of air because of poor fit or movement of the mask. Some patients may get entangled with the circuit. Fitting the mask too tightly can lead to skin irritation and skin abrasions at the contact site—the nasal bridge is the usual site of skin and bony erosion. Many patients complain of nasal or oral dryness, nasal congestion, sneezing, and even nosebleeds, though the use of heated humidity can reduce these symptoms in most patients. Chin straps can help to keep the mouth closed, thereby reducing oral dryness in patients who keep their mouth open during PAP therapy. Using intranasal ipratropium can help rhinorrhea. Pressures in the lower range are well tolerated, but some patients may experience hyperinflation at higher pressures. In those patients, the CPAP apparatus can be modified to deliver lower pressure during exhalation. Swallowing air (aerophagy) may be associated with CPAP use and can be reduced by using lower pressure. Pneumothorax is potentially a serious complication but occurs rarely in the usual pressure range used for sleep apnea. Pneumocephaly is also rare and is related to air leakage from the nose to the cranium. TABLE 45-5 Complications Related to Positive Airway Pressure Therapy Cause

Complication

Machine

Noise

Circuit

Entanglement, rebreathing

Interface

Skin abrasions, claustrophobia, leaks, rebreathing

Airflow and pressure Nose

Dryness on nose and throat, rhinorrhea, congestion, epistaxis Discomfort Conjunctivitis Discomfort, expiratory difficulty, hyperinflation, pneumothorax Aerophagy Pneumocephalus

Sinus Eyes Chest Gastrointestinal system Central nervous system

The major reason for the failure of CPAP therapy is lack of adherence to the treatment plan. Most new CPAP machines have the capability to provide hourly, nightly, and long-term data about when the machine is turned on and the actual usage of the machine. Because the beneficial effect of PAP therapy is directly proportional to the amount of time it is used, all-night usage should be encouraged. Arbitrarily, a patient is considered adherent if the CPAP machine usage exceeds 4 hours per night on 70% of the nights under consideration. Patient adherence during the first month predicts long-term usage. Adherence is better in patients with severe symptoms and in better-educated individuals. A higher pressure does not reduce patient adherence, as is sometimes assumed. Patient adherence to therapy can be improved by positive reinforcement and treatment of PAP-related side effects (e.g., uncomfortable mask, oronasal dryness). Only approximately 55% of patients use CPAP regularly—an adherence rate similar to the intake rate of oral medications for other medical diseases. The Centers for Medicare and Medicaid Services has recommended AHI-based criteria for CPAP therapy. Reimbursement for CPAP is approved if the patient has an AHI of 15 or greater (moderate and severe sleep apnea). Reimbursement is also approved for patients with an AHI greater than or equal to 5 and less than or equal to 14 (mild sleep apnea) who meet at least one of the following criteria: (1) symptoms of excessive daytime sleepiness; (2) impaired cognition, mood disorders, or insomnia;

or (3) cardiovascular disease such as hypertension, ischemic heart disease, or history of stroke. Stop and Think You are asked to help a patient with OSA who is not adherent to the use of CPAP. What can you do to help?

Oral Appliances Oral appliances are used to enlarge the oropharynx by either advancing the mandible or keeping the tongue in a forward position.84,85 Mandibular repositioning appliances (MRAs) cause forward and downward movement of the mandible when attached to one or both dental arches. Tongue-retaining devices (TRDs) keep the tongue in the anterior position by creating negative pressure in a plastic bulb, a flange that fits between the lips and the teeth. Oral appliances increase the airway space in both the retropalatal and retroglossal areas. These devices also increase upper airway muscle tone, thereby making it easier for the airway to remain open. Previously, these appliances required dental impressions, bite registration, and fabrication by a dental laboratory. Newer appliances, however, are available in prefabricated thermolabile forms that can be molded in the office or at home. Oral appliances are generally used in patients who present with snoring, upper airway resistance syndrome, or mild sleep apnea that does not respond to conservative therapy. Such devices can also be used in patients who have moderate or severe sleep apnea and cannot use PAP therapy. Oral appliances are not considered the first-line therapy for severe sleep apnea. Oral appliances are effective in reducing the severity of symptoms and various objective measures used to express the severity of sleep apnea. Most patients experience significant improvements in the intensity and frequency of snoring, along with a reduction in daytime sleepiness. Apnea and hypopnea are improved, although the rate of improvement depends on how improvement is defined.86 The success rate is approximately 65% if the most liberal definition of improvement (i.e., 50% reduction in AHI) is adopted. The success rates are 52% and 42% if AHI

reductions down to 10 or 5 are used, respectively. Nearly half of patients continue to have significant apneas even when they use these devices, and 10% may have worsening of AHI. The four main predictors of successful therapy with oral appliances are lower severity of OSA, lower BMI, more severe OSA when the patient sleeps on his or her back compared with his or her side, and the amount of mandibular or tongue advancement by the appliance.87 The level of CPAP needed to alleviate moderate to severe OSA has also been shown to predict successful oral appliance therapy.88 The least improvement is noted in obese patients with severe OSA, particularly those who do not have significant improvement in apneas in the nonsupine posture. The usual protrusion of mandible necessary to improve OSA varies between 5 and 10 mm. Improvement is seen in only one-third of patients if the protrusion is 50% of the maximum, but increases with more protrusion. The adherence rate with oral appliances is high, and approximately three-fourths of patients use their appliance regularly. Adherence rates decline somewhat over time because of side effects and lack of efficacy, with these rates being similar to those for CPAP in various crossover studies. Although some oral discomfort occurs, most patients tolerate these appliances well. Common side effects include mouth dryness, excessive salivation, tooth discomfort, occlusive change, and jaw pain. Side effects may improve with continued use. In addition, long-term use may result in a mild reduction in overbite or overjet and minor movements of teeth. In some patients, bite changes persist after cessation of therapy. Currently, oral appliances and CPAP are considered first-line therapy for mild sleep apnea. The patient acceptance rate of the oral appliances is high, and many patients prefer them to CPAP therapy. The reduction in apneas and hypopneas and oxygen desaturation is less with oral appliances than with CPAP therapy, but the improvement in symptoms is similar. The improvement in apneas and hypopneas is better with oral appliances than with surgical therapy.87 Patients without teeth are unable to use MRAs, but may be able to use TRDs. Patients should have at least six teeth in each dental arch to be able to hold an MRA, and they should be able to open the mouth and protrude the mandible forward. Significant temporomandibular joint problems and severe bruxism are contraindications for oral appliance therapy.

Surgery Patients who fail medical treatment, do not tolerate CPAP, or desire a long-term solution may seek surgical management of their sleep apnea. Surgical approaches include tracheostomy, uvuloplatopharyngoplasty (UPPP), palatal implants, genioglossal advancement, bariatrics, and a variety of other nasal, oral, and airway surgeries.89 Tracheostomy is very effective in eliminating apnea and reversing the consequences of apnea; however, complications commonly occur. Most patients are reluctant to have this procedure done; consequently, tracheostomy is rarely performed for OSA. Although many surgical procedures can be undertaken to correct anatomic abnormalities and to open the upper airway (Box 45-2), UPPP remains a common surgical procedure.90,91 BOX 45-2 Surgical Therapies for Sleep Apnea Syndromes Uvulopalatopharyngoplasty (UPPP) Genioglossal advancement Partial glossectomy Hyoid bone advancement Maxillomandibular advancement Tracheostomy Combinations

Upper airway obstruction in sleep apnea usually occurs at the retropalatal and/or retroglossal area. UPPP enlarges the posterior pharynx by removing the uvula, tonsils, and excessive tissue from the lateral pharyngeal wall and pharyngopalatal arch. Following surgery, as many as 99% of patients report symptomatic improvement. Objective improvement (50% reduction in apneas) occurs in two-thirds of patients, and cure (reduction of apneas to the normal range) is seen in fewer than half. Unfortunately, many patients have recurrence of symptoms of OSA after experiencing an initial improvement. Some patients have worsening of apneas and hypopneas after surgery. Many modifications of UPPP, including laser-assisted uvuloplasty (LAUP) and radio frequency ablation, have not proved any more successful. The efficacy of UPPP is highest in patients with mild to moderate sleep apnea. Patients with severe OSA and particularly those who have excessive body weight are not helped much by this procedure. The

failure of UPPP is probably related to the multiple etiologies of OSA and multiple sites of airway obstruction. Numerous modalities—including computed tomography of the upper airway, cephalometric analysis, pharyngeal pressure measurements, the Mueller maneuver, and direct visualization by nasoendoscope—have been used to predict the site of airway obstruction and the success of UPPP, but none of the techniques has been consistently helpful. Many other surgical procedures have been used for enlarging the upper airway. In some centers, the overall success rate with additional procedures has been reported to be better than the success rate with UPPP alone. For example, correction of a deviated nasal septum and resection of enlarged turbinates and nasal polyps can enlarge the nasal passage. The tongue (genioglossus muscle) is attached to the inner side of the mandible at the geniotubercle. Pulling the geniotubercle forward to attach it to the front part of the mandible (mandibular osteotomy) can put tension on the tongue, preventing it from falling back to the pharynx. Moving the lower jaw forward alone or with the upper jaw (mandibular or maxillomandibular osteotomy) can increase the space at the base of the tongue. Maxillomandibular advancement is a highly effective treatment modality with success rates ranging between 75% and 100%.92 Although first described in the 1980s, hypoglossal nerve stimulation to open up the upper airway has gained favor as a therapy for sleep apnea.93 In this approach, a device similar to a pacemaker with an extension wire to the tongue is implanted in the chest wall. The device monitors the patient’s breathing and sends an impulse to the tongue to make it go forward. About 75% of patients treated with hypoglossal nerve stimulation see improvement in their sleep apnea symptoms, with about 50% returning to the normal range.89 Surgical procedures are associated with pain, bleeding, infection, and even deaths. Persistent side effects related to UPPP surgery occur in about half of patients and include difficulty swallowing, globus sensation, and voice changes.89,91 Because of the risk of complications and the low success rates, surgical therapy is usually considered only when patients do not want to use PAP or oral appliances. If significant anatomic abnormalities are causing airway obstruction, such as enlarged tonsils, adenoids, or a deviated nasal septum, surgical therapy may be considered as the primary therapy.

Pharmacologic Therapy Many pharmacologic agents have been tried as treatment for sleep apnea, but none has proved consistently effective. Drugs have the potential to improve apneas by many different mechanisms. Because apneas occur more frequently during REM sleep, medication-induced reduction of this sleep stage may be beneficial. Most antidepressant agents significantly reduce REM sleep time. In those patients who have mild sleep apnea and for whom the majority of their apneic episodes occur in REM sleep, a trial of a nonsedating tricyclic antidepressant (e.g., protriptyline) or selective serotonin reuptake inhibitor (SSRI) such as fluoxetine can be undertaken to see if improvement occurs in apneas and oxygen desaturation. These antidepressants also reduce upper airway narrowing by increasing the upper airway muscle tone. Medroxyprogesterone stimulates ventilation and was initially shown to have some beneficial effect, but subsequent studies did not find any improvement in apneas. Because of the limited clinical benefit and the potential for many side effects, drug therapy is not considered a standard therapy for OSA. Oxygen therapy can improve nocturnal oxygen desaturation as well as the frequency of apnea. However, a high concentration of inspired oxygen therapy may prolong apneic episodes and should be avoided. In patients who present with acute respiratory failure, oxygen therapy is used in conjunction with CPAP and diuretic therapy. Long-term oxygen therapy usually is reserved for patients who remain hypoxemic despite other forms of therapy. Treatment of diseases that cause upper airway narrowing and apnea may be beneficial. For example, treatment of nasal allergies and use of nasal steroids, decongestants, and antihistamines may improve nasal breathing in patients with rhinitis.94 About 10% of patients with snoring and apneas can benefit from nasal vasoconstrictors. Apneas commonly occur in patients with hypothyroidism and acromegaly. Hypothyroidism causes narrowing of the upper airways and reduced ventilatory drive; thus, its presence should be considered during evaluation of patients with sleep apnea. Drug therapy of these endocrine disorders is associated with an improvement of apneas and nocturnal oxygen desaturation, and it may potentially reduce the need for long-term PAP. Some patients remain significantly sleepy in spite of adequate therapy

of sleep apnea. The reason for the residual sleepiness is not clear, but may be related to hypoxemia-driven damage to wake-promoting regions of the brain.95 Wakefulness-promoting medications such as modafinil and armodafinil may be considered in patients who continue to remain sleepy.96,97 These medications improve daytime alertness, but create a potential risk—namely, that patients may reduce the usage of CPAP therapy. Patients need to be informed that wakefulness-promoting medications do not reduce apneas or apnea-related hypoxemia, and that they should continue using PAP. Respiratory Recap Treatment of Obstructive Sleep Apnea ∎ Many types of treatments exist, including mechanical, surgical, and pharmacologic approaches. ∎ The mechanical approach using positive airway pressure is one of the most common and effective treatments for OSA. ∎ Only 55% of patients use the PAP device every night during sleep.

Mechanical Devices In selected patients, nasopharyngeal tubes that can keep the upper airway open have been used to treat sleep apnea successfully.97,98 The control of apnea and hypopnea is less than with CPAP therapy, and the quality of sleep remains poor. Moreover, nasopharyngeal tubes are not well tolerated and have limited clinical utility. Both external and internal dilators have been investigated as treatments for patients with OSA.97–100 They produce improvement in snoring intensity and some reduction in apneas, but patients continue to have oxygen desaturation and poor quality of sleep. Nasal dilators can be tried to reduce snoring, but are not recommended for therapy of moderate and severe sleep apnea.

Mortality Associated with Obstructive Sleep Apnea Many studies have shown that patients with untreated sleep apnea have increased cardiovascular mortality, although the mortality rates found in

such research have varied. Mortality rate variability seems to be related to multiple factors, including the severity of disease, age, obesity, hypertension, medical illnesses, and therapy. Most studies show increased mortality in patients with moderate to severe OSA, whereas the role of mild sleep apnea is not clear. Increased mortality rates have been shown in both clinical and community populations with sleep apnea. A study of a community population (the Wisconsin Sleep Cohort) with 18 years of follow-up showed that, after adjusting for age, sex, and BMI, allcause mortality was 3.8 times higher in patients with severe OSA compared with those with no sleep-disordered breathing.70 In the same study, the cardiovascular mortality in patients with severe OSA was 5.2 times that in normal subjects. Other studies have found annual mortality rates ranging from 2% to 4% but have also emphasized the contribution of associated risk factors. Sleep apnea causes increased highway and industrial accidents.41,42,101,102 The odds of occupational accidents are nearly double in persons with OSA.102 Persons with sleep apnea who undergo surgery are also vulnerable to increased mortality in the perioperative period from anesthesia and medications, especially when it is undiagnosed or untreated. Nocturnal hypoxemia, an important pathophysiologic feature of OSA, strongly predicts sudden cardiac death (SCD) independently of well-established risk factors.103 Cardiovascular events such as angina and myocardial infarction and the death rates in patients with severe OSA who are treated with CPAP therapy are similar to those in controls,104 perhaps because of nonadherence to therapy—fewer than half of patients use the CPAP device for more than 4 hours per night. Successful therapy of sleep apnea by using CPAP more than 5.5 hours per night is associated with substantial improvements in sleepiness, memory, functional status, and blood pressure, as well as reduced rates of cardiovascular mortality. Motivational enhancements (ME) delivered during brief appointments and phone calls can increase CPAP adherence.105 Respiratory Recap Mortality Associated with Obstructive Sleep Apnea ∎ Untreated OSA can result in serious complications and even death.

∎

Proper diagnosis and patient adherence to required treatments are imperative. The respiratory therapist plays an important role in the diagnosis, treatment, education, and management of the patient with OSA.

Central Sleep Apnea Central sleep apnea is diagnosed when the patient experiences simultaneous cessation of airflow and ventilatory effort. Because of their apneas, such patients experience fragmentation of sleep with nocturnal awakening, resulting in daytime sleepiness. There is considerable overlap in both clinical symptoms and polysomnographic findings between OSA and CSA patients. If more than 50% of the apneas are scored as central, then CSA is considered the primary diagnosis.71 Patients with central sleep apnea are usually not obese and have milder sleep-related symptoms. Snoring and daytime sleepiness are less common, but patients frequently complain about insomnia and restless sleep. Nocturnal hypoxemia is less severe compared to persons with OSA. In most cases of CSA, patients demonstrate an increased ventilatory response to CO2. CSA encompasses several clinical conditions, including idiopathic CSA (ICSA), Cheyne-Stokes breathing, high altitude–induced periodic breathing, narcotic-induced central apnea, and obesity hypoventilation syndrome (OHS).106,107 Rarely, central sleep apnea may occur without any known cause; this condition is called primary or idiopathic central sleep apnea. Both central and obstructive apneas may occur with acute administration of opioids. In long-term users of methadone, morphine, and hydrocodone, CSA may be seen in as many as 50% of patients.

Cheyne-Stokes Breathing Cheyne-Stokes breathing (or Cheyne-Stokes respiration), also known as periodic breathing, is characterized by prolonged periods of waxing and waning of ventilation separated by central apneas or hypopneas (Figure 45-7). It is usually seen in males who are older than 60 years of age; it is rarely seen in females. This pattern of breathing is seen in 25% to 40% of patients who have congestive heart failure and in approximately 10% of patients with stroke.

FIGURE 45-7 Cheyne-Stokes breathing. Upper: oronasal airflow. Middle: chest movements. Lower: abdominal movements.

Description Central apneas in Cheyne-Stokes breathing occur because PaCO2 drops below the apneic threshold. Carbon dioxide is the primary stimulus for respiration. When PaCO2 levels decrease by a few mm Hg from baseline (usually 3–6 mm Hg), breathing comes to a standstill. The PaCO2 level at which the subjects stop breathing is called the apneic threshold. During central apneas in congestive heart failure, the patient’s blood CO2 increases during the apneic episode. When that blood reaches the brain, it stimulates an increase in breathing so that CO2 is lowered in pulmonary blood. Because circulatory time is prolonged, it takes a while for the blood with a lower PaCO2 level to reach the brain and decrease ventilation. The respiratory center response, in turn, lags behind the changes in blood CO2 and blood CO2 changes are exaggerated, resulting in periods of hyperventilation and apnea. On polysomnogram, the apnea–ventilation cycle duration reflects the circulation time for blood to move from the lungs to the chemoreceptors. A Cheyne-Stokes breathing pattern typically occurs during the transition from wakefulness to sleep, mostly in sleep stages 1 and 2, and rarely in stage 3 and REM sleep. Treatment of Cheyne-Stokes breathing is mainly directed toward improving cardiac function.107 Nocturnal oxygen therapy reduces the frequency of apneas and improves daytime symptoms. Some medications, including theophylline and hypnotics, can also help ameliorate this condition.

Adaptive servo-ventilation (ASV) has been used to treat central sleep apnea and Cheyne-Stokes breathing. This technique uses servocontrolled inspiratory pressure support. Similar to BPAP and CPAP, ASV provides EPAP to control obstructive events. ASV differs from CPAP or BPAP in that it provides breath-by-breath adjustment of inspiratory pressure and uses a backup rate to normalize breathing relative to a predetermined target. ASV increases IPAP for hypopnea and decreases IPAP for hyperpnea. When minute ventilation falls below the set target, ASV increases IPAP to provide the ventilation needed. When the patient’s breathing stabilizes, IPAP is rapidly reduced back toward the minimum required. Cheyne Stokes respirations, when treated with adaptive servo-ventilation, have been shown to be associated with harm.108 The American Academy of Sleep Medicine recommends that physicians stop prescribing ASV to treat central sleep apnea in patients with symptomatic heart failure and left ventricular ejection fraction ≤ 45%.109

High-Altitude Periodic Breathing High-altitude periodic breathing is characterized by cyclical periods of central apnea and hyperpnea with a cycle length of 12 to 34 seconds. This pattern of breathing is seen in almost all people living at altitudes higher than 7600 meters and in some individuals at altitudes lower than 5000 meters. In high altitude, hypoxemia also becomes a factor in driving respiration. Individuals will hyperventilate due to hypoxemia, which drives CO2 levels below the apneic threshold and results in periods of apnea.

Obesity Hypoventilation Syndrome Obesity hypoventilation syndrome is defined as the combination of obesity (BMI ≥ 30 kg/m2) and arterial hypercapnia (PaCO2 ≥ 45 mm Hg) during wakefulness. Hypercapnia worsens during sleep, particularly during REM sleep. Both obstructive and central apneas can be seen in patients with OHS. The patient with OHS who first presents for evaluation of a sleep complaint is clinically almost indistinguishable from the typical obese,

snoring, sleepy patient with sleep apnea. If blood gases are not drawn, the clinician may miss the presence of OHS. Only careful analysis of the sleep study will reveal hypoventilation. In particular, the OHS sleep study will show a prolonged (rather than intermittent) desaturation pattern. In the past, arterial blood gases were routinely drawn for all patients presenting for evaluation of sleep disorders. The present practice is to rely on noninvasive oximetry; however, hypercapnia can go unrecognized with such testing. Elevated serum bicarbonate on the venous blood is often the only hint that an arterial PaCO2 needs to be sampled. Although patients with hypercapnia may have low oxygen saturation while awake, it is often only modestly reduced until sleep. Noninvasive measurement of hypercapnia by end-tidal CO2 has proven difficult and yields inconsistent results for technical and clinical reasons, which is why obtaining a blood gas for assessment of PaCO2 is recommended in any patient presenting with an elevated venous bicarbonate level and/or associated chronic obstructive pulmonary disease (COPD) or a predisposition to respiratory depression (e.g., medication use such as opioids).110

Restless Legs Syndrome Restless legs syndrome (RLS) is a sensorimotor disorder characterized by irresistible urges to move the legs accompanied by uncomfortable symptoms in legs that are difficult to describe. RLS causes paresthesias (abnormal sensations) or dysesthesias (unpleasant abnormal sensations), with sensations varying in severity from uncomfortable to irritating to painful. Descriptions of these symptoms include “ants are crawling under my skin,” “soda is running in my veins,” and “there is a creepy crawly feeling.” These symptoms usually occur during periods of rest and reclining. Although the symptoms may be present all day, they worsen in the evenings. The most distinctive or unusual aspect of this condition is that lying down and trying to relax activates the symptoms. Most people with RLS have difficulty falling asleep and staying asleep.

Prevalence Approximately 10% of the U.S. population may have RLS. Several studies have shown that moderate to severe RLS affects approximately 2% to 3% of adults (more than 5 million individuals). Childhood RLS is estimated to affect almost 1 million school-age children, with one-third having moderate to severe symptoms.111 RLS occurs in both men and women, although the incidence is about twice as high in women. It may begin at any age, and the cause is not known, but may be genetic. Many individuals who are severely affected are middle-aged or older, and the symptoms typically become more frequent and last longer with age. Approximately 80% of the patients with RLS symptoms have periodic leg movement during sleep (PLMS).111 Such movements are frequently associated with arousals, causing both insomnia and daytime sleepiness. PLMS is characterized by involuntary leg twitching or jerking movements during sleep that typically occur every 15 to 40 seconds, sometimes throughout the night. The symptoms cause repeated awakening and severely disrupted sleep. Although many individuals with RLS also develop PLMS, most people with PLMS do not experience RLS. PLMS may be a variant of RLS and, therefore, may respond to similar

treatments. Considerable evidence suggests that RLS is related to a dysfunction in the brain’s basal ganglia circuits that use the neurotransmitter dopamine, which is needed to produce smooth, purposeful muscle activity and movement. Disruption of these pathways frequently results in involuntary movements. Individuals with Parkinson disease, another disorder of the basal ganglia’s dopamine pathways, often have RLS as well.

Treatment of RLS Movements such as walking or stretching often relieve symptoms. Consequently, people with RLS will often pace or frequently move their legs. Finding and treating an associated medical condition, such as peripheral neuropathy or diabetes, can sometimes control RLS symptoms. Lifestyle changes and activities that may reduce mild to moderate symptoms include decreased use of caffeine, alcohol, and tobacco; supplements to correct deficiencies in iron, folate, and magnesium; a regular sleep pattern; moderate exercise; and massage of the legs, a hot bath, and application of a heating pad or ice pack. Medications are usually helpful, but no single medication effectively manages RLS for all individuals. Thus, trials of different drugs may be necessary to find the best option for a specific patient. In addition, when taken regularly, medications may lose their effect over time or even worsen symptoms, making it necessary to change them periodically. Drugs prescribed to treat RLS commonly include dopaminergic agents, which increase dopamine and are used to treat Parkinson disease. These agents, given at bedtime, are the initial treatment of choice. Ropinirole, pramipexole, and rotigotine are FDA approved to treat moderate to severe RLS. These drugs are generally well tolerated but can cause nausea, dizziness, or other side effects. Good short-term results of treatment with levodopa plus carbidopa have been reported. With chronic use of this medication, however, a person may begin to experience symptoms earlier in the evening and then in the afternoon until finally the symptoms are present around the clock. Gabapentin enacarbil can also be prescribed to treat moderate to severe RLS. It metabolizes in the body to become gabapentin. Other

medications may be prescribed off-label (not specifically designed to treat RLS) to relieve some of the symptoms. These include benzodiazepines, opioids, and anticonvulsants. Side effects of these medications can actually cause sleep apnea, so they should be used only under careful supervision. Left untreated, RLS can cause exhaustion, daytime fatigue, and depression. Many people with RLS report that their job, personal relationships, and activities of daily living are strongly affected as a result of their sleep deprivation and inability to concentrate.

Key Points Sleep apnea is common and is associated with significant complications and even death in patients who remain untreated. Persons who exhibit symptoms suggestive of sleep apnea should see a sleep specialist who can perform polysomnography, leading to the appropriate diagnosis and treatment. The most common type of sleep-disordered breathing is obstructive sleep apnea (OSA). Central sleep apnea (CSA) encompasses several clinical conditions, including idiopathic CSA (ICSA), Cheyne-Stokes breathing, high altitude–induced periodic breathing, narcotic-induced central apnea, and obesity hypoventilation syndrome (OHS). Rarely, central sleep apnea may occur without any known cause, in which case it is called primary or idiopathic central sleep apnea. Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an irresistible desire to move one’s legs accompanied by uncomfortable symptoms in the legs that can occur throughout the day but is most common in the evening. Respiratory therapists should understand the basics of polysomnography and sleep-disordered breathing because they may frequently be in contact with persons who have undiagnosed sleep apnea. Several treatment modalities are available to alleviate the symptoms and reverse most of the complications associated with sleep apnea. Respiratory therapists have an important role in the diagnosis, treatment, and management of sleep-disordered breathing. Patient education is a key component of patient adherence to treatment of OSA. Successful therapy of sleep-disordered breathing can significantly improve quality of life. Patient and family involvement in care plans is important to achieve adherence to care plans, including properly and consistently using CPAP, taking medications, or following other treatments. Consistent implementation of care plans can effectively manage patients’ symptoms and morbidities.

Without successful and effective treatment of sleep apnea, patients risk worsening of chronic diseases, accidents, and even death.

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CHAPTER

46 Perioperative Management of Lung Transplant Recipients Jordan W. Whitson

© Andriy Rabchun/Shutterstock

OUTLINE Lung Transplant History Disease States for Transplantation Transplant Recipient Criteria Lung Allocation Score Donor Evaluation and Selection Donor Management Surgical Procedure Postoperative Management

OBJECTIVES 1. 2. 3. 4. 5. 6. 7.

Summarize the history of lung transplantation. List the patient populations most commonly referred and who receive lung transplantation. Describe the clinical changes that should prompt referral for lung transplant evaluation. List selection criteria for lung transplantation. Define the Lung Allocation Score (LAS) and listing practices. Discuss donor selection criteria. Compare donation following brain death and donation following cardiac death.

8. Describe management of donors prior to organ acquisition. 9. Describe the means by which lungs are transplanted into recipients, specifically extracorporeal membrane oxygenation and cardiopulmonary bypass. 10. Describe postoperative management of lung transplant recipients.

KEY TERMS donation after brain death donation following circulatory determination of death (DCDD) human leukocyte antigen (HLA) Lung Allocation Score (LAS) lung transplant lung transplant candidacy lung transplant window primary graft dysfunction (PGD)

Introduction Since the first successful lung transplant in 1983, lung transplantation has become a standard of care to treat many end-stage lung diseases. With the evolution of postoperative management and organ allocation, the landscape has changed dramatically in terms of disease states requiring transplantation, donor selection, and perioperative management. The process by which a patient is evaluated and deemed appropriate for transplant requires coordination among a number of provider teams and may vary depending on the center involved. The same may be said about selection of the donor itself, as well as the postoperative management of the recipient. As more is learned about the nature of immunosuppression, rejection, and the diseases for which transplantation is undertaken, the perioperative landscape is gradually changing. Pulmonary arterial hypertension, for example, has seen a decline in transplant numbers (or rather the percentage of transplants performed) over the past 20 years as a result of improvements in available therapies. The same can be said for chronic obstructive pulmonary disease (COPD), owing to implementation of the Lung Allocation Score (LAS). The impact of human leukocyte antigen (HLA) antibodies on long-term graft function has led to a more selective approach to both donor and recipient selection, and simultaneously inspired novel therapies for the development of antibodies after transplant. The innovations that have improved survival for other disease states, such as lung-protective ventilation and extracorporeal membrane oxygenation support, have made lung transplantation possible for numerous candidates who may not have survived the procedure even 15 years ago.

Lung Transplant History Much has changed since the first lung transplant was performed in 1963 by Dr. James Hardy on a 58-year-old prisoner with metastatic lung cancer.1 While this patient survived only 18 days following the procedure owing to progressive renal failure, the clinical team noted a marked improvement in his arterial oxygenation. Chest radiograph and angiogram confirmed successful anastomosis. While the initial outcome might have been poor, the success of the anastomosis led to multiple attempts at lung transplant in subsequent decades, with eventual success coming nearly 20 years following the initial attempt. In 1983, the Toronto Lung Transplant Group performed the first successful lung transplant on a 58-year-old male with pulmonary fibrosis. With the use of cyclosporine and azathioprine, the patient survived for 7 years, establishing the basis for the current immunosuppressive regimen. This procedure was followed in 1986 by the first successful double-lung transplant for emphysema. In the subsequent decade, the success of this approach became apparent. By 1987, approximately 45 transplants had been performed; just 3 years later, more than 400 such procedures had been carried out worldwide. Throughout the 1990s, there were, on average, 1400 transplants per year, with those numbers increasing significantly in the following decades (Figure 46-1).2 Advances in surgical technique, donor and recipient selection, and medical management improved survival from an average of 4 years in the 1980s and 1990s to 5 to 6 years now.3,4 As more strides are made in organ procurement and treatment of rejection, among other aspects of care, further improvements in lung transplantation are expected.

FIGURE 46-1 Timeline showing the number of adult lung transplants per year. Data from Chambers DC, Yusen RD, Cherikh WS, Goldfarb SB, Kucheryavaya AY, Khusch K, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult lung and heart–lung transplantation report—2017; focus theme: allograft ischemic time. J Heart Lung Transplant 2017;36(10):1047.

Description

Disease States for Transplantation Just as surgical techniques and medical management have changed, so, too, have the indications for transplantation evolved over the years. With some variation, the four major groups in which transplant is performed include patients with COPD/emphysema, cystic fibrosis (CF)/bronchiectasis, idiopathic pulmonary fibrosis (IPF), and pulmonary arterial hypertension (PAH) (Figure 46-2).5 In the late 1980s and early 1990s, at a time when lung transplantation had become the standard of care for many end-stage lung diseases, the majority of transplants were performed for the treatment of COPD/emphysema due, in part, to the absence of the LAS system and lower short-term mortality compared to the other diseases such as pulmonary hypertension and IPF. In 1990, for example, idiopathic pulmonary arterial hypertension (IPAH) accounted for twice the number of CF transplants and nearly as many IPF transplants. The introduction of intravenous epoprostenol in 1995 decreased those numbers by nearly 75% by 1998, and then by an additional 50% by 2005. Introduction of the LAS system in 2005 led to a nearly 10% decline in COPD transplants, whereas IPF transplants increased by nearly the same number in the subsequent decade.

FIGURE 46-2 Timeline showing indications for adult lung transplants. Data from Whelan TP, Dunitz JM, Kelly RF, Edwards LB, Herrington CS, Hertz MI, Dahlberg PS. Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant 2005;24(9):1269.

Description Interestingly, the disease state itself affects the type of procedure used. For many years, single-lung transplant was the preferred approach to patients with IPF. Over the past 15 years, however, data regarding improvement in long-term survival, in combination with an improvement in surgical technique, have led to a nearly 60% increase in the rate of bilateral lung transplant for IPF. Similar data exist for COPD, albeit only for patients younger than 60 years of age.6,7 In each of the four major disease-candidate categories, the question of when to refer for consideration of transplantation often arises (Table 46-1). Although no specific guidelines exist, a general consensus regarding timing of referral has occurred. For cystic fibrosis, a decline in FEV1 to 50 mm Hg, a decrease in PaO2 to 50 mm Hg and/or a decrease in PaO2 to 50 mm Hg and/or PaO2 < 60 mm Hg FEV1 < 25% predicted BODE index of 5 to 6

Pulmonary vascular disease

NYHA functional class III or IV symptoms during escalating therapy Use of parenteral targeted therapy Known or suspected pulmonary veno-occlusive disease 6-minute walk distance < 350 meters Cardiac index < 2 L/min/m2 Development of progressive right heart failure or syncope

BODE, body mass index, airflow obstruction, dyspnea, exercise; DLCO, diffusing capacity of lung for carbon monoxide; FEV1, forced expiratory volume in the first second of expiration; FVC, functional residual capacity; NIV, noninvasive ventilation; NYHA, New York Heart Association.

Respiratory Recap Disease States for Transplantation ∎ COPD/emphysema ∎ Cystic fibrosis/bronchiectasis ∎ Idiopathic pulmonary fibrosis ∎ Pulmonary arterial hypertension

Transplant Recipient Criteria Identifying a patient’s lung transplant window and lung transplant candidacy is challenging. When evaluating a transplant window, a number of considerations must be considered. First, the clinician must assess the disease type and disease severity. A patient with newly diagnosed IPF on room air would be considered too early for transplantation. Certainly, disease progression is possible, but if one were to consider the general survival rate of lung transplantation (a 5year survival rate of 85%), the patient may take that long to even progress to the point where a listing is indicated. In contrast, a similar patient who requires 20 L/min of oxygen and is unable to walk the distance from the waiting room to the exam table may be past the window for transplant; this patient might be unable to be rehabilitated to the point that surviving transplantation becomes likely. The ideal window is one in which tangible disease progression is observed, but where exertional capacity is not so limited that rehabilitation is no longer an option. The more challenging task is to determine candidacy. In most cases, the process to determine candidacy involves input from a number of specialists, including psychiatry, cardiothoracic surgery, nutrition, physical therapy, occupational therapy, financial and social work, and pulmonology. A wide array of laboratory and radiographic investigations as well as right and left heart catheterizations, measurement of esophageal pH, and manometry are performed on all patients. Certain disease states may then warrant additional studies (Table 46-2). Patients with sarcoidosis or severe, long-standing pulmonary hypertension will also need cardiac magnetic resonance imaging (MRI), whereas candidates with cystic fibrosis may undergo computed tomography (CT) of the sinus. TABLE 46-2 Studies Performed for Full Transplant Evaluation Labs

Reassessment Interval

ABO (two results required)

Two

PFT with arterial blood gas

Unless done in past 4 weeks

HLA antibody screen

Unless done in past 4 weeks

PPD skin test (or quantiFeron gold)

Within 1 year of listing

Serologies (HBV surface antigen, HCV antibody, HIV, EBV, CMV)

Repeat negative studies every 6 months if listed

CBC, CMP, magnesium



Sputum culture (AFB, fungal, bacterial, or cystic)

Within 2 months of listing

Studies

Reassessment Interval

Chest x-ray (posterior–anterior and lateral)

Unless done in past 4 weeks

CT chest scan

Within 6 months of listing or every 6 months while listed

Diaphragmatic fluoroscopy

Within 1 year of listing

O2 titration/6-minute walk test

Within 1 year of listing

scan

Once

Barium swallow

Once

Cardiac Evaluation

Reassessment Interval

Electrocardiogram

Within 1 year of listing

2-D echocardiogram with microcavitation

Every 6 months while listed

Age < 50 years: right heart catheterization

Within 6 months of listing; repeat every 6 months while listed

Age 40–50 years: CT coronary angiography or LHC

Once

Age > 50 years: right and left heart catheterization

Right heart catheterization within 6 months of listing; repeat every 6 months while listed

Gastrointestinal Evaluation

Reassessment Interval

Age ≥ 18 years: 24-hour pH probe/esophageal manometry

Once

Age < 18 years: BRAVO study

Once

Conditional Tests

Indications

Screening mammogram

Female age ≥ 40

Pap test

Female age ≥ 16 if no hysterectomy

Pelvic exam

Females post-hysterectomy for benign reasons

Colonoscopy

Age ≥ 50 years

Carotid ultrasound

Age ≥ 50 years

Liver ultrasound

Age < 50 years

CT scan abdomen pelvis for surgical planning and malignancy screening

Age > 50 years and/or if significant cardiovascular disease or anticipated need for iABP

Nuclear medicine GFR

If concern for CKD or previous CNI exposure

Sinus CT

Cystic fibrosis

Bone density (DEXA)

Within 5 years of COPD, CF

Cardiac MRI

Sarcoidosis, severe pulmonary hypertension

Liver FibroScan

Concerns for possible liver disease

More so than determination of the transplant window, establishing the basis for an acceptable or desirable transplant candidate varies significantly between centers. Depending on the comfort of the medical and surgical staff, patients of a certain age or with certain comorbidities may be considered too high risk at some centers, whereas they may be considered average risk at other centers. In some cases, a program may consider an age of 65 years or greater an absolute contraindication to listing; other centers may not have an upper-age limit. The same may be said about certain comorbid diseases, such as pulmonary hypertension,

coronary artery disease, and esophageal dysfunction.11 Stop and Think A patient with COPD asks if she is a candidate for transplantation. How would you respond?

Some criteria are deemed to represent a high or unacceptable risk regardless of the center (Table 46-3). The presence of active malignancy, a malignancy in the previous 2 to 3 years that is not localized (such as stage I breast cancer or prostate cancer Gleason score ≤ 6), or a previous malignancy with a high risk of recurrence will typically preclude transplantation.12 Likewise, chronic infection with highly virulent or resistant microbes that are poorly controlled prior to transplant (e.g., certain strains of Burkholderia cenocepacia or active Mycobacterium tuberculosis) may exclude patients from transplant listing for fear of progression following the introduction of immunosuppressive therapy.13 The perioperative use of opioids or benzodiazepines also complicates postoperative management of pain and anxiety and, in most cases, may exclude candidates from transplant. Finally, some factors may represent correctable contraindications. The lack of pulmonary rehabilitation or the presence of obesity (typically defined as being at more than 130% of ideal body weight) may be corrected with a referral from the pulmonologist or strict dietary discretion and exercise, respectively.14 TABLE 46-3 Exclusion Criteria for Transplantation Malignancy in the last 2 years (with the exception of localized malignancies with an expected 5-year survival of >80%); patients with malignancies at high risk for recurrence must be 5 years free of cancer Untreatable advanced dysfunction of another major organ system (heart, liver, kidney, or brain) unless a candidate for multiple-organ transplant Age > 60 years and in need of multiple-organ transplant Uncorrected atherosclerotic disease with suspected or confirmed end-organ ischemia or dysfunction or coronary artery disease not amenable to revascularization

Uncorrectable bleeding diathesis Chronic infection with highly virulent and/or resistant microbes that are poorly controlled prior to transplant (including genomovar 3 Burkholderia cenocepacia) Evidence of active Mycobacterium tuberculosis infection Significant chest wall/spinal deformity expected to cause severe restriction after transplant Excessive obesity or malnutrition, generally defined as 130% ideal body weight Psychiatric or psychological condition associated with the inability to cooperate with the medical/allied health team and/or adhere to complex medical therapy Current or historic repeated or prolonged documented nonadherence to medical therapies and appointments Active substance addiction (e.g., alcohol, tobacco, narcotics, or illicit substances) Severely limited functional status with poor rehabilitation potential Severe or symptomatic osteoporosis Chronic, active use of narcotics or benzodiazepines Severe esophageal dysmotility Multiple comorbid conditions that, when combined, make transplant an unsafe risk Current disease that is too early for transplantation

One condition of particular concern and debate among lung transplant centers is the presence of human leukocyte antigens (HLA). These proteins are found on most cells of the body; the immune system uses them to recognize native versus foreign entities. In the case of transplantation, blood samples are drawn from recipients and potential donors and analyzed for certain HLA types. Numerous markers may be either shared or targeted by antibodies in the donor–recipient pair. These antibodies may be innate or formed later in life (e.g., after a blood transfusion) and, depending on the percentage of mismatch, may preclude transplantation or require augmented immunosuppression at the time of transplantation.15

After a patient is determined to be both within the transplant window and an acceptable transplant candidate, the patient is typically relocated, if necessary, to a certain time and/or distance from the transplant and rehabilitation center. Certain benchmarks must be met prior to listing the patient, meaning that the patient can actively accept organs. An understanding of post-transplant expectations—for both the patient and caregivers—may be completed through a series of lectures and literature, while optimization of the patient’s physical condition may be achieved with a pulmonary rehabilitation program.

Lung Allocation Score Prior to May 2005, all patients actively listed for lung transplant were selected based on listing time. As a result, patients with more slowly progressive diseases, such as COPD, were more likely to undergo transplantation than those with diseases more prone to rapid declines in lung function and high waiting list mortality, such as IPF or severe pulmonary hypertension. Recognizing the disadvantage at which this practice placed the latter group, the Organ Procurement and Transplant Network (OPTN) implemented the Lung Allocation Score (LAS) in May 2005 with the goal of maximizing overall survival benefits among patients on the waiting list along with those undergoing transplantation. The scoring algorithm utilizes clinical data, including respiratory function, hemodynamics, and diagnosis, and balances these data with waitlist mortality and post-transplant survival rates. When donor organs become available, those patients with the highest scores within the Organ Procurement Organization (OPO) region receive priority.16 The LAS is applied to all recipients aged 12 and older (Table 46-4). Considering a number of factors, a number from 0 to 100 is assigned to the patient. The United Network for Organ Sharing (UNOS) requires most of the available data to be either current (within the past 6 months) or a zero value, with some exceptions made if the patient is deemed unable to complete a test due to his or her clinical condition. Likewise, if certain instances arise in which it is believed that a patient’s assigned/calculated LAS does not accurately reflect the circumstances, a petition may be submitted to UNOS for modification and adjudication. TABLE 46-4 Lung Allocation Score Variables for Prediction of Waitlist Survival • Diagnosis • Age • Body mass index • Diabetes • NYHA functional class • Forced vital capacity (% predicted)

• • • •

Oxygen requirement at rest Continuous mechanical ventilation Pulmonary artery systolic pressure (for all groups except PAH) 6-minute walk distance < 150 feet

Variables for Prediction of Post-Transplant Survival • Diagnosis • Age • Creatinine • NYHA functional class • Forced vital capacity (PAH and ILD groups only) • Pulmonary capillary wedge pressure ≥ 20 mm Hg (ILD group only) • Continuous mechanical ventilation ILD, interstitial lung disease; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension. Modified from Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ, et al. International guidelines for the selection of lung transplant candidates: 2006 update-a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25(7):745–755.

In addition to the LAS score, other considerations include blood type compatibility, chest cavity size, and age of the donor. A patient with a high LAS score with incompatible blood type or HLA profile may not be a candidate for an available organ. By the same token, that same patient may be a perfect blood and HLA match but, if the donated lungs are either too small to adequately oxygenate the patient or too large to fit within the recipient’s chest cavity, transplantation may not be possible. Distance from the transplant center within that OPO region is another important consideration for some programs, regardless of the patient’s LAS.

Donor Evaluation and Selection Optimal selection of and care for donor lungs are paramount in the process of transplantation. Just as with recipient candidacy, the selection of an appropriate donor depends on thorough evaluation and the input of many different teams. The evaluation begins with the notification of the local OPO—typically a provider with experience in the consent of families for organ donation—whose intervention depends largely on whether the donation is made following brain death or circulatory determination of death. The majority of lung transplants involve donation after brain death. An important topic in and of itself, brain death is diagnosed in a number of ways, typically with a combination of clinical and radiographic examination. It is important that the patient meet the appropriate evaluation criteria: a core temperature ≥ 36º C (97º F), systolic blood pressure ≥ 100 mm Hg, eucapnia (PaCO2 35 to 45 mm Hg), absence of hypoxia, and euvolemia. The clinical portion of the exam must demonstrate an absent brain-originating motor response (such as response to pain or decerebrate/decorticate posturing), absent corneal and oculovestibular reflexes, absent gag and cough with tracheal suctioning, and positive apnea test. The apnea test involves monitoring the donor’s respiratory response in the setting of PaCO2 > 60 mm Hg and arterial pH < 7.28 over a period of 8 minutes while the donor is disconnected from the ventilator. A positive test involves a PaCO2, measured prior to ventilator reconnection, of >60 mm Hg or >20 mm Hg from baseline, and no breathing activity.17 Many centers also measure brain blood flow, typically via nuclear medicine or MRI; these modalities can evaluate the filling of cerebral arteries. Their use is predicated upon the notion that brain death is typically accompanied by elevated intracranial pressure from tissue edema/mass effect that, when exceeding the systemic arterial pressure, results in absence of cerebral blood flow. Respiratory Recap

Apnea Test ∎ This test is used to assess brain death. ∎ PaCO2 is normalized. ∎ The patient is disconnected from the ventilator for up to 8 minutes. ∎ If respiratory activity occurs, the patient is reconnected to the ventilator. ∎ A positive test (consistent with brain death) is PaCO2 > 60 mm Hg (or >20 mm Hg from baseline), and no breathing activity.

Donation following circulatory determination of death (DCDD) is less commonly seen, largely because the warm ischemic time often renders donated tissues nonviable. However, DCDD donors have increased in the United States from 1% to 4% of lung transplants from 2011 to 2016. Situations in which DCDD may be considered include irreversible brain injury and end-stage musculoskeletal disease, where the donor may not meet criteria for brain death. As opposed to donation after brain death, DCDD is based on the notion of organ procurement following death and requires cardiopulmonary criteria to prove absence of circulation.18 This testing is typically performed with the use of an indwelling arterial line or Doppler study and involves at least 2 minutes of clinical observation to declare cardiac death. With regard to withdrawal of life-sustaining treatment, a limit of 60 to 120 minutes is usually considered the upper limit for consideration of organ recovery.19 Several studies have compared graft survival between the two modalities. In these studies (a systematic review, an international multicenter registry study, and a 6-year single-center study),20–23 researchers noted a higher incidence of primary graft dysfunction (PGD) and long-term bronchiolitis obliterans syndrome (BOS) with DCDD but no significant difference in survival based on the type of donation.21 With regard to donor selection, there are no controlled data to define the ideal candidate. Some aspects—such as blood type compatibility and size, discussed in previous sections—are deemed essential criteria, but most centers maintain their own criteria and definition of the perfect donor. In general, these guidelines include (but are not limited to) donor age younger than 55 years, ABO compatibility, PaO2 > 300 mm Hg on FIO2 of 1.0 and positive end-expiratory pressure (PEEP) of 5 cm H2O, absence of significant chest trauma, no evidence of aspiration, and no prior cardiopulmonary surgery.24 In addition, a subset of extended donors

may be considered in the appropriate circumstance. In these cases, there is an individual-recipient risk but a population-recipient benefit from accepting donors older than the age of 55 years or those with a smoking history of greater than 20 pack years.25,26 By the same token, while a clear chest x-ray is ideal, the presence of radiographic abnormality (e.g., pulmonary edema) may be overlooked in the setting of intact lung compliance and PaO2, as no demonstrable impact upon graft function has been demonstrated in these cases. With regard to size matching, the criteria are typically based on donor and recipient height, with some consideration also given to estimates of lung volume made from chest x-rays. Obtaining a donation of the optimal lung size may not be possible in many cases. For example, patients with advanced IPF may have smaller chest cavities due to the tendency for lung volumes to diminish as the disease progresses. Nevertheless, a close match is preferred. The use of oversized donor lungs may reduce the risk of grade 3 PGD compared to use of undersized lungs.27,28

Donor Management Donor lung preservation involves the maintenance and protection of donor lungs from the time of lung procurement until the implantation in the recipient. This is where factors such as temperature, oxygenation, and warm and cold ischemic time are considered. Management is typically overseen by the local OPO, which will work to coordinate lung procurement with other organs and may be used for separate recipients. A good deal of management is predicated upon prevention of pulmonary interstitial fluid overload, with close attention paid to PaO2. The ventilator criteria include a plateau pressure, and ideally a peak airway pressure, of less than 30 cm H2O.29 Meeting these criteria may require the use of diuretics with concurrent vasopressors to maintain mean arterial pressures in the donor as well as reconciliation of PEEP for optimization of oxygenation while minimizing potential deleterious effects on venous return and cardiac output. In the setting of brain injury with development of diabetes insipidus, use of desmopressin is often implemented. In addition, some studies have suggested that use of thyroid hormone treatment can be beneficial in patients with hemodynamic instability and/or decreased ejection fraction (300

Absent

1

>300

Present

2

200–300

Present

3

VATS). The most common complication is atelectasis, which may result from lung isolation during the surgery or poor respiratory effort due to pain after surgery. Some degree of air leak is present in almost all patients after lung resection; typically peripheral in origin, these air leaks usually resolve within 24 to 48 hours after surgery. Air leak that persists after 5 days qualifies as persistent air leak and carries with it a higher morbidity and prolonged hospital stay. Bronchopleural fistula (BPF) can develop at any time but most commonly arises 8 to 12 days after surgery. Its development can be life-threatening

due to tension pneumothorax or alveolar flooding. BPF is more common after pneumonectomy than other procedures and may manifest on x-ray as failure of the pneumonectomy space to fill with fluid.58 Pulmonary edema, acute respiratory distress syndrome, and pneumonia also occur frequently after thoracic surgery and confer a much poorer prognosis in patients undergoing such surgery. Less common thoracic surgery complications include hemothorax, chylothorax, lung torsion, empyema, and cardiac herniation. Respiratory Recap Treatment of Lung Cancer ∎ Chemotherapy ∎ Radiotherapy ∎ Targeted therapy ∎ Surgery

Complications Malignant pleural effusions (MPE) are common with NSCLC, both at diagnosis and as the disease progresses. MPE is associated with poor prognosis and in lung cancer patients is linked to larger tumors, mediastinal node involvement, and adenocarcinoma.58 Such effusions induce a strong sensation of breathlessness, which is distressing to patients and reduces quality of life. Treatment for MPE focuses on drainage to reduce dyspnea with minimal discomfort for the patient and freedom from hospitalization for the patient and family. Simple thoracentesis often results in quick reaccumulation of pleural fluid and return of symptoms. Although the recommended treatment is talc pleurodesis, this procedure requires hospitalization of the patient. By comparison, use of indwelling pleural catheters can reduce hospitalization times.59 One complication of pleural fluid drainage is reexpansion pulmonary edema, which has traditionally been associated with drainage of large volumes of pleural fluid. A large cohort study reported that pulmonary edema was rare, however: The one case that occurred involved drainage of only 1.5 liter of fluid.60 A significant number of patients with lung cancer develop obstruction of the large conducting airways at some point in the course of their disease. This obstruction can take the form of a mass within the lumen of the large airway (endoluminal obstruction) or compression of the airway from outside the lumen (extraluminal) from locally metastatic intrathoracic disease. It is difficult to relate the degree of compromise of the airway to the severity of obstruction, however, as many factors can impact the degree of obstruction: changes in intrathoracic pressure, respiratory muscle strength, length of the obstruction, and perceived sense of dyspnea.61 This form of obstruction markedly increases dyspnea and is life-threatening. In the workup, PFTs with flow-volume loops will show classic fixed or variable intrathoracic or extrathoracic obstruction and bronchoscopy. Management includes options such as rigid bronchoscopy, Nd:YAG laser, electrocautery, cryotherapy, and airway stents. An important consideration is the requirement for supplemental oxygen, as local fire and thermal injury risk is increased in the presence

of high FIO2. Hemoptysis is common both at presentation and in the course of progression of established lung cancer. It occurs in as many as 20% of patients with lung cancer at presentation and develops in 19% to 32% of patients during the course of the disease. Massive hemoptysis carries a high mortality rate (38%). Hemoptysis late in the progression of the disease often limits treatment options to nonsurgical interventions. In the setting of acute respiratory failure, rigid bronchoscopy by a trained physician can allow for removal of a clot, use of endobronchial blockers, and application of direct pressure, while maintaining a patent airway and facilitating stent placement.62 When time permits, bronchial artery embolization is an option. Respiratory Recap Complications of Lung Cancer ∎ Malignant pleural effusion ∎ Malignant central airway obstruction ∎ Massive hemoptysis

Palliative and End-of-Life Care Palliative Care Early palliative care represents an important element in the management of patients with lung cancer.63 In one study, patients were randomized to early palliative care plus standard oncologic care or standard oncologic care alone independent of the prognosis for recovery. The group who received palliative care scored higher on the quality of life scale, had less depression, and had longer median survival (11.6 versus 8.9 months). Palliative care in that study consisted of a consult with a palliative interprofessional team that addressed physical and psychological symptoms, set goals for care, and consulted with decision making and coordination of care. Several additional studies followed shortly thereafter, and the ACCP incorporated those recommendations into the third edition of its evidence-based clinical practice guidelines for diagnosis and management of lung cancer.64 As front-line clinicians at the bedside of these patients, respiratory therapists must recognize their role in this effort. Palliative care comprises an organized multidisciplinary patient-centered approach to relieving suffering from physical and emotional symptoms and addresses both the patient and the family.

Symptom Control in End-of-Life Care Chronic cough is a frequent and troubling symptom in patients with lung cancer, occurring in 47% to 86% of patients with lung cancer; it increases related pain and makes sleep difficult. A U.K. collaborative task force developed evidence-based guidelines to address cough in patients with lung cancer.65 Its pyramid for management is based on treating cancerspecific triggers for cough and comorbidities (COPD, bronchitis, reflux, medications) that might be responsible for this symptom. The U.K. group constructed an escalating series of treatment options for cancer-related cough, including glycerol, a trial of oral steroids, opioids, antitussives, nebulized local anesthetics, and a variety of experimental pharmacologic options. One option not mentioned by the U.K. task force was nebulized opioids, which have anecdotally been shown to be effective in selected

patients who failed to respond to antitussives, beta agonists, steroids, and oral opioids.66 The sensation of breathlessness is common in end-stage lung cancer and can prove very distressing to patients and families. Dyspnea may be part of the presenting symptom complex or develop at any time in the course of the disease. This symptom is present in more than 50% of patients with advanced cancer.67 The respiratory therapist is frequently asked to assess patients with this troublesome complaint. The perception of dyspnea is a complex phenomenon that combines the sensory input felt by the patient and the patient’s subjective response to the sensation. To effectively manage the symptom, the respiratory therapist must address both aspects. It is first important to make sure that the increased work of breathing prompting the dyspnea is not related to a treatable effect of the primary disease, such as airway compression or atelectasis. Patients with lung cancer often have comorbidities that can cause dyspnea, such as congestive heart failure, reactive airways disease, or bronchitis. The ACCP consensus guidelines on the management of dyspnea68 stress the importance of quantifying the dyspnea using standard scales such as a visual analog scale or the Borg scale, allowing for grading of severe dyspnea and objective assessment of the response to treatment. The ACCP guidelines recommend supplemental oxygen in those patients who are hypoxemic at rest with minimal activity, although this therapy has not been shown to be effective in the absence of hypoxemia. Nonpharmacologic interventions include pursed-lip breathing techniques, mindfulness-based relaxation techniques, and noninvasive positive pressure ventilation. A recent randomized controlled trial also demonstrated the benefit of an intervention that respiratory therapists had long thought was helpful—a fan blowing air on the face.69 The cornerstone of pharmacologic management of dyspnea is opioids.69,70 Morphine, fentanyl, and hydromorphone have all demonstrated efficacy with both oral and parenteral routes of delivery. Nebulized morphine in a dose of 20 mg every 4 hours has also been shown to be effective in reducing dyspnea.70

Case Study: Metastatic Lung Cancer A 72-year-old man sees his physician because of new onset of headaches. The patient currently smokes and has smoked 2 packs of cigarettes a day for the past 40 years. His past medical history is remarkable for two myocardial infarctions. His medications include daily aspirin, atenolol, and captopril (all for his heart). His family history and social history are unremarkable. His physical examination is remarkable for marked gait instability and asymmetric deep tendon reflexes, which are consistent with a pathologic condition in the central nervous system. His chest radiograph reveals a 5-cm mass in the right mid-lung zone with enlargement of the mediastinum, which is consistent with substantial adenopathy in the paratracheal region and the aorticopulmonary window. A right-sided pleural effusion also is present. A CT scan of the head reveals three intracranial lesions, a finding consistent with metastatic disease. A diagnostic thoracentesis yields a positive result for adenocarcinoma of the lung. This patient has metastatic NSCLC, stage III. The metastatic lesion is evident from the pleural effusion and head CT scan. For diagnostic certitude, drainage of the pleural effusion should be performed; this will likely both confirm the diagnosis and stage the patient as stage IV. The therapeutic goal in this situation is best served with palliative care. The patient sought attention for his headaches, and treatment should focus on this symptom. Because the patient has several intracranial metastases, surgical resection of these lesions is not recommended. This decision is based on discussion with the patient and his family regarding his wishes. Although treatment would not offer a cure, chemoradiotherapy and radiation may be offered if the patient has a good performance status. Even so, the median survival is likely be only 10 to 14 months.

Key Points Lung cancer is a common disease and can often be prevented. A tissue-based diagnosis generally is required in case of suspected lung cancer. Techniques may include analysis of sputum or pleural fluid or analysis of bronchoscopic, surgical, or needle biopsy specimens. Lung cancer generally is classified as small cell or non-small cell cancer. Small cell lung cancer generally is treated with chemotherapy or radiotherapy, or both, but is rarely amenable to surgery. Surgical resection is the preferred treatment for early-stage nonsmall cell lung cancer. Chemotherapy and radiotherapy in patients with nonresectable NSCLC who have a good performance status are the standard of care. For patients with advanced disease and a poor performance status, supportive care and palliation remain the only options available. Prevention and early diagnosis are future areas of emphasis in lung cancer.

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CHAPTER

48 Neonatal and Pediatric Respiratory Disorders Sherry L. Barnhart

© Andriy Rabchun/Shutterstock

OUTLINE Apnea of Prematurity Respiratory Distress Syndrome Bronchopulmonary Dysplasia and Chronic Lung Disease Transient Tachypnea of the Newborn Pneumonia in the Neonate Meconium Aspiration Syndrome Persistent Pulmonary Hypertension of the Newborn Congenital Diaphragmatic Hernia Congenital Pulmonary Anomalies Air Leak Syndrome Retinopathy of Prematurity Bronchiolitis Laryngotracheobronchitis Epiglottitis

OBJECTIVES 1. List the factors that may predispose an infant or child to pulmonary disease.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Explain the pathophysiology of pulmonary diseases affecting the newborn and child. Identify the signs and symptoms of pulmonary diseases affecting the newborn and child. Discuss diagnosis of pulmonary diseases affecting the newborn and child. Recognize the radiographic appearance of various diseases of the newborn and child. Integrate the history, physical examination, laboratory, and radiographic findings that are used in the diagnosis of diseases of the infant and child. Discuss treatment options for pediatric pulmonary disease. Explain the significance of monitoring oxygen at preductal and postductal sites. Discuss how hypoxia in a neonate affects the pulmonary vasculature. Describe the development of retinopathy of prematurity. Define apnea of prematurity and periodic breathing. Differentiate between pulmonary agenesis, pulmonary aplasia, and pulmonary hypoplasia. Compare laryngotracheobronchitis and epiglottitis.

KEY TERMS air leak syndrome apnea of prematurity bronchiolitis bronchogenic cyst bronchopulmonary dysplasia (BPD) chronic lung disease (CLD) congenital diaphragmatic hernia (CDH) congenital pulmonary airway malformation (CPAM) epiglottitis laryngotracheobronchitis (LTB) meconium aspiration syndrome (MAS) persistent pulmonary hypertension of the newborn (PPHN) pulmonary agenesis pulmonary aplasia pulmonary hypoplasia pulmonary sequestration respiratory distress syndrome (RDS) retinopathy of prematurity (ROP) transient tachypnea of the newborn (TTN)

Introduction Respiratory illness is the most common cause of infant and childhood morbidity in developed countries. Many disorders result in respiratory distress and place an infant or child at high risk of cardiopulmonary failure. Respiratory disease may begin early in life, even in utero, and remain a challenging problem that affects the infant’s survival and quality of life. It has many etiologies. In utero abnormalities, such as congenital diaphragmatic hernia, can inhibit lung development. Maternal factors, such as medication or illicit drug use, often cause severe respiratory depression. Events at birth will affect the infant’s respiratory status, as occurs with transient tachypnea of the newborn and meconium aspiration syndrome. Premature birth with lungs that are unable to adequately support gas exchange may result in apnea and respiratory distress syndrome. In an unfortunate twist, therapy for respiratory disorders can actually lead to more disease, as is the case with chronic lung disease, air leaks, and retinopathy of prematurity. For a child, acute respiratory tract infections may be either mild or life threatening. Infections resulting in bronchiolitis, laryngotracheobronchitis, and epiglottitis are often causes for emergency department and hospital admissions. Although we have witnessed significant advances in the medical management of infants and children, the fact remains that all of the factors just described continue to affect neonatal and pediatric respiratory care.

Apnea of Prematurity The successful progression from fetal to neonatal life depends on complex physiologic changes that include moving from fetal respiratory activity to normal spontaneous breathing. When an infant is born premature, the immaturity of the central respiratory control center interrupts this normal transition and often leads to apnea. The standard definition of apnea of prematurity is cessation of breathing for at least 20 seconds or for shorter periods if the apnea is followed by bradycardia, oxygen desaturation, cyanosis, or pallor.1 Apnea of prematurity differs from the periodic breathing common to premature and some full-term infants. Periodic breathing is a respiratory pattern characterized by periodic pauses of breathing lasting between 5 and 10 seconds, which are then followed by regular breathing. It has no pathologic significance, does not result in bradycardia or cyanosis, and spontaneously resolves without the need for intervention. Apnea of prematurity affects at least 85% of infants born at less than 34 weeks’ gestation and 50% of infants with a birth weight less than 1500 grams.2 It is the most common cause of apnea in neonates, with peak incidence usually occurring between 2 and 7 days’ postnatal age.

Pathophysiology and Etiology Apnea of prematurity is largely due to immaturity of the medullary brain stem center that regulates breathing. This immaturity leads to impaired responses to hypoxia and hypercapnia and produces an exaggerated inhibitory response to stimulation of airway receptors. Apnea is traditionally classified as obstructive, central, or mixed, depending on the presence or absence of upper airway obstruction. Central apnea is characterized by a lack of airflow, chest wall motion, or inspiratory efforts. In obstructive apnea, inspiratory efforts and chest wall motion persist, but airflow is absent. Mixed apnea—the most common type associated with apnea of prematurity—includes components of both central and obstructive apnea: inspiratory efforts with airway obstruction preceding or following central apnea.

Respiratory Recap Apnea of Prematurity ∎ Cessation of breathing for at least 20 seconds ∎ Caused by immaturity of the brain stem ∎ Treatment: respiratory stimulants, oxygen, continuous positive airway pressure (CPAP), and mechanical ventilation ∎ Potential use of home apnea monitor

Clinical Manifestations In premature infants who are breathing spontaneously with no assistance, apnea usually occurs on the first or second day of life. If lung disease exists or the infant is receiving any form of mechanical ventilation, including noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP), apnea may be delayed or not present until the infant no longer needs ventilator assistance. Bradycardia, hypotension, cyanosis, pallor, and oxygen desaturation typically accompany the apneic episodes. Apnea of prematurity has usually resolved by 37 weeks’ postconceptional age but may persist beyond term, especially in infants delivered at 24 to 28 weeks’ gestation.3 If apnea presents immediately after birth, first presents in a premature infant who is older than 2 weeks, or reoccurs after a 1- to 2-week period without apnea, it may signify an underlying pathophysiologic condition. Immediate investigation of possible causes is always warranted.

Diagnosis The diagnosis of apnea of prematurity is made only after other disorders have been considered and excluded. Clinicians routinely perform several studies to confirm the diagnosis. Laboratory studies performed when infection is suspected include a complete blood count, blood and spinal fluid cultures, and urinalysis. Electrolyte levels and glucose levels are tests useful in diagnosing a metabolic process. Chest radiographs and electrocardiograms (ECGs) are routine, whereas clinicians may order echocardiograms if the patient’s symptoms suggest cardiac disease.

Imaging studies of the head and neck may be obtained if obstructive apnea is suspected. A swallow study or abdominal ultrasound can detect gastrointestinal problems.

Management Clinical management of apnea of prematurity includes cardiorespiratory monitoring and tactile stimulation. When apnea lasts for only a few seconds, stimulating the infant by patting the infant or flicking the feet is usually the only intervention needed. Pharmacologic treatment with methylxanthines, most often caffeine or theophylline, has been used since the 1970s to stimulate respirations, thereby reducing the frequency of apnea and need for mechanical ventilation. Caffeine is preferred over theophylline because it has a longer half-life that allows for once-daily dosing, a larger gap between therapeutic and toxic levels, and fewer side effects.4 The frequency and severity of the apneic episodes determine the required treatment. When apnea results in oxygen desaturation, the clinical team should administer oxygen and apply manual ventilation in case of prolonged apnea. Humidified high-flow nasal cannula, nasal CPAP, or NIV is initiated when the apneic events result in oxygen desaturation or become more frequent despite methylxanthine therapy. In severe cases that include apnea with oxygen desaturation and bradycardia, intubation and mechanical ventilation may be indicated.5 Box 48-1 provides a treatment protocol for apnea of prematurity. Although the time interval is not clearly established, methylxanthine therapy is often discontinued when the patient has not experienced any significant apneic events for 5 to 7 days. The infant is discharged without methylxanthine treatment if no further events occur. BOX 48-1 Protocol for Treating Apnea of Prematurity Monitor with a cardiorespiratory monitor and pulse oximeter. Provide tactile stimulation and reposition the infant’s head and neck. Administer oxygen for bradycardia or oxygen desaturation. Begin methylxanthine therapy (caffeine is preferred). Apply high-flow nasal cannula or nasal continuous positive airway pressure. Intubate and begin mechanical ventilation.

Some infants develop recurrent apnea, in which case medication is restarted. If the infant continues to need methylxanthines at discharge, an impedance monitor (apnea monitor) is often provided for use at home. This monitor documents and stores data on apneic, bradycardic, and tachycardic events. If their infant has recurrent apnea, parents and other caregivers should receive training in cardiopulmonary resuscitation as well as observation and stimulation techniques. They also are instructed on monitor use, including how to apply monitor leads and correctly respond to alarms. The monitor can be safely discontinued after the infant has had no true and significant apneic and bradycardic events for 1 to 2 months after discharge home.6 Box 48-2 lists the indications for apnea monitoring at home. BOX 48-2 Indications for Home Apnea Monitoring in Infants Methylxanthine treatment at home Bradycardia with methylxanthine use Gastroesophageal reflux disease (GERD) with apnea Documented apparent life-threatening event (ALTE) Risk of central apnea Twin or sibling with sudden infant death syndrome (SIDS)–related death* * The American Academy of Pediatrics does not recommend home apnea monitoring to prevent SIDS.

Stop and Think A neonate born at 28 weeks’ gestation has received caffeine for 12 days. He is ready for discharge home. Bradycardia and apnea spells that resolve on their own are noted during feedings. Would you order an impedance (apnea) monitor for home use, or would you recommend delaying discharge until there are no further events?

Complications and Outcomes Apnea that leads to hypoxemia and bradycardia increases the risk of cerebral injury; however, treatment with caffeine decreases this risk.7 Apnea due to prematurity usually resolves by 44 weeks’ conceptional age. It does not place an infant at a higher risk for sudden infant death syndrome (SIDS).8

Respiratory Distress Syndrome Infants born before the 37th week of gestation are considered premature. The consequences of a premature birth are complex, with the earliest recognized complication being respiratory distress syndrome (RDS). Previously referred to as hyaline membrane disease, RDS is the most common cause of respiratory distress in the premature infant and occurs most often in infants born at less than 28 weeks’ gestation. RDS rarely occurs in term infants.9 Respiratory Recap Respiratory Distress Syndrome ∎ Complication of prematurity ∎ Clinical signs: tachypnea, retractions, nasal flaring, and expiratory grunting ∎ Treatment: oxygen, surfactant replacement, CPAP, mechanical ventilation, and supportive therapy

Pathophysiology and Etiology Box 48-3 lists factors that may predispose an infant to RDS. The risk of RDS may decrease if the mother has pregnancy-induced hypertension, prolonged rupture of membranes, or a history of narcotic addiction. The stress of these situations helps the lungs to mature. Antenatal corticosteroid therapy for mothers with preterm labor accelerates maturation of the neonate’s lung and significantly reduces the incidence of RDS and mortality. BOX 48-3 Risk Factors Associated with Respiratory Distress Syndrome Male infant Hypothermia Premature birth Maternal diabetes Perinatal asphyxia Multifetal pregnancy

Family history of respiratory distress syndrome Cesarean delivery without labor

High surface tension and a lack of pulmonary surfactant in the lungs are responsible for the development of RDS in premature infants. Surfactant comprises a complex mixture of phospholipids and proteins that is produced by type II pneumocytes and stored in the lamellar bodies. Its synthesis begins near 20 weeks’ gestation and continues throughout the rest of the pregnancy, with this production accelerating around 36 weeks. As surfactant spreads along the alveolar air–liquid interface, surface tension decreases; thus, lower pressures are required to keep alveoli inflated. In the premature infant, immature type II alveolar cells produce less surfactant, causing alveoli to collapse.10 The result is decreased compliance, reduced functional residual capacity (FRC), diffuse atelectasis, and increased airway resistance and dead space.11 Well-perfused but poorly ventilated areas result in ventilation-perfusion mismatch, accompanied by hypoxia and right-to-left shunting of blood. Because of the premature infant’s weak respiratory muscles and overly compliant chest, work of breathing increases as lung compliance is reduced. Hypercarbia and respiratory acidosis quickly develop as the diaphragm and intercostal muscles become fatigued. Prolonged hypoxemia leads to vasoconstriction of pulmonary arteries, decreased pulmonary blood flow, and direct damage to the respiratory epithelium, allowing plasma to leak into the alveoli. Hyaline membranes then form in the alveoli—hence the term hyaline membrane disease.12,13

Clinical Manifestations RDS is suspected in the premature infant who develops respiratory distress at or shortly after delivery. Tachypnea with a respiratory rate of 60 breaths per minute or greater is often the initial symptom. Other hallmark clinical signs include nasal flaring, subcostal and intercostal retractions, and expiratory grunting. Grunting occurs as air is forced through the partially closed glottis in an attempt to increase the FRC. As the work of breathing continues, grunting becomes ineffective, and the alveoli collapse. Cyanosis and hypoxia are common, and breath sounds are diminished. Examination may reveal an inactive infant who has

edema and decreased perfusion in the peripheral extremities. Oxygen requirements and apnea often increase after birth, such that within 48 hours the infant has rapidly progressed to respiratory failure with hypercarbia and respiratory acidosis. Extremely premature neonates with severe atelectasis and loss of compliance may have lungs so stiff that they are apneic before they leave the delivery room.

Diagnosis Clinical features and risk factors aid in the diagnosis, which is confirmed with physical findings, chest radiographs, and lab values consistent with RDS. A detailed history is also critical in the differential diagnosis. Details should include gestational age and maternal history. Age is important: RDS typically occurs in premature infants, whereas term infants tend to develop transient tachypnea and post-term infants may have meconium aspiration syndrome. Information concerning labor and delivery should include fetal heart tracings, color and amount of amniotic fluid, method of delivery, and maternal temperature. Pneumonia due to β-hemolytic Streptococcus has been associated with rupture of membranes occurring more than 24 hours prior to delivery. Transient tachypnea of the newborn usually occurs in term infants following cesarean delivery without maternal labor. Although the chest radiograph may not be typical in the first few hours after birth, RDS is characterized by a large thymus, markedly decreased lung expansion, atelectasis, and a diffuse symmetric reticulogranular (ground glass) appearance that extends to the periphery of the lungs. With infants with severe disease, the chest radiograph may progress to complete whiteout, which can prove difficult to distinguish from pneumonia (Figure 48-1).

FIGURE 48-1 Chest radiograph of a preterm infant presenting with a bilateral diffuse fine granular (ground glass) appearance and reduced lung expansion, typical of respiratory distress syndrome. Courtesy of Chetan Chandulal Shah, MBBS, DMRD, MBA, Arkansas Children’s Hospital.

Description Biochemical tests of lung maturity began in 1971 with the introduction of the lecithin-to-sphingomyelin (L/S) ratio. Lecithin and sphingomyelin are both phospholipids found in the amniotic fluid. Lecithin levels increase as the fetal lung matures and begins producing surfactant, whereas the amount of sphingomyelin remains fairly constant. A calculated L/S ratio of 2 or greater is considered an accurate indication that sufficient surfactant is being produced and the risk of RDS is low. Recent studies, however, indicate that gestational age—and not the presence of a mature fetal lung index—correlates most highly with improved neonatal outcomes. Although widely used at one time, today the L:S ratio is rarely obtained to confirm lung maturity or to diagnose RDS. Instead, diagnosis is primarily based on gestational age and clinical symptoms.14,15

Management When there is a high risk of delivery occurring between 23 and 34 weeks’ gestation, mothers are given tocolytics to delay delivery and then receive corticosteroids 24 to 48 hours before delivery. This protocol has been shown to accelerate fetal lung maturation and surfactant production, thereby decreasing the incidence of RDS as well as intraventricular hemorrhage and neonatal mortality.16 Maintaining an airway with adequate oxygenation is vital in the management of RDS. Depending on the infant’s clinical presentation, initial oxygen therapy may be delivered using blow-by oxygen, a hood, or resuscitation bag and mask. In very-low-birth-weight infants, clinicians seek to maintain the fraction of inspired oxygen (FIO2) to keep the oxygen saturation as measured by pulse oximetry (SpO2) between 85% and 92% or the PaO2 at 50 to 80 mm Hg. Nasal CPAP should be considered when the infant develops increasing respiratory distress and the heart rate is greater than 100 beats/min. In some institutions, heated and humidified high-flow nasal cannulas with flows greater than 2 L/min are used in place of nasal CPAP.17 The high-flow therapy may prevent the need for intubation and mechanical ventilation, or it may be used to facilitate

extubation.18,19 Before the use of exogenous surfactant therapy, RDS was associated with significant morbidity and mortality. Since its introduction in the 1980s, surfactant replacement therapy for RDS has proven to be one of the greatest advances in neonatal care.20 Today it is a standard of care for the infant with RDS; early administration is associated with a significant reduction in mortality, duration of mechanical ventilation, and incidence of air leaks.21 Two approaches have emerged in surfactant replacement therapy: prophylactic and rescue treatment. In an attempt to replace surfactant before an infant develops severe RDS, prophylactic treatment consists of surfactant administration in the delivery room. It is given within 10 to 30 minutes following intubation and radiographic confirmation of RDS features. Prophylactic surfactant replacement is associated with a lower incidence and severity of RDS and pulmonary air leaks.22 This approach does have a notable disadvantage: Some infants who might manage well on CPAP may be unnecessarily treated with intubation and ventilation, increasing their risk of bronchopulmonary dysplasia. By contrast, in rescue treatment, surfactant is administered within the first 12 hours after birth and only to those infants who have a diagnosis of RDS and require mechanical ventilation. Early rescue surfactant replacement is defined as administering surfactant within 1 to 2 hours of birth, whereas late rescue replacement is administration that occurs 2 or more hours after birth.23 A criticism of rescue therapy is that the delay in surfactant replacement could result in progression of RDS. Two types of surfactant preparations are available to treat RDS. The natural surfactants are derived from animal sources, including minced lung extracts from cows or pigs or surfactant extracted after lavage of cow lungs. The latest synthetic surfactants contain biologically active peptides or whole proteins that mimic the human surfactant protein.24,25 Prior to surfactant replacement, the infant must be intubated and the endotracheal tube placement confirmed with a chest radiograph. If needed, the infant is suctioned prior to instillation of surfactant. Suctioning is then avoided for at least 2 hours after surfactant administration unless the infant develops airway compromise. A bolus, portions of small aliquots, or infusion of surfactant is administered in-line through an adapter port on the proximal end of the endotracheal tube.

Currently, insufficient evidence exists to recommend the optimal method of delivery, number of doses, or body position.23 Although data on their effectiveness are limited, alternatives to intratracheal administration include nebulized surfactant, delivery with a laryngeal mask, and use of laryngoscopy to guide a thin intratracheal catheter. All of these approaches eliminate the need for intubation.26–28 To reduce the need for prolonged pressure ventilation and the risk of developing bronchopulmonary dysplasia, some institutions provide intubation and ventilation primarily for surfactant administration and then quickly extubate the infant to nasal CPAP.29 Lung compliance can change rapidly following surfactant replacement, which often necessitates adjusting ventilator and FIO2 settings. Close monitoring of ventilator waveforms, transcutaneous CO2 levels, blood gas values, and SpO2 is essential in determining safe and effective settings. To reduce the risk of hyperoxia and pulmonary air leaks, FIO2 is weaned and tidal volumes or peak inspiratory pressures are reduced within a few minutes following administration. With the clinical goal of maintaining FRC, CPAP applied to the stiff lungs of the infant with RDS results in improved lung compliance, alveolar inflation, and oxygenation, which in turn decrease intrapulmonary shunting and work of breathing. CPAP is indicated when the FIO2 required is greater than 0.30 and the infant continues to have respiratory distress, or whenever the required FIO2 is greater than 0.40, regardless of the presence of respiratory distress. Nasal CPAP may be applied shortly after birth in an attempt to avoid mechanical ventilation and prolonged intubation, thereby preventing ventilator-induced lung injury—a type of damage that may lead to chronic lung disease. Pressures of 4 to 7 cm H2O are usually adequate, although pressures up to 10 cm H2O may be necessary to improve alveolar recruitment in the infant with severely noncompliant lungs. Pressures greater than 10 cm H2O do not appear to provide any important benefit and, in fact, may increase the risk of gastric insufflation. Extremely premature infants weighing less than 1000 g with a gestational age less than 28 weeks are typically intubated and placed on ventilator support immediately after delivery so they can receive preventive surfactant.30 CPAP may also be applied following mechanical ventilation.

Extubation to CPAP stabilizes the infant’s airways and may decrease the risk of respiratory failure and the need for reintubation. When the FIO2 is weaned to less than 0.40, CPAP pressure can be decreased by 1 cm H2O until a level of 4 cm H2O is reached. At that point, CPAP is discontinued and the infant receives oxygen therapy with a low-flow nasal cannula or oxygen hood.31 Heated, humidified high-flow nasal cannula appears to have a similar effect to nasal CPAP when it is applied early for respiratory distress or immediately postextubation.18,19 For some infants, CPAP or high-flow nasal cannula alone cannot adequately support ventilation, especially in very-low-birth-weight infants (38° C), irritability, and a muffled-sounding voice. The child appears toxic and drooling. In contrast to laryngotracheobronchitis, the respiratory pattern of the child with epiglottitis is one of very deliberate slow breaths with large tidal volumes—an effort to reduce turbulent airflow and airway resistance. Suprasternal and substernal retractions are evident, with nasal flaring and cyanosis in case of severe obstruction. The typical presentation for the younger child is the tripod position: sitting upright supported by both hands and leaning forward with the neck extended in a sniffing position in an attempt to keep the airway open. Inspiratory stridor may diminish as airway obstruction worsens. The older child may only exhibit subtle signs of respiratory difficulty, such as increased respiratory distress when lying flat, voice changes, and dysphagia.187

Diagnosis Manipulation of the epiglottis with a tongue depressor, radiographs, and blood gas analysis are painful and anxiety-provoking procedures that greatly increase the risk of complete airway obstruction. For that reason, they should be avoided and diagnosis made by history and clinical presentation alone. If the diagnosis is in question, however, lateral neck films can help confirm the diagnosis and rule out other disorders, including LTB, foreign body aspiration, and retropharyngeal abscess. Patient age, clinical presentation, and radiographic findings contribute to differentiation from LTB.194 Table 48-1 lists factors that assist in the differential diagnosis. The radiograph typically reveals an enlarged epiglottis, described as the thumb sign, and a distended hypopharynx. If a neck radiograph is performed, healthcare providers should not leave the child alone. In addition, the child must remain in an upright position during the study because the supine position may result in total airway obstruction. TABLE 48-1 Clinical Differentiation of Epiglottitis and

Laryngotracheobronchitis Laryngotracheobronchitis

Epiglottitis

Age

6 months to 3 years

2 to 6 years

Gender

More prevalent in males

No prevalence difference

Onset

2- to 4-day history of cold symptoms

Sudden, within 4 to 8 hours

Seasons

Fall through spring

All

Fever

Low-grade

High

Respiratory rate

Late-onset tachypnea

Bradypnea with deliberate, large tidal volumes

Heart rate

Late-onset tachycardia

Early-onset tachycardia

Retractions

Mild to severe

Severe

Stridor

Inspiratory and expiratory

Inspiratory

Cough

Barking seal

Minimal

Voice

Hoarse

Muffled

Drooling

No

Yes

Dysphagia

No

Yes

Position

No effect on stridor

Supine worsens stridor

Appearance

Irritable, restless

Toxic, acutely ill

Radiograph

Anteroposterior view: steeple sign

Lateral neck view: thumb sign

Management The overriding goal in treating the child with epiglottitis is to maintain a secure airway. Many patients respond to intravenous antibiotics and

supplemental oxygen and do not require intubation, but all must be closely monitored in an intensive care setting.195 If epiglottitis is severe and emergency intubation is indicated, intubation is performed in the operating room, where an emergent tracheostomy can be performed if needed. After the patient is anesthetized, fiberoptic-assisted intubation is performed and airway specimens obtained for culture and sensitivity. As with LTB, intubation of the swollen airway requires an endotracheal tube one size smaller than estimated for age and weight. Extubation should be attempted only after an air leak is noted and the patient shows clinical improvement. A nasotracheal tube is preferred because it is more stable and better able to keep secured. If the child needs to be transported to another facility, the airway must be secured and the child should be sedated to prevent anxiety that can worsen airway compromise.188 Stop and Think A 2-year-old child presents to the emergency department with stridor, marked suprasternal and substernal retractions, and a temperature of 102° F (39° C). The parents state that he has had nasal congestion for more than 24 hours and is more restless than normal. What treatment should be provided at this time, and what tests may be performed to confirm a diagnosis?

Complications and Outcomes With quick response to antibiotic therapy and corticosteroid administration, intubation is usually required for no more than 48 hours. Nearly half of patients with epiglottitis will develop another infection, most often pneumonia and otitis media. Bacteremia can also lead to cellulitis and meningitis. Accidental extubation increases the risk of airway complications. The mortality rate can be as high as 10% when patients have airway obstruction without intubation, in contrast to only 1% when intubation is performed. Introduction of the Hib vaccine in 1985 has led to a marked decrease in the number of cases of epiglottitis. Thus, 41 cases were reported per 100,000 children in 1987, compared with 1.3 cases per 100,000 children in 1997.196

Key Points Apnea of prematurity is due to immaturity of the brain stem. Apnea of prematurity is treated with respiratory stimulants, oxygen, CPAP, and mechanical ventilation. Home apnea monitoring may be used with apnea of prematurity. Respiratory distress syndrome is a complication of prematurity. Clinicians can use biochemical tests of amniotic fluid to evaluate infants’ lung maturity. Treatment of respiratory distress syndrome includes oxygen, surfactant replacement, CPAP, mechanical ventilation, and supportive therapy. A milder form of bronchopulmonary dysplasia, chronic lung disease occurs in premature infants with progressive deterioration of lung function. Chronic lung disease is formally defined as a continued need for oxygen therapy at 36 weeks’ gestation. Causes of chronic lung disease in newborns are multifactorial and include ventilator- and oxygen-induced injury. Treatment of chronic lung disease in newborns includes oxygen, mechanical ventilation, corticosteroids, and bronchodilators. Transient tachypnea of the newborn is a self-limiting disorder of term and near-term infants. Pneumonia can occur at any gestational age and includes congenital, intrapartum, and postnatal forms. Treatment of neonatal pneumonia focuses on eradicating the infection, along with supportive care. Meconium aspiration syndrome occurs when the infant aspirates stained amniotic fluid. Meconium aspiration syndrome usually occurs in infants born at term or post-term. Treatment of meconium aspiration syndrome includes suctioning, oxygen therapy, mechanical ventilation, inhaled nitric oxide, extracorporeal membrane oxygenation, and surfactant replacement. Persistent pulmonary hypertension of the newborn occurs when fetal circulation persists after birth.

Echocardiography is used to make the diagnosis of persistent pulmonary hypertension of the newborn. Treatment of persistent pulmonary hypertension of the newborn includes oxygen, mechanical ventilation, inhaled nitric oxide, extracorporeal membrane oxygenation, and supportive therapy. Congenital diaphragmatic hernia is an abnormality in which the infant’s diaphragm allows the abdominal organs to protrude into the thorax. Treatment of congenital diaphragmatic hernia includes delivery room stabilization, mechanical ventilation, inhaled nitric oxide, extracorporeal membrane oxygenation, surgery, and supportive therapy. The type and severity of a congenital pulmonary anomaly depend on the time during fetal lung development at which an insult occurred, resulting in the malformation. Early diagnosis of congenital pulmonary anomalies using fetal ultrasound, CT, and MRI imaging has improved prognosis; today, prognosis depends largely on the presence of associated congenital malformations and the health of the normally developed lung. Air leak syndrome in the newborn includes four conditions: pulmonary interstitial emphysema, pneumothorax, pneumomediastinum, and pneumopericardium. Transillumination is used to make an immediate diagnosis of pneumothorax. Retinopathy of prematurity affects the growth of the blood vessels needed to support the retina. Prevention is the best treatment for retinopathy of prematurity; it includes restriction of oxygen therapy, steroid therapy, reduced exposure to light, and adequate nutrition. The greatest incidence of bronchiolitis occurs in infants aged 3 to 6 months. Respiratory syncytial virus is the most common cause of bronchiolitis. Treatment of bronchiolitis includes nasotracheal suctioning, hydration, and oxygen. Bronchodilator therapy, systemic corticosteroids, and chest physiotherapy are not recommended for the treatment of

bronchiolitis. Laryngotracheobronchitis (LTB) is the most common cause of infectious upper airway obstruction in children between the ages of 6 months and 3 years. Treatment of LTB includes corticosteroids, racemic epinephrine, oxygen, heliox, and, in rare cases, intubation. Epiglottitis is a life-threatening bacterial infection. Common findings in epiglottitis include drooling, dysphagia, dysphonia, and dyspnea. Many cases of epiglottitis respond to antibiotics and oxygen. If epiglottitis is severe and intubation is indicated, the clinician should perform this procedure in the operating room.

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Part 4 Applied Sciences for Respiratory Care

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CHAPTER

49 Respiratory Anatomy William F. Galvin William Randall Solly

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OUTLINE Growth and Development of the Respiratory System Gross Anatomy of the Respiratory System Anatomy of the Thorax Microanatomy of the Respiratory System

OBJECTIVES 1. 2. 3. 4. 5. 6. 7. 8.

Explain the purpose of the respiratory system. List and briefly explain the five stages of fetal development. Describe key changes in the transition from prenatal to postnatal development. Describe the gross anatomy of the respiratory system. Describe the anatomy of the upper airway. Describe the anatomy of the lower airway. Discuss the relationships between the bony elements of the thorax. Identify and explain the roles of the diaphragm, accessory inspiratory muscles, and abdominal muscles. 9. Describe the visceral pleura, parietal pleura, and pleural space. 10. Describe the microanatomy of the respiratory system. 11. Describe the mucociliary apparatus.

12. 13. 14. 15.

Describe the smooth muscle function of the airways. Compare macrophages and dendritic cells found in the respiratory system. Compare alveolar type I and type II cells. Describe the interstitial space in the lungs.

KEY TERMS abdominal muscle accessory muscle acinus alveolar stage alveolus bronchus canalicular stage carina channels of Lambert concha dendritic cell diaphragm embryonic stage epiglottis external respiration glottis or glottic opening hilum internal respiration laryngopharynx larynx lobe macrophage mast cell mediastinum mucociliary apparatus nasopharynx oropharynx parietal pleura pericardium phrenic nerve pleural space pores of Kohn pseudoglandular stage saccular stage segment senescence thorax trachea type I cell type II cell ventilation

visceral pleura work of breathing

Introduction A thorough and in-depth understanding of the growth and development of the human lung is fundamental and indispensable to the respiratory therapist. It is virtually impossible to gain an appreciation of the physiology of the lung and the pathophysiology of respiratory diseases without first knowing the anatomy of the respiratory system. One must first know the parts (anatomy) and their function (physiology) before understanding abnormalities associated with respiratory diseases (pathophysiology). The respiratory system is a gas exchanger as well as a gas distributor. Gas exchange occurs through respiration, which comprises five distinct processes: ventilation, perfusion, diffusion, external respiration, and internal respiration. Ventilation is the movement of air from the atmosphere to the lung. Perfusion entails the movement (or circulation) of blood through the cardiovascular system. Diffusion is the movement of gases (oxygen and carbon dioxide) from a relatively high pressure to a low pressure across the alveolar-capillary membrane. External respiration is gas exchange at the interface of the alveoli and the blood, and internal respiration is gas exchange at the interface of the blood and the tissues. Gas exchange occurs exclusively at the acinus or alveolar level, the functioning portion of the lung located at the very end of the respiratory tract. Gas distribution—the other major function of the respiratory system—entails gas traversing the pathways of the upper airway as well as the conducting airways of the lower respiratory tract. Respiratory Recap Basic Terminology Anatomy = parts Physiology = function Pathophysiology = functional changes in abnormal condition/disease

Respiratory Recap

Key Respiratory Concepts Ventilation = movement of air from atmosphere to the lungs Perfusion = movement or circulation of blood Diffusion = movement of gas across the alveolar-capillary membrane Respiration = gas exchange External respiration = gas exchange between alveoli and blood Internal respiration = gas exchange between blood and tissues

The components of the respiratory system and their function are essential concepts that all respiratory therapists must understand. This chapter focuses on the individual components and the normal development of the respiratory system. It provides a general overview of this growth and development from the earliest stage of conception, a fetus, to the fully functioning stage of adult. In addition, it addresses the gross anatomy of the respiratory system, the anatomy of the thorax, and the microanatomy of the respiratory system.

Growth and Development of the Respiratory System The growth and development of the respiratory system is a remarkable phenomenon evolving from embryo, to fetus, to neonate, to infant, to child, to adolescent, through adulthood, and finally to the elderly state of senescence, when function begins to diminish and eventually declines to death. This evolution begins at conception with the fertilization of a single cell, which then grows and develops progressively and proportionately into a fully functioning organ. It transitions from the microscopic to the macroscopic, entailing a single bud at the beginning of the embryonic stage, to a developing infant consisting of some 50 million alveoli, to a fully developed adult with a surface area of approximately 70 m2 and 300 million alveoli. Degeneration begins later in life during senescence (old age) and continues until death. Table 49-1 summarizes the life stages of development. TABLE 49-1 Life Stages of Development Life Stage

Period

Embryo

Conception to end of 8th week of gestation

Fetus

9th week of gestation to birth

Neonate

Birth to end of week 4

Infant

End of week 4 to 1 year

Child

1 year to puberty

Adolescent

Puberty to adulthood

Adult

Approximately 18 years to old age

Senescence

Old age to death

Prenatal Development The prenatal period begins with fertilization and ends with birth. The time spent in prenatal development is called gestation—a phase that entails growth (increase in size and number of newly formed cells) as well as development (continuous process of change from one life phase to another). Prenatal development is often expressed in terms of lung stages, gestational age, and developmental events. Table 49-2 represents the five stages of lung development as well as the corresponding gestational age and significant developmental events. Figure 49-1 provides a visual illustration of these events.

FIGURE 49-1 Stages of development.

TABLE 49-2 Stages of Lung Development, Approximate Gestational Age, and Significant Developmental Events Stage

Gestational Age

Significant Developmental Events

Embryonic

4–6 weeks

Development of proximal airways (trachea and major bronchi, early formation of segmental bronchi)

Pseudoglandular

6–16 weeks

Development of conducting airways (smooth muscle, cilia, mucous glands, goblet cells, and respiratory bronchioles)

Canalicular

17–26 weeks

Development of vascular bed and framework of respiratory acini

Saccular

27–36 weeks

Development of gas exchange units (presence of surfactant and early development of alveoli)

Alveolar

36–beyond birth

Rapid alveolar development (increase in size and number)

Embryonic Stage The first period of lung development, the embryonic stage, spans approximately 2 months. It entails primitive development of the lung. This stage begins at approximately 21 days after conception with the formation of a lung bud that emerges from the foregut, an out-pouching of the pharynx. The lung bud elongates, forming the trachea and two bronchial buds that go on to become the main stem bronchi. The pharynx evolves to become the esophagus, and the main stem bronchi evolve to form lobar bronchi and finally remnants of segmental bronchi. Simultaneously, three germ layers evolve and give rise to eventual formation of respiratory epithelium, pulmonary interstitium, smooth muscle, blood vessels, and cartilage. Figure 49-2 illustrates lung development from week 4 through week 8.

FIGURE 49-2 Lung development, week 4 through week 8.

Pseudoglandular Stage Starting around week 6 of gestation and extending through week 16, the lung takes on a glandular appearance termed the pseudoglandular stage. This stage is marked with continued growth and development of the conducting airways and near-complete development of the diaphragm. Cilia begin to appear on the surface of the epithelium, goblet cells and mucous glands emerge, and smooth muscle presents on the large bronchi. A fetus at this stage of development is highly unlikely to survive premature delivery.

Canalicular Stage The canalicular stage represents the third stage of lung development and extends from approximately week 17 through week 26. It is so

named because of the term’s connotation of canals or channels, signifying the formation of a capillary network around the air passages. Additionally, this stage reflects the appearance of type I and type II alveolar cells, which give rise to development of the alveolar-capillary membrane as well as the production of surfactant. This stage is quite significant, as limited gas exchange becomes possible. Thus, a prematurely born fetus is capable of extrauterine survival at this stage if provided with intensive and advanced medical care.

Saccular Stage The fourth stage of lung development is the saccular stage. The hallmark of this stage is a marked increase in the potential gasexchanging surface area of the lung. It is so named because the terminal structures of the airways develop into saccules, which eventually become alveoli.

Alveolar Stage The final stage of lung development, called the alveolar stage, is marked by significant alveolar maturation and proliferation. The estimated number of alveoli ranges from 20 to 150 million, with an average of approximately 50 million present at birth. This number will reach its peak at approximately 300 million by age 8, when alveolar development is considered complete. While completely developed, the fluid-filled nature of the lung precludes its ability to function in a gas-exchanging capacity. Respiratory Recap Five Stages of Lung Development ∎ Embryonic ∎ Pseudoglanduar ∎ Canalicular ∎ Saccular ∎ Alveolar

Postnatal Lung Development While the postnatal period theoretically extends from birth until death, this section highlights the significant developmental events that occur at the time of birth as well as the major differences between infants/children and adults. Subsequent sections of this chapter address the gross anatomy and microanatomy of the adult lungs and adult thorax. Prior to the first breath, the infant lung is filled with fluid. Throughout gestation, this fluid maintains lung expansion and facilitates pulmonary growth. It is constantly replenished, at a rate of approximately 250 to 300 mL per day, and continuously flows to the oropharynx, where it is swallowed or expelled into the amniotic fluid. While the body applies various mechanisms to reduce and clear lung fluid at the time of birth, an infant’s first breath must be deep and forceful: An exceedingly high transpulmonary pressure gradient is required to open and replace the remaining lung fluid. Although this pressure gradient varies, reports estimate that approximately 40 to 80 cm H2O pressure and a volume of approximately 40 mL are needed to overcome the surface tension of the alveoli and the viscosity of the remaining lung fluid. Subsequent breaths require a lower transpulmonary pressure, as more and more alveoli remain inflated after each successive breath. In the normal term infant, fluid removal to the interstitial space is complete within several breaths, although the capillaries and lymphatics may take several hours to remove all of the excess fluid from the interstitial space. In addition to the replacement of fluid with air within the lung of the newborn, other anatomic differences exist between the infant/child and the adult. The head and the upper airway of the infant are significantly different compared to the corresponding structures in the adult. The infant’s head is larger and heavier relative to the size of its body, the nasal passages are proportionately smaller than those of the adult, and the tongue much larger relative to the size of the oral cavity. The infant’s jaw is much rounder, the larynx is positioned higher in the neck, and the cricoid ring is the narrowest portion of the upper airway compared to the glottis in the adult. Many of these anatomic variations make the infant a preferential nose breather. More problematically, they increase the infant’s susceptibility to airway obstruction.

Gross Anatomy of the Respiratory System The gross anatomic structures of the respiratory system comprise the upper and lower respiratory tracts (Figure 49-3). The upper respiratory tract begins at the entry points of the nose and mouth and ends at the larynx. It includes the nose, mouth, nasal and oral cavities, pharynx, tongue, epiglottis, soft and hard palates, and the larynx. The lower respiratory tract extends from the trachea to the alveoli and includes the trachea, right and left main stem bronchi, lobar and segmental bronchi, bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli. Table 49-3 lists the major structures of the respiratory system and provides a brief description and explanation of their function.

FIGURE 49-3 Anatomy of the respiratory system.

Description TABLE 49-3 Major Components of the Respiratory System Component

Description

Function

Nose

Centered above the mouth as well as inside and below the space between the eyes

Contains the nostrils, which provide entrances to the nasal cavity

Nasal cavity

Hollow space behind the nose

Transports air to the pharynx; it filters, warms, and moistens air

Oral cavity

The mouth cavity, containing the teeth, tongue, salivary glands, and other oral structures

Allows passage of air and food; transports air to the pharynx as well as warming and moistening it; aids in the production of vocal sounds

Paranasal sinuses

Hollow spaces in certain skull bones

Serve as resonant chambers; help reduce the weight of the skull

Pharynx

A chamber located behind the nasal cavity, oral cavity, and larynx; also known as the throat

Transports air to the larynx

Epiglottis

Flap-like cartilaginous structure at the back of the tongue, near the entrance to the trachea

Covers the opening to the trachea when swallowing occurs

Larynx

Enlargement at top of the trachea; commonly known as the voice box; it houses the vocal cords

Produces sounds; transports air to the trachea; helps filter, warm, and moisten incoming air

Trachea

Tubular structure in the neck through which air passes

Warms, filters, and moistens air; transports air to the lungs

Bronchial tree (including bronchi and bronchioles)

Tubes that branch outward, connecting the trachea to the alveoli

Conducts air from trachea to alveoli, with a mucous lining that filters incoming air

Lungs

A pair of organs in the chest that are responsible for providing oxygen to the blood and for exhaling carbon dioxide waste

Contain air passages, alveoli (the area where oxygen and carbon dioxide exchange occurs), blood vessels, connective tissues, lymphatic vessels, and nerves of the lower respiratory tract

Upper Respiratory Tract The air conditioning and filtering operations of the upper airway begin when air enters the upper respiratory tract (Figure 49-4). Primary entry occurs through two external openings in the nose called nostrils or external nares. The nostrils open into the nasal cavity, which is composed of bone and cartilage. Mucus-coated epithelial membranes

line the cavities, with this mucus-secreting epithelium being called the respiratory mucosa. The nasal conchae, also known as turbinates, are bony ridges that laterally project into the nasal cavity. The main function of this area is to filter, warm, and humidify the inspired air. The frontal and sphenoid sinuses are located above (superior to the nasal cavity), while the hard and soft palates lie below (inferior to the nasal cavity). Within the cavity, sensory neurons allow for the sense of smell (via the olfactory nerve) and initiate reflexes that cause sneezes or a sense of breathlessness.

FIGURE 49-4 Anatomy of the upper respiratory tract.

Description As air travels through the nasal passages, it continues downward toward the pharynx, which combines with the inner ear canals. The pharynx encompasses three regions: the nasopharynx, oropharynx, and laryngopharynx (hypopharynx). The nasopharynx is a passageway lined with ciliated epithelial and goblet cells. It is reserved for air movement only; the remainder of the pharynx serves to carry air and food. The

oropharynx is located distal to the mouth and is lined with stratified squamous epithelium that is continuous with the oral cavity. The two masses in the back of the throat are the tonsils. The adenoids consist of a single pharyngeal tonsil located high in the throat behind the nose and the roof of the mouth (soft palate) and are not visible through the mouth. The uvula is the visible projection of the middle of the soft palate, which is easily seen in an open mouth. Enlargement of these structures may impede breathing, especially during sleep. The laryngopharynx is the most inferior portion of the pharynx. In the pharynx, the air and food passages coincide below the oral cavity. Air is directed to the larynx by the negative thoracic pressure generated primarily by the diaphragm, and food is directed posterior into the esophagus by a complex coordination of muscles during swallowing. The epiglottis, a valve-like structure, can close the entry to the larynx, preventing aspiration of food particles. The larynx is a cartilaginous structure that serves as the passageway for air between the pharynx and trachea. The hyoid bone is seated above the larynx. The epiglottis is the uppermost cartilage of the larynx. The largest cartilage of the larynx is the thyroid cartilage, which protrudes more prominently in men (the Adam’s apple). The only complete ring cartilage around the airway is the cricoid cartilage, which is located below the thyroid cartilage. In an emergency, the clinician can open the cricothyroid membrane (between the two cartilages) to obtain access to the lower airways. Small cartilage pairs—the corniculates and arytenoids —complete the posterior larynx. The vocal cords are mucosal folds supported by elastic ligaments, and the opening between the cords is called the glottis or glottic opening. The glottis is a triangular slit. When an individual swallows food or liquid, the glottis closes to prevent food or liquid from entering the trachea. When air moves through the vocal cords, they vibrate to create sounds. Respiratory Recap Major Components of the Upper Respiratory Tract ∎ Nasal cavity ∎ Oral cavity

∎ Pharynx (nasal, oral, laryngeal) ∎ Larynx

Lower Respiratory Tract Major structures of the lower respiratory tract include the trachea, main stem bronchi, bronchioles, and alveoli. The trachea, commonly called the windpipe, is a large hollow tube that bifurcates at the carina into the two primary bronchi. This structure marks the beginning of the conducting system. Because it resembles an inverted tree, the trachea is often referred to as the tracheobronchial tree. Measuring 10 to 13 cm in length, it is protected and supported by 16 to 20 C-shaped pieces of cartilage, which keep the trachea open even during the negative thoracic pressures of inspiration. The adult trachea is approximately 2.0 to 2.5 cm in diameter. The mucosa that lines the trachea and a majority of the tracheobronchial tree is pseudostratified ciliated columnar epithelium. Smoking destroys the cilia that line the airways. The trachea bifurcates asymmetrically at a point in the division called the carina, with the right main stem bronchus branching out at a smaller angle (20 to 30 degrees from vertical) than the left (45 to 55 degrees). Consequently, foreign bodies are more likely to be aspirated into the right bronchus, and endotracheal suction catheters more commonly advance into the right lung. The main bronchi continue to divide in a pattern known as dichotomous branching: Each consecutive airway splits into two progressively smaller airways, giving rise to lobar bronchi, then to segmental bronchi, and finally to approximately 40 subsegmental bronchi. The lobar bronchi correspond to the five lobes of the lung and the segmental bronchi to the 18 segments of the lung. The airways continue to divide as they penetrate deeper into the lung, where hundreds of smaller bronchi branch into thousands of bronchioles. Up until this point, the airways have been supported by cartilage. In contrast, the bronchioles, which are less than 1 mm in diameter, do not contain any cartilage. They retain their patency and avoid collapse during exhalation by adhering to the retractile forces of the lung’s elastic

parenchymal tissue. The bronchioles continue to divide and branch into still smaller airways called terminal bronchioles. Terminal bronchioles number approximately 30,000 to 40,000 and have a diameter of approximately 0.65 mm. They represent the last component of the conducting airway, the conducting zone. The respiratory bronchioles, the alveolar ducts, alveolar sacs, and the alveoli constitute the 16th to 23rd generations of airway branching and the end of the lower respiratory tract. Collectively, they form the acinus or respiratory zone (Figure 49-5). Surrounding the acinus is a rich capillary network where gas exchange occurs. Figure 49-6 illustrates the conducting zone (trachea to respiratory bronchioles) as well as the respiratory zone (respiratory bronchioles to alveoli). Table 49-4 provides structural characteristics of the entire tracheobronchial tree, including each anatomic structure and its diameter, the generation and area served, and the total cross-sectional area represented by each structure.

FIGURE 49-5 Acinus: terminal bronchioles, alveolar ducts, alveolar sacs, and alveoli.

Description

FIGURE 49-6 Airways of the conducting zone and the respiratory zone. Reproduced from Hicks G. Cardiopulmonary anatomy and physiology, 4th ed. St. Louis, MO: Mosby; 1999:687.

Description TABLE 49-4 Structural Characteristics of Tracheobronchial Tree

Modified from Lumb A. Nunn’s applied respiratory physiology, 7th ed. St. Louis: Elsevier; 2011.

Respiratory Recap Major Components of the Lower Respiratory Tract ∎ Trachea ∎ Main stem bronchi ∎ Bronchioles ∎ Alveoli

Anatomy of the Thorax The thorax contains an infrastructure composed of the chest wall and the vertebrae, with major organs residing in this area. The chest wall (i.e., skin, ribs, intercostal muscles) protects the lungs from injury. Thoracic muscles such as the diaphragm perform the work of breathing. A serous membrane called the parietal pleura adheres firmly to the chest wall, whereas the visceral pleura covers the surface of each lung. Fluid within the pleural cavity prevents friction and allows the two surfaces to slide smoothly against each other during respiration. The thorax or thoracic cavity is divided into three regions: the mediastinum, a right pleural cavity, and a left pleural cavity. The mediastinum contains major blood vessels, the esophagus, and the heart, whereas the pleural cavities contain the lungs (Figure 49-7).

FIGURE 49-7 Thorax: mediastinum and right and left pleural cavity.

Description

Bony Thorax The bony elements of the thorax provide support and protection for the heart and lungs. The elements making up the thorax include the sternum, ribs, thoracic vertebrae, clavicles, and scapulae. The vertebrae allow movement, rotation, and elevation of the thoracic ribs. The sternum, which anchors the ribs to the front of the chest wall, is subdivided into three parts: the manubrium, the body, and the xiphoid process. The manubrium connects to the first two ribs, and the body of the sternum connects directly to the third through seventh ribs. The xiphoid process forms the tip of the sternum. These bony elements protect the contents of the thorax, help expand and relax the chest via contraction of respiratory muscles during inspiration and expiration, and stabilize the chest wall during changes in intrapleural pressure (Figure 49-8).

FIGURE 49-8 Bony structures of the thorax in relation to the lungs.

Description The 12 pairs of ribs correspond to their vertebrae of origin. The first through seventh ribs play an important role in ventilation. These ribs lift like bucket handles (outward and upward), while the sternum rises like a pump handle. In contrast, the lower ribs rotate toward the back. Obstructive lung disorders such as chronic bronchitis or emphysema limit this expansion. Normally, the anterior–posterior (AP) diameter is approximately half of the width of the chest. However with obstructive disease, air trapping expands the lungs and increases the AP diameter of the chest, forming the so-called barrel chest. Respiratory Recap Bony Elements of the Thorax

∎ Sternum ∎ Ribs ∎ Thoracic vertebrae ∎ Clavicles ∎ Scapulae

Respiratory Muscles The muscles of respiration are divided into primary and accessory, with the accessory muscles further divided into accessory muscles of inspiration and accessory muscles of expiration. The major muscle of respiration is the diaphragm. This large muscle provides the primary force for the work of breathing. Normally dome-shaped, it attaches to the large vertebrae, the ribs, and the xiphoid process. Fibers of the diaphragm connect to a broad connective sheet called the central tendon. During inspiration, the diaphragm contracts and flattens, causing lung expansion. During exhalation, the elastic recoil of the lungs and relaxation of the diaphragm allow the lungs to return to their endexpiratory volume and position. The diaphragm moves approximately 1.5 cm during normal tidal breathing. By comparison, at high levels of stress and movement with increasing work of breathing, the diaphragm can move as much as 6 to 10 cm with each breath. When diaphragmatic contraction draws the central tendon down, flattening the diaphragm, intrathoracic pressure decreases, creating a pressure differential with atmospheric pressure. Due to how it attaches to the ribs, the diaphragm creates a zone of apposition, which causes outward movement of the thorax during inspiration. The diaphragm receives its major nerve supply from the phrenic nerve, which exits the cervical region at C3–C5. A hiccup is a reflex spasm of the diaphragm caused by an irritation of the phrenic nerve. Cervical fractures between C1 and C5 are likely to affect the phrenic nerve and disrupt or impair the ability to breathe. The accessory muscles of inspiration comprise the scalene, sternocleidomastoid, pectoralis major, trapezius, and external intercostal muscles. The accessory muscles of expiration consist of the internal

intercostal, rectus abdominis, external abdominis oblique, internal abdominis oblique, and transverse abdominis muscles. Various muscles contracting in synchrony maintain the elasticity and ease of lung movement. Contraction of a coordinated set of muscles of respiration moves air into the lungs, leading to inspiration. Although exhalation is typically passive, thoracic muscles can fix the chest, and abdominal muscles can contract to force air out of the lungs, most dramatically in coughing or sneezing. During exercise, accessory muscles can be recruited on inspiration and expiration to increase the respiratory effort. Accessory muscles are coordinated with diaphragm movement during inspiration. The external intercostals, located between each rib pair, assist with inspiration by lifting the ribs; the internal intercostals aid with expiration by fixing the chest wall. Figure 49-9 depicts the muscles of the chest wall involved in ventilation. Other accessory muscles of inspiration that expand the chest wall are the scalenes, sternocleidomastoids, pectoralis majors, and trapezius. One way to evaluate whether patients are in respiratory distress is to observe a retraction at the notch above the clavicles during inspiration. The accessory muscles of expiration (which is normally passive) will assist with exhalation if resistance to expiration is significant or demands on ventilation greatly increase, as with exercise. These muscles include the rectus abdominis, external abdominis oblique, internal abdominis oblique, transversus abdominis, and internal intercostal muscles. Consequently, active exhalation can be observed in case of contraction of the abdomen. In patients with severe obstructive disease that leads to increased work of breathing, both inspiratory and expiratory accessory muscles are often active.

FIGURE 49-9 Muscles of the chest wall involved in ventilation.

Description

Stop and Think If a patient sustains a spinal cord injury at the level of C3, which muscle groups are affected? If the injury is at C6, which muscle groups are affected?

Respiratory Recap

Muscles of Ventilation ∎ Diaphragm ∎ Accessory muscles of inspiration ∎ Accessory muscles of expiration

Lungs The cone-shaped lungs have a broad and concave base surrounded by the thoracic ribs and diaphragm. There are five lobes and 18 segments (Figure 49-10). Normal adult lungs weigh about 800 g and contain about 90% gas and 10% tissue. The tops of the lungs, called the apices, extend from above the clavicle to the first vertebra. During quiet breathing, at end-expiration, the anterior portion of the lung borders the sixth rib. The medial portion of each lung is adjacent to the mediastinum and contains an opening called the hilum—a region where the bronchi and the pulmonary vessels enter the lungs. Each lung is divided into lobes, which are separated by fissures; each lobe is divided into segments according to the branching of the tracheobronchial tree (Table 49-5).

FIGURE 49-10 Lobes and segments of the lungs.

Description TABLE 49-5 Lobes and Segments of the Lungs Lung

Lobe

Segments

Right

Upper

Apical Anterior Posterior Lateral Medial Superior Anterior basal Posterior basal Lateral basal Medial basal

Middle Lower

Left

Upper Lower

Apical posterior Anterior Superior lingular Inferior lingular Superior Anterior medial basal Lateral basal Posterior basal

The right lung is larger (and therefore heavier) than the left lung, due to the left lung sharing a portion of its hemithorax with the heart. The right lung is divided into upper, middle, and lower lobes that are separated by horizontal and oblique fissures. The horizontal fissure separates the middle and upper lobes; the oblique fissure separates the middle and lower lobes. The left lung is divided into two lobes (upper and lower) separated by an oblique fissure. Bronchoscopists and those assisting with bronchoscopic procedures need a thorough knowledge of lobe and segment anatomy. It is also important when positioning patients for postural drainage. The lungs consist of two major anatomic divisions: the airways and the parenchyma (the functional part of an organ). Within the lung

parenchyma, adults have approximately 300 million alveoli. Each alveolus is between 200 and 300 microns in diameter. The small pulmonary capillaries that provide perfusion to the alveoli cover 85% to 90% of the alveolar surface area. The alveolar sacs originate from a single terminal bronchiole referred to as a primary lobule. The lungs have approximately 130,000 primary lobules, each containing 2000 alveoli. Capillary blood and alveolar gas are separated by the vascular endothelium, interstitial space, and alveolar epithelium. Gas exchange occurs via diffusion across the alveolar-capillary membrane encompassing the alveolar sacs (Figure 49-11).

FIGURE 49-11 Gas exchange at the alveolar-capillary membrane.

The alveolar epithelium is composed of two principal cell types: type I and type II cells. Type I cells comprise the structural squamous pneumocytes that cover 90% to 95% of the alveolar surface. They serve as the major sites of alveolar gas exchange. Their thickness ranges from 0.1 to 0.5 micron. Type II cells cover the remaining 5% to 10% of the alveolar surface. Small and cuboidal in shape, they are the primary source of surfactant production. Surfactant helps inflate the alveoli and prevent collapse by reducing the surface tension of the air–fluid interface within the alveoli. Adjacent alveoli communicate through connections called the pores of Kohn and channels of Lambert. Alveolar macrophages, or type III cells, play a defensive role by removing bacteria from the acini or lung units. The interstitium (the space between cells) contains a gel-like substance composed of acid molecules that are contained in two major compartments: tight space and loose space. Tight space is the area in the alveoli between the alveolar epithelium and the pulmonary capillary endothelium; loose space surrounds the bronchioles, respiratory bronchi, alveolar ducts, and alveolar sacs. Collagen (a connective tissue protein) surrounds the interstitium and limits alveolar distention beyond hazardous limits. The lungs and their covering, the pleura, also are well endowed with lymphatic circulation and lymph nodes. The open-ended lymphatic vessels are found superficially around the lungs just beneath the visceral pleura. These vessels function primarily to remove excess fluid and protein molecules that leak from the capillaries. Lymphatic drainage also allows the lungs to remove bacteria or foreign products and helps achieve homeostasis in the lungs. The lymphatic vessels exit the lungs at the hilum, and lymph (i.e., a clear or milky fluid called chyle) drains away from the lung toward the mediastinal lymph nodes. The mediastinal nodes serve as the storage sites for lymph fluid, which eventually returns to the circulation via the thoracic duct. Respiratory Recap Anatomy of the Lungs ∎ Airways and alveoli ∎ Lobes and segments

Pleurae Each lung is covered with a lining, called the visceral pleura, whereas the chest wall is lined by the parietal pleura. The visceral pleura covers the surface of the lungs, extending into the fissures between the lobes. On the medial surface of the lung, the visceral pleura is reflected onto the mediastinum to become part of the parietal pleura. Thus, the pleurae isolate the right and left lungs from the heart, which sits within its own container, the pericardium. Ciliated mesothelial cells line both pleurae. The area between the two pleurae is the pleural space (Figure 4912), a cavity containing a small amount of thin fluid (