Practical Trends in Anesthesia and Intensive Care 2019 9783030438739, 3030438732

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Practical Trends in Anesthesia and Intensive Care 2019 Davide Chiumello Editor

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Practical Trends in Anesthesia and Intensive Care 2019

Davide Chiumello Editor

Practical Trends in Anesthesia and Intensive Care 2019

Editor Davide Chiumello San Paolo Hospital, Intensive Therapy Department University of Milan Milan Italy

ISBN 978-3-030-43872-2    ISBN 978-3-030-43873-9 (eBook) https://doi.org/10.1007/978-3-030-43873-9 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

1 The Role of the Heart in Weaning Failure����������������������������������������������   1 Fabio Guarracino and Giulia Brizzi 1.1 Weaning as an Intense Exercise����������������������������������������������������������   2 1.2 The Diagnosis of Weaning Failure of Cardiovascular Origin������������   3 1.3 Transthoracic Echocardiography��������������������������������������������������������   4 1.4 Conclusions����������������������������������������������������������������������������������������   8 References����������������������������������������������������������������������������������������������������   8 2 MDR Infections in the ICU ����������������������������������������������������������������������  11 Enrico Tagliaferri, Francesco Menichetti, and Gianni Biancofiore 2.1 Infections and Resistance: The Problem Dimension��������������������������  11 2.2 Infections and Resistance: Definitions������������������������������������������������  13 2.3 MDR Gram Positive����������������������������������������������������������������������������  13 2.3.1 MRSA ������������������������������������������������������������������������������������  14 2.3.2 Potential Role for the New Antibiotics ����������������������������������  15 2.3.3 VRE����������������������������������������������������������������������������������������  15 2.4 MDR Gram Negative��������������������������������������������������������������������������  16 2.4.1 ESBL-Producing Enterobacteriaceae�������������������������������������  16 2.4.2 AmpC-Producing Enterobacteriaceae������������������������������������  17 2.4.3 XDR P. aeruginosa ����������������������������������������������������������������  18 2.4.4 XDR A. baumannii�����������������������������������������������������������������  19 2.4.5 KPC-Producing K. pneumoniae and Other Carbapenemase-Producing Enterobacteriaceae (CRE)����������  19 2.5 Empiric Therapy ��������������������������������������������������������������������������������  20 2.6 Duration of Therapy����������������������������������������������������������������������������  21 2.7 Role of Additional Therapies in Gram-Negative MDR/XDR Bacteria Septic Shock������������������������������������������������������  22 2.8 Prevention and Control of MDR Infections in the ICU����������������������  22 2.9 Antimicrobial Stewardship ����������������������������������������������������������������  23 References����������������������������������������������������������������������������������������������������  23 3 The Diaphragmatic Dysfunction������������������������������������������������������������   27 Paolo Formenti, Valentina De Giorgis, and Davide Chiumello 3.1 Introduction��������������������������������������������������������������������������������������   27

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3.2 The Diaphragm ��������������������������������������������������������������������������������   28 3.3 Anatomy and Respiratory Function��������������������������������������������������   28 3.4 Diaphragmatic Dysfunction and Fatigue������������������������������������������   29 3.4.1 Diaphragmatic Dysfunction��������������������������������������������������   30 3.5 Invasive Evaluation of Diaphragmatic Function������������������������������   31 3.6 Noninvasive Evaluation of Diaphragmatic Function: The Ultrasound����������������������������������������������������������������������������������   31 3.7 Diaphragmatic Displacement������������������������������������������������������������   31 3.7.1 Limits of the Technique��������������������������������������������������������   33 3.8 Thickness and Thickening Fraction��������������������������������������������������   33 3.9 Conclusion������������������������������������������������������������������������������������������  36 References����������������������������������������������������������������������������������������������������  36 4 Neuromuscular Blocking Agents: Review on Agents (NMBA and Antagonists) and Monitoring����������������������������������������������  41 Beatrice Penzo, Laura Petrò, and Andrea DeGasperi 4.1 Introduction����������������������������������������������������������������������������������������  41 4.2 Neuromuscular Blocking Agents (NMBAs): The Classification��������������������������������������������������������������������������������  43 4.2.1 Neuromuscular Junction and Basic Physiology of Neurotransmission ������������������������������������������  43 4.3 Depolarizing Neuromuscular Blocking Agents: Succinylcholine (SCh) ����������������������������������������������������������������������  46 4.3.1 Side Effects ����������������������������������������������������������������������������  47 4.4 Nondepolarizing Neuromuscular Blocking Agents (NDNMBAs)��������������������������������������������������������������������������  49 4.4.1 Aminosteroidal NDNMBAs ��������������������������������������������������  52 4.4.2 Benzylisoquinoline Derivatives����������������������������������������������  53 4.5 Monitoring Neuromuscular Function in Anesthesia ��������������������������������������������������������������������������������������  54 4.5.1 Train of Four (TOF) ��������������������������������������������������������������  56 4.5.2 Post-Tetanic Twitch Count (PTC) ������������������������������������������  56 4.5.3 Double-Burst Stimulation (DBS) ������������������������������������������  57 4.6 Neuromuscular Blockade Antagonization������������������������������������������  57 4.6.1 Acetylcholinesterase Inhibitors (ACEIs) ������������������������������  58 4.6.2 Sugammadex (SUG) ��������������������������������������������������������������  58 4.7 Future Perspectives ����������������������������������������������������������������������������  59 References����������������������������������������������������������������������������������������������������  60 5 Extracorporeal Circulation in Acute Respiratory Failure: High Flow Versus Low Flow����������������������������������������������������������������������  63 Alessio Caccioppola, Valentina Galanti, Sara Froio, Silvia Coppola, and Davide Chiumello 5.1 Introduction����������������������������������������������������������������������������������������  63 5.2 General Principles of Treatment ��������������������������������������������������������  64 5.3 History������������������������������������������������������������������������������������������������  65

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5.4 Techniques������������������������������������������������������������������������������������������  66 5.4.1 Extracorporeal Membrane Oxygenation (ECMO)�����������������  67 5.4.2 Extracorporeal CO2 Removal (ECCO2R) ������������������������������  68 5.5 Indications and Contraindications������������������������������������������������������  70 5.6 Complications ������������������������������������������������������������������������������������  72 5.7 Managing Considerations ������������������������������������������������������������������  74 5.7.1 Ventilation During Extracorporeal Circulation����������������������  74 5.7.2 Anticoagulation����������������������������������������������������������������������  74 5.7.3 Pharmacokinetic Implications������������������������������������������������  75 5.7.4 Weaning from Extracorporeal Circulation������������������������������  76 5.7.5 Economic Impact��������������������������������������������������������������������  76 5.7.6 Ethical Considerations������������������������������������������������������������  76 5.7.7 Selected Centers����������������������������������������������������������������������  77 5.8 Conclusions����������������������������������������������������������������������������������������  78 References����������������������������������������������������������������������������������������������������  78 6 Acute Asthma Exacerbations in Children: From Emergency Room to Intensive Care Unit Management��������������  83 Fabrizio Racca and Luigi Montagnini 6.1 Introduction����������������������������������������������������������������������������������������  83 6.2 Pathophysiology����������������������������������������������������������������������������������  84 6.2.1 Asthma Evaluation������������������������������������������������������������������  84 6.2.2 Exacerbations Treatment��������������������������������������������������������  86 6.3 Emergency Department Management������������������������������������������������  88 6.4 Intensive Care Unit Management ������������������������������������������������������  89 6.4.1 Primary Preintubation Therapies in PICU������������������������������  90 6.4.2 Noninvasive Positive Pressure Ventilation������������������������������  91 6.4.3 The Decision to Intubate��������������������������������������������������������  93 6.4.4 Supportive Measures During Invasive Ventilation������������������  94 6.4.5 Invasive Mechanical Ventilation ��������������������������������������������  95 6.4.6 Adjunctive Therapies��������������������������������������������������������������  98 6.5 Weaning from Mechanical Ventilation������������������������������������������������  99 6.5.1 Criteria for Discharge from the PICU������������������������������������  99 References���������������������������������������������������������������������������������������������������� 100 7 An Update on the Nonoperating Room Anesthesia�������������������������������� 105 Edoardo De Robertis, Michela Neri, and Rachele Simonte 7.1 Introduction and Historical/Cultural Contest�������������������������������������� 105 7.2 Definition of Analgesia and Procedural Sedation ������������������������������ 108 7.3 Risks of NORA/PSA�������������������������������������������������������������������������� 109 7.4 Patients Who Strictly Require an Anesthetic Assessment and Management�������������������������������������������������������������������������������� 109 7.5 Minimum Monitoring Requirements�������������������������������������������������� 110 7.6 Setting Requirements�������������������������������������������������������������������������� 112 7.7 General Minimum Requirements�������������������������������������������������������� 112

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7.8 Postprocedural Assistance and Discharge������������������������������������������ 113 7.9 Conclusions���������������������������������������������������������������������������������������� 114 References���������������������������������������������������������������������������������������������������� 114 8 Pediatric Airway Management ���������������������������������������������������������������� 117 Giovanna Chidini and Monsellato Stefania 8.1 Peculiar Anatomic and Physiologic Characteristics in Children������������������������������������������������������������������������������������������ 118 8.2 Approach to Intubation in Children���������������������������������������������������� 120 8.3 Pediatric Airway Evaluation �������������������������������������������������������������� 120 8.4 Equipment and Materials�������������������������������������������������������������������� 121 8.5 Anesthesiologic Procedures���������������������������������������������������������������� 122 8.5.1 Planned Difficult Intubation���������������������������������������������������� 124 8.6 Elective Fiberoptic-Guided Intubation and the Use of Supraglottic Airway Devices (SGA)���������������������������������������������� 125 8.7 Unpredicted Difficult Intubation�������������������������������������������������������� 127 8.8 Conclusions���������������������������������������������������������������������������������������� 128 References���������������������������������������������������������������������������������������������������� 128 9 Goal-Directed Fluid Therapy�������������������������������������������������������������������� 131 Marta Iaconi, Chiara Manganelli, Fernando Piscioneri, and Luigi Tritapepe 9.1 Introduction���������������������������������������������������������������������������������������� 131 9.2 Rationale �������������������������������������������������������������������������������������������� 134 9.3 Global Post-operative Complications ������������������������������������������������ 135 9.4 Renal Complications�������������������������������������������������������������������������� 135 9.5 Infectious Complications�������������������������������������������������������������������� 135 9.6 Gastrointestinal Complication������������������������������������������������������������ 135 9.7 Cardiovascular Complication�������������������������������������������������������������� 136 9.8 Application������������������������������������������������������������������������������������������ 136 9.9 GDFT�������������������������������������������������������������������������������������������������� 136 9.10 Protocols �������������������������������������������������������������������������������������������� 140 References���������������������������������������������������������������������������������������������������� 141 10 Management of Acute Ischemic Stroke���������������������������������������������������� 143 Luciana Mascia, Iacopo Battaglini, and Anna Teresa Mazzeo 10.1 Introduction�������������������������������������������������������������������������������������� 143 10.2 Ischemic Cerebral Stroke������������������������������������������������������������������ 144 10.2.1 Clinical Features������������������������������������������������������������������ 144 10.2.2 Initial Management, Clinical Assessment, and Monitoring of the Acute Stroke Patient������������������������ 145 10.2.3 Assessment of Vital Functions �������������������������������������������� 145 10.2.4 Basic Diagnostic Tests �������������������������������������������������������� 146 10.2.5 Airway Control�������������������������������������������������������������������� 146 10.2.6 Management of Changes in Body Temperature������������������ 147 10.2.7 Cardiovascular Monitoring and Blood Pressure Management���������������������������������������������������������� 147

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10.2.8 Neuroimaging in the Acute Phase of Stroke������������������������ 148 10.2.9 Treatment Strategies in Acute Ischemic Stroke ������������������ 149 10.3 Intravenous Thrombolysis���������������������������������������������������������������� 149 10.4 Endovascular Treatment�������������������������������������������������������������������� 150 10.5 Choice of the Therapeutic Strategy�������������������������������������������������� 151 10.6 Complications and Potential Critical Events in the Setting of Reperfusion Therapies������������������������������������������������������������������ 152 10.7 Potential Critical Events During Intravenous Thrombolysis������������ 152 10.7.1 Brain Hemorrhage���������������������������������������������������������������� 153 10.7.2 Systemic Hemorrhage���������������������������������������������������������� 153 10.7.3 Angioedema ������������������������������������������������������������������������ 154 10.8 Potential Critical Events During Endovascular Treatment �������������� 154 10.8.1 Interhospital Transfers, “Drip and Ship” ���������������������������� 154 10.8.2 Blood Pressure Management ���������������������������������������������� 155 10.8.3 Choice of Sedation�������������������������������������������������������������� 155 10.8.4 Extubation���������������������������������������������������������������������������� 156 10.8.5 Complications of Endovascular Treatment�������������������������� 156 10.9 Intensive-Care Management of Acute Stroke Patients���������������������� 157 10.9.1 Cerebral Edema�������������������������������������������������������������������� 157 10.9.2 Decompressive Craniectomy ���������������������������������������������� 157 10.9.3 Glycemic State Management ���������������������������������������������� 159 10.9.4 Start of Antiplatelet Therapy������������������������������������������������ 159 10.9.5 Deep Vein Thrombosis Prophylaxis������������������������������������ 159 10.9.6 Initiation of Anticoagulation Therapy���������������������������������� 160 10.9.7 Tracheostomy���������������������������������������������������������������������� 160 10.9.8 Dysphagia Screening ���������������������������������������������������������� 160 10.9.9 Neurorehabilitation�������������������������������������������������������������� 161 References���������������������������������������������������������������������������������������������������� 161 11 Delirium: From the Operating Room to the ICU ���������������������������������� 165 Jacopo Tramarin, Giuseppe Accurso, Marinella Puglisi, and Cesare Gregoretti 11.1 Introduction�������������������������������������������������������������������������������������� 165 11.2 Definition������������������������������������������������������������������������������������������ 166 11.3 Incidence ������������������������������������������������������������������������������������������ 166 11.4 Pathophysiology�������������������������������������������������������������������������������� 167 11.5 Risk Factors�������������������������������������������������������������������������������������� 167 11.6 Identification of Delirium ���������������������������������������������������������������� 168 11.7 Postoperative Delirium Risk Prediction�������������������������������������������� 169 11.8 Delirium Prevention�������������������������������������������������������������������������� 169 11.9 Pharmacologic Prophylaxis�������������������������������������������������������������� 169 11.10 Nonpharmacological Measures�������������������������������������������������������� 170 11.10.1 Mobilization������������������������������������������������������������������������ 170 11.10.2 Sleep������������������������������������������������������������������������������������ 171 11.10.3 Perioperative������������������������������������������������������������������������ 171 11.10.4 Sedation Bundles ���������������������������������������������������������������� 172

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11.11 Delirium Treatment�������������������������������������������������������������������������� 172 11.12 Conclusions�������������������������������������������������������������������������������������� 172 References���������������������������������������������������������������������������������������������������� 173 12 Preoperative Evaluation of the Patient Candidate for Major Abdominal Surgery������������������������������������������������������������������ 177 Angelo Gratarola and Carlotta Fontaneto 12.1 Cardiovascular Risk�������������������������������������������������������������������������� 180 12.1.1 Presence of Active Cardiac Pathologies������������������������������ 180 12.1.2 Cardiovascular Risk Depending on the Type of Surgery���������������������������������������������������������������������������� 180 12.1.3 Factors In Patient-Related Cardiac Risk������������������������������ 181 12.1.4 Functional Capacity ������������������������������������������������������������ 181 12.2 Respiratory Risk�������������������������������������������������������������������������������� 183 12.3 Renal Risk���������������������������������������������������������������������������������������� 186 12.4 Hemorragic Risk ������������������������������������������������������������������������������ 186 12.4.1 PONV���������������������������������������������������������������������������������� 188 References���������������������������������������������������������������������������������������������������� 190 13 Monitoring the Depth of Anesthesia�������������������������������������������������������� 193 Franco Cavaliere and Carlo Cavaliere 13.1 Awareness ���������������������������������������������������������������������������������������� 194 13.2 EEG and Anesthesia�������������������������������������������������������������������������� 197 13.3 EEG Recording and Processing�������������������������������������������������������� 198 13.4 Commercially Available Devices������������������������������������������������������ 199 13.5 Auditory Evoked Potential Monitoring�������������������������������������������� 201 13.6 Indications to Monitoring the Anesthesia Depth������������������������������ 201 13.7 Use in Critically Ill Patients�������������������������������������������������������������� 202 13.8 Evaluation of Antinociception���������������������������������������������������������� 202 13.9 Conclusions�������������������������������������������������������������������������������������� 203 References���������������������������������������������������������������������������������������������������� 204 14 How Do I Prepare Myself and My Staff for a Difficult Airway? ������������������������������������������������������������������������������ 207 Massimiliano Sorbello, Ida Di Giacinto, and Rita Cataldo 14.1 Introduction�������������������������������������������������������������������������������������� 207 14.2 What Makes an Airway Difficult?���������������������������������������������������� 208 14.3 Direct or Indirect Laryngoscopy? ���������������������������������������������������� 210 14.4 Face Mask Ventilation and Supraglottic Airway Devices ���������������� 211 14.5 Spontaneous Breathing Techniques�������������������������������������������������� 212 14.6 Extubation ���������������������������������������������������������������������������������������� 214 14.7 Cricothyrotomy and (Emergency) Front of Neck Access (eFONA) ���������������������������������������������������������������� 215 14.8 The New Challenge: Non-technical Skills���������������������������������������� 216 14.9 Airway Management as a Continuum of Care���������������������������������� 216 References���������������������������������������������������������������������������������������������������� 217

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The Role of the Heart in Weaning Failure Fabio Guarracino and Giulia Brizzi

Contents 1.1  Weaning as an Intense Exercise 1.2  The Diagnosis of Weaning Failure of Cardiovascular Origin 1.3  Transthoracic Echocardiography 1.4  Conclusions References

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In most patients, weaning from mechanical ventilation can occur as soon as the cause of respiratory failure is resolved, but about 20–30% of patients are considered difficult to wean [1]. Weaning failure is usually defined as an unsuccessful spontaneous breathing trial (SBT) or need for ventilator support within 48 h after extubation [2]. As confirmed in numerous studies [3–5], extubation failure causes an increase in length of stay in hospital and intensive care unit and is associated with an increase in mortality. As noted by several authors [6], previous respiratory disease, previous cardiac disease, and old age are predictors of weaning failure, and we should give these patients special attention. The pathophysiology of weaning failure is complex and requires a systematic differential diagnostic approach to identify the primary cause of weaning failure, and this can improve the possibilities to overcome a new SBT. Weaning failure may be due to impaired respiratory mechanics, respiratory muscle dysfunction, cardiac dysfunction, cognitive dysfunction, and metabolic disorders [7]. F. Guarracino (*) · G. Brizzi Department of Anaesthesia and Critical Care Medicine, Cardiothoracic Anaesthesia and Intensive Care, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 D. Chiumello (ed.), Practical Trends in Anesthesia and Intensive Care 2019, https://doi.org/10.1007/978-3-030-43873-9_1

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The transition from positive inspiratory pressure during mechanical ventilation to negative airway pressure during spontaneous breathing tests the patient’s physiological reserve. Weaning fails when the ventilatory needs of the patient overcome the ventilatory capacity.

1.1

Weaning as an Intense Exercise

Lungs and heart are functionally and anatomically coupled, so the transition from mechanical ventilation to spontaneous breathing leads to profound cardiovascular effects that could be the underlying reason for the weaning failure. During mechanical ventilation with positive airway pressure, the intrathoracic pressure rises during inspiration, while during spontaneous breathing, the intrathoracic pressure becomes negative due to the activation of the inspiratory muscles. This pressure drop during the weaning trial suddenly increases venous return and increases left ventricle afterload. In addition, there is an increase in the sympathetic tone related to stress (documented by the increase in serum catecholamine levels), hypercapnia, and hypoxemia, which could further increase left ventricle afterload. There is an increase in the heart oxygen demand and an increase in the respiratory muscle oxygen demand. There is also an increase in work of breathing (WOB). All these mechanisms may induce cardiovascular dysfunction, which is clinically expressed by an increase in pulmonary arterial occlusion pressure (PAOP), increase in left ventricle (LV) filling pressure, and finally pulmonary edema (WiPO “weaning-induced pulmonary edema”) (Fig. 1.1). intrathoracic Pr.

sympathetic tone

venous return

PaO2

PaCO2

PVR

WOB

myocardial ischemia

right ventricle dilatation ventricular interdependence

LV afterload

LV preload

LV compliance

LV EDP

Pr = pressure, WOB = work of breathing, PVR = pulmonary vascular resistences, LV = left ventricle, EDP = end diastolic pressure

Fig. 1.1  Mechanisms involved in weaning-induced pulmonary oedema

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It is clear that spontaneous breathing should be considered an intense physical exercise [8]. Numerous studies have documented that the transition from mechanical ventilation to spontaneous breathing induces an increase of stress for the heart that can induce myocardial ischemia in patients with coronary artery disease (CAD). However, even in the absence of coronary artery disease, inspiratory efforts can alter the diastolic function of the left ventricle with impaired relaxation, reduced compliance, and increased filling pressures, leading to cardiogenic pulmonary edema with resulting respiratory failure. It is therefore essential that clinicians are aware that the transition to spontaneous breathing is an intense physical exercise, which can put the heart in a situation of excessive workload, with increased myocardial oxygen demand and consumption, induce myocardial ischemia, or promote heart failure [9]. It is a common experience to find patients in the intensive care unit who may need mechanical ventilation for a strictly cardiological reason, such as an acute heart failure, or we may find ourselves in front of a cardiac patient who needs mechanical ventilation for a different reason, such as trauma or surgery and considering the role of the heart in the weaning process is fundamental.

1.2

 he Diagnosis of Weaning Failure T of Cardiovascular Origin

Although the first description of myocardial dysfunction as the underlying cause of weaning failure was made in 1988 by Lemaire et al. in patients with COPD and concomitant cardiovascular disease [10], it was then underestimated over the following years. In 2002, the definition of “weaning-induced heart failure” [11] was introduced. Since then, this condition is increasingly recognizable, but its true incidence is unknown. In some studies, the authors believe that the cardiac cause is responsible for about 30% of weaning failure [12] cases, while in other centers, where this condition is evaluated systematically, the incidence is higher [13–17]. Clinically, cardiovascular etiology as the predominant cause of weaning failure is not easy to identify: first, because the patient could have a subclinical condition of cardiovascular dysfunction that expresses itself clinically in conditions of increased oxygen demand and consumption, such as a stressful spontaneous breathing trial and second, because the objective (tachypnea, hypoxemia, hypercapnia) and subjective (discomfort, dyspnea, anxiety) symptoms of weaning failure are not specific and do not allow a differential diagnosis between cardiac and noncardiac causes of weaning failure [18]. For this reason, the cardiovascular origin of weaning failure could be underestimated and, due to this, undertreated. Diagnosis is simple when pulmonary edema develops shortly after the initiation of an SBT in a cardiopathic patient, but it may be much more difficult to diagnose in a patient with an unknown underlying heart disease. The diagnosis of WiPO was historically based on the measurement of the PAOP, with a cutoff value of 18 mmHg, but today the indications for right catheterization have been considerably reduced due to its invasiveness and complications. Today, therefore, the diagnosis of WiPO

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is based on noninvasive approaches that include transthoracic echocardiography, lung ultrasonography, myocardial markers (BNP and NT-proBNP), signs of hemoconcentration, and the measurement of extravascular lung water (EVLW).

1.3

Transthoracic Echocardiography

Ultrasound in the Intensive Care Unit is a fundamental tool because it permits the diagnosis of WiPO, but also identifies the underlying causes (Fig. 1.2). In patients with acute respiratory failure, it allows the diagnosis of pulmonary edema of cardiac origin by identifying the elevated left ventricular filling pressure, usually associated with an LV diastolic dysfunction of variable severity, irrespective of systolic function [19]. We would have the same echocardiographic approach for WiPO due to a failed SBT. Not surprisingly, patients with impaired diastolic function, especially of high grade, have a higher rate of weaning failure than patients with normal diastolic function [20], and many studies underline the importance of diastolic dysfunction rather than left ventricular systolic failure in a failed weaning [21]. The evaluation of diastole has classically been based on the analysis of transmitral flow and pulmonary vein flow through the application of the pulsed-wave Doppler. Two methods were then added to these Doppler techniques: color M-mode Doppler and tissue Doppler imaging (TDI) at the level of the mitral annulus. These have been shown to have a good correlation with the left ventricular filling pressures and pulmonary pressures recorded with invasive methods. With the transthoracic echocardiography, the mitral flow can be evaluated in the apical four-chamber view using the Pulsed-wave Doppler with the sample volume

Echocardiography role in the phases of weaning process

Before SBT

During SBT

Risk stratification

Predicting success

E’ < 8 cm sec E/A > 2 LVEF < 40%

After failed SBT

Diagnosis of cause

Detection of latent diastolic dysfunction

Fig. 1.2  The role of echocardiography throughout the weaning process

E/E’ > 12 cm sec

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Fig. 1.3  Pulsed Doppler sampling of the transmitral flow for the assessment of E/A ratio

between the mitral leaflet tips during diastole (Fig. 1.3). In normal conditions, we measure two velocities: peak early diastolic transmitral flow velocity (E) and peak late diastolic transmitral flow velocity (A). The E velocity represents the rapid filling phase that immediately follows the opening of the mitral valve, while A velocity represents the atrial filling phase of the diastole, which occurs when the left atrium pressure rises above LV pressure, due to the contraction of the LA. In normal hearts, the majority of filling occurs during early diastole. Therefore, E is higher than A velocity, and E/A ratio is greater than 1. When a diastolic dysfunction occurs, the E/A ratio is altered. From the apical four-chamber view, we can also measure the mitral annulus velocity using pulsed-tissue Doppler imaging, placing the region of interest at the level of septal or lateral mitral annulus. Three waveforms are visualized per cardiac cycle: the peak systolic wave (S′), early diastolic wave (E′), and end-diastolic wave produced by atrial contraction (A′). Normally, E′ is higher than A′ and E′/A′ ratio is greater than 1. The derived E/E′ ratio is commonly used to estimate the grade of LV diastolic dysfunction, and it closely correlates with left ventricular filling pressure. Lateral E/E′ ≤ 13 is consistent with a PAOP ≤15 mmHg. In contrast, higher E/E′ values have been reported in patients who have experienced weaning failure. Unfortunately, we do not have a validated E/E′ cutoff that can predict weaning failure because it differs in different studies (range: 7.8–14.5) due to distinct sites of

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E′ measurement (lateral or septal), different characteristics of study populations, and variable cumulative fluid balance at the time of SBT [22–24]. In a recent meta-analysis, including 7 studies with a total of 433 patients, it was shown that a higher baseline E/E′ ratio and an increase in left ventricular filling pressures during SBT were significantly associated with weaning failure [20]. In a selected population of difficult-to-wean patients, Lamia and colleagues found that at the end of an SBT, the combination of E/A  >  0.95 and E/E′  >  8.5 allowed an accurate detection of weaning-induced PAOP elevation associated with LV diastolic dysfunction [25]. Another recent study by Moschietto et al. [23] has shown that a higher E/E′ value before SBT was a predictor of weaning failure. The cutoff value to predict weaning failure was 14.5 with a sensitivity of 75% and specificity of 95.8%. The group that failed the weaning process showed a marked increase in the E/E′ ratio, while no significant change was observed in patients who successfully completed weaning. These data are aligned with previous studies that showed an increase in PAOP during SBT only in patients who failed the weaning trial [26]. The increase in E′ during SBT can also play an important role. The study by Moschietto [23] shows that in the group of patients who fail the weaning trial there is a smaller basal E′ value and that this does not increase during SBT, while it increases in the group that is successfully weaned. This agrees with the increase of E′ in healthy subjects during physical exercise, while in subjects with impaired left ventricular relaxation E′ does not change during exercise, and therefore, as during SBT, filling of the left ventricle could dramatically rise due to the inability of the heart to improve relaxation. In patients with impaired diastolic relaxation, even a relatively small increase in end-diastolic volume can lead to an exaggerated increase in left ventricular filling pressure, despite a normal EDV. This increased sensitivity to changes in volume may explain the appearance of pulmonary edema during SBT. In the study by Moschietto et al., the systolic function, assessed by the ejection fraction of the left ventricle, is not a good predictor of weaning failure and WiPO is much more related to the diastolic function of the LV than to the systolic function. In their study, there is no statistically significant difference between patients with low LVEF who failed weaning and those who failed weaning despite having a normal systolic function. This agrees with previous studies [27] in which the LVEF does not differ in those who failed weaning trial and in those who instead succeed. However, other studies also focus on the systolic function as a predictor of weaning failure [24]. In the context of weaning from the mechanical ventilator, echocardiography to measure diastolic function should be done systematically during SBT or immediately after weaning failure and before any cardiac dysfunction treatment is started. In patients without a known cardiac disease but presenting comorbidities potentially connected to a borderline systolic function, or to an alteration of the diastolic function or in patients with a positive fluid balance, echocardiography must be used as a screening tool to objectively identify those who are at risk of weaning failure due to cardiac origin. Before SBT, patients with high E/E′ values, or with significant valvular diseases or pulmonary hypertension must be constantly monitored with

1  The Role of the Heart in Weaning Failure

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ultrasound during the weaning process. During SBT, the increases in left ventricular filling pressure are identified using echocardiography, even if there is not a validated cutoff of the E/E′ ratio that can predict weaning failure. Mayo et al. [9] also suggest a systematic approach during the weaning trial in which echocardiography is performed initially and may reveal patients at risk of weaning failure for whom we will have to pay more attention to increase the chances of success. Then echocardiography will have to be repeated during weaning to highlight situations that may appear only during the SBT effort and finally after a failed SBT to identify the causes. In their study, a low left ventricle systolic function was also considered a negative predictive factor. Based on the Guidelines for the evaluation of diastolic function [28], weaning failure due to cardiac origin can be suspected when: • High left ventricular filling pressure with E/A > 2 if LVEF is reduced. • E/E′ ratio > 12 if the LVEF is normal. In practice, transthoracic echocardiography is performed immediately before disconnection from the mechanical ventilator and after 15–30 min of SBT (or earlier if the patient shows signs and symptoms of discomfort). This hemodynamic evaluation should be rapid and focused on the few measurements that immediately orientate the diagnosis, like the evaluation of the left ventricular filling pressure and the pulmonary systolic pressure; a mitral regurgitation, even transient, should be sought. In an asymptomatic patient, it is possible to proceed with extubation with a low risk of failure in the absence of an increase in the E/E′ ratio, in the absence of a substantial increase in PAPs, in the absence of SBT-induced mitral regurgitation, and in the absence of new regional wall motion abnormalities. This new echocardiographic approach also allows the clinician to choose a personalized therapy to prepare the patient for a new attempt of SBT, which is generally postponed for 24  h, to then be re-evaluated daily. Once the patient is again under mechanical ventilation, the causes of the weaning failure must be identified and the treatment of WiPO is linked to the identification of the underlying mechanism. For example, a positive fluid balance, responsible for an increased left ventricular filling pressure, should lead us to start a diuretic therapy. Liu et al. [16] have recently shown that patients who develop WiPO at the first attempt of SBT can be successfully extubated after diuretic and vasodilator therapy in order to achieve a positive passive leg rising test, i.e., reaching a state of fluid responsiveness. Excessive afterload is suspected in the event of a rapid increase in arterial blood pressure simultaneously with an increase in left ventricular filling pressure induced by the SBT. In this case, we could also find an acute reduction in the left ventricular ejection fraction and a worsening of a preexisting mitral regurgitation. In this case, the therapy is carried out with vasodilator drugs and nitrates could be a good choice also in case of new regional wall motion abnormalities induced by an SBT-related ischemia.

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Levosimendan, a calcium sensitizer with inotropic and vasodilator activity, could play an important role in the future in weaning failure of cardiac origin when administered 24 h before the extubation attempt. To date, there are no validated studies on the use of Levosimendan in the weaning process. Once the mechanism leading to weaning failure and WiPO has been corrected, the patient must be re-evaluated with echocardiography during the new SBT. In patients extubated after a favorable SBT, Silva et al. [29] showed that a combination of transthoracic echocardiography and lung and diaphragmatic ultrasound could predict a possible postextubation respiratory distress. The identification of interstitial pulmonary edema and high left ventricular filling pressures were identified as the strongest predictors of respiratory failure.

1.4

Conclusions

Weaning failure has complex and multifactorial pathogenesis. Cardiac etiology is gaining considerable interest and is increasingly diagnosed with an incidence of at least 30% in all cases of weaning failure. Early identification of patients who are at high risk of failing the weaning trial would indicate the therapies that could help the heart better tolerate the physical effort to which it will be subjected during the spontaneous breathing trial. This stress is due to the transition from positive pressure ventilation to spontaneous breathing, a real intense physical exercise to which our patients are subjected. Not only the cardiac patient is at high risk of failing the weaning trial, but also many patients with borderline cardiac function, with alteration of diastolic function, with chronic obstructive pulmonary disease could present weaning failure of cardiac origin, especially when there is a positive fluid balance. The weaning process can trigger a diastolic dysfunction in a noncardiopathic patient leading to WiPO. The diagnosis of weaning-induced pulmonary edema (WiPO) is linked to the measurement of high left ventricular filling pressures and other echocardiographic parameters, to myocardial markers (BNP and NT-proBNP), signs of hemoconcentration, and measurement of extravascular lung water (EVLW). Echocardiography can guide us in all phases of weaning, allowing us to identify patients at risk of failure and to make a differential diagnosis. Therefore, we can begin a therapy and with echocardiography monitor the hemodynamic effects we have achieved. Echocardiography has therefore a fundamental role in the management of patients with weaning failure of cardiac origin.

References 1. Heunks LM, van der Hoeven JG. Clinical review: the ABC of weaning failure—a structured approach. Crit Care. 2010;14:245. 2. Boles JM, Bion J, Connors A, Herridge M, Marsh B, Melot C, Pearl R, Silverman H, Stanchina M, Vieillard-Baron A, Welte T. Weaning from mechanical ventilation. Eur Respir J. 2007;29:1033–56. https://doi.org/10.1183/09031936.00010206.

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3. Epstein SK, Ciubotaru RL. Independent effects of etiology of failure andtime to reintubation on outcome for patients failing extubation. Am J Respir Crit Care Med. 1998;158:489–93. 4. Thille AW, Richard JC-M, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care Med. 2013;187:1294–302. 5. Béduneau G, Pham T, Schortgen F, Piquilloud L, Zogheib E, Jonas M, Grelon F, Runge I, Terzi N, Grangé S, Barberet G, Guitard PG, Frat JP, Constan A, Chretien JM, Mancebo J, Mercat A, Richard JM, Brochard L. WIND (Weaning according to a New Definition) Study Group and the REVA (Réseau Européen de Recherche en Ventilation Artificielle) Network. Epidemiology of weaning outcome according to a new definition. The WIND study. Am J Respir Crit Care Med. 2017;195(6):772–83. 6. Thille AW, Harrois A, Schortgen F, Brun-Buisson C, Brochard L.  Outcomes of extubation failure in medical intensive care unit patients. Crit Care Med. 2011;39(12):2612–8. 7. Doorduin J, van der Hoeven JG, Heunks LMA. The differential diagnosis for failure to wean from mechanical ventilation. Curr Opin Anesthesiol. 2016;29:150–7. 8. Pinsky MR. Breathinbg as exercise: the cardiovascular response to weaning from mechanical ventilation. Intensive Care Med. 2000;26:1164. 9. Mayo P, Volpicelli G, Lerolle N, et al. Ultrasonography evaluation during the weaning process: the heart, the diaphragm, the pleura and the lung. Intensive Care Med. 2016;42:1107. 10. Lemaire F, Teboul JL, Cinotti L, Giotto G, Abrouk F, Steg G, et  al. Acute left ventricular dysfunction during unsuccessful weaning from mechanical ventilation. Anesthesiology. 1988;69:171–9. 11. Jubran A.  Weaning-induced cardiac failure. In: Mancebo J, Net A, Brochard L, editors. Mechanical ventilation and weaning. Update in intensive care and emergency medicine, vol. 36. Berlin: Springer; 2002. p. 184–92. 12. Epstein SK. Etiology of extubation failure and the predictive value of the rapid shallow breathing index. Am J Respir Crit Care Med. 1995;152:545–9. 13. Cabello B, Thille AW, Roche-Campo F, Brochard L, Gómez FJ, Mancebo J.  Physiological comparison of three spontaneous breathing trials in difficult-to-wean patients. Intensive Care Med. 2010;36:1171–9. 14. Dres M, Teboul JL, Anguel N, Guerin L, Richard C, Monnet X.  Extravascular lung water, B-type natriuretic peptide and blood volume contraction enable diagnosis of weaning-induced pulmonary edema. Crit Care Med. 2014;42:1882–9. 15. Caille V, Amiel JB, Charron C, Belliard G, Vieillard-Baron A, Vignon P. Echocardiography: a help in the weaning process. Crit Care. 2010;14:R120. 16. Liu J, Shen F, Teboul JL, Anguel N, Beurton A, Bezaz N, et al. Cardiac dysfunction induced by weaning from mechanical ventilation: incidence, risk factors, and effects of fluid removal. Crit Care. 2016;20:369. 17. Roche-Campo F, Bedet A, Vivier E, Brochard L, Mekontso Dessap A. Cardiac function during weaning failure: the role of diastolic dysfunction. Ann Intensive Care. 2018;8:2. 18. Boles JM, Bion J, Connors A, Herridge M, Marsh B, Melot C, et al. Weaning from mechanical ventilation. Eur Respir J. 2007;29:1033–56. 19. Vignon P, Colreavy F, Slama M. Pulmonary edema: which role for echocardiography in the diagnostic work-up? In: De Backer D, Cholley BP, Slama M, et al., editors. Hemodynamic monitoring using echocardiography in the critically ill. Berlin: Springer; 2011. p. 177–94. 20. de Meirelles Almeida CA, Nedel WL, Morais VD, et al. Diastolic dysfunction as a predictor of weaning failure: a systematic review and meta-analysis. J Crit Care. 2016;34:135–41. 21. Teboul JL. Weaning-induced cardiac dysfunction: where are we today? Intensive Care Med. 2014;40:1069–79. 22. Lamia B, Maizel J, Ochagavia A, et  al. Echocardiographic diagnosis of pulmonary artery occlusion pressure elevation during weaning from mechanical ventilation. Crit Care Med. 2009;37:1696–701. 23. Moschietto S, Doyen D, Grech L, et al. Transthoracic echocardiography with Doppler tissue imaging predicts weaning failure from mechanical ventilation: evolution of the left ventricle relaxation rate during a spontaneous breathing trial is the key factor in weaning outcome. Crit Care. 2012;16:R81.

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24. Papanikolaou J, Makris D, Saranteas T, et  al. New insights into weaning from mechanical ventilation: left ventricular diastolic dysfunction is a key player. Intensive Care Med. 2011;37:1976–85. 25. Lamia B, Maizel J, Ochagavia A, Chemla D, Osman D, Richard C, et al. Echocardiographic diagnosis of pulmonary artery occlusion pressure elevation during weaning from mechanical ventilation. Crit Care Med. 2009;37:1696–701. 26. Jubran A, Mathru M, Dries D, Tobin MJ. Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med. 1998;158:1763–9. 27. Mekontso-Dessap A, de Prost N, Girou E, Braconnier F, Lemaire F, BrunBuisson C, Brochard L. B-type natriuretic peptide and weaning from mechanical ventilation. Intensive Care Med. 2006;32:1529–36. 28. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10:165–93. 29. Silva S, Ait Aissa D, Cocquet P, et al. Combined thoracic ultrasound assessment during a successful weaning trial predicts postextubation distress. Anesthesiology. 2017;127:666–74.

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MDR Infections in the ICU Enrico Tagliaferri, Francesco Menichetti, and Gianni Biancofiore

Contents 2.1  Infections and Resistance: The Problem Dimension 2.2  Infections and Resistance: Definitions 2.3  MDR Gram Positive 2.4  MDR Gram Negative 2.5  Empiric Therapy 2.6  Duration of Therapy 2.7  Role of Additional Therapies in Gram-Negative MDR/XDR Bacteria Septic Shock 2.8  Prevention and Control of MDR Infections in the ICU 2.9  Antimicrobial Stewardship References

2.1

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Infections and Resistance: The Problem Dimension

After many decades of antibiotic therapy, resistance has emerged as one of the most important determinants of outcome in patients with serious infections. More than 700,000 healthcare-associated infections, many caused by antibiotic-resistant bacteria, occur annually in the US with almost half in critically ill patients [1]. Infections due to antibiotic-resistant microorganisms accounted for an estimated 33,110 attributable deaths and 874,541 disability-adjusted life years (DALYs) in Europe in 2015 [2]. The drug-resistance phenomenon already imposes a very heavy burden on healthcare with regard to mortality and health-care costs with infections caused by

E. Tagliaferri · F. Menichetti Infectious Diseases Unit, University of Pisa, Pisa, Italy G. Biancofiore (*) Transplant Anesthesia and Critical Care, University of Pisa, Pisa, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 D. Chiumello (ed.), Practical Trends in Anesthesia and Intensive Care 2019, https://doi.org/10.1007/978-3-030-43873-9_2

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Gram-negative organisms often more prevalent than Gram-positive infections in many settings [3]. Moreover, some further studies prognosticate worrying trends, with an expected rising impact on global health through years, leading to more than ten million annual deaths worldwide in 2050 [3]. A majority of these deaths are, and will be, related to Gram-negative infections, particularly healthcare-acquired infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), multidrug-­ resistant (MDR) Acinetobacter baumannii, and Pseudomonas aeruginosa. In Europe, the prevalence of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae is extremely high in some countries like Greece and Italy, and strains producing carbapenem-hydrolyzing oxacillinase-48 (OXA-48) and New Delhi metallo-betalactamase (NDM) are rapidly increasing [2]. The incidence of infections due to resistant Gram-negative pathogens has dramatically increased in the nosocomial setting [1–5]. In particular, Intensive Care Units (ICU) are often considered the epicenter of development, amplification, and dissemination of drug-­ resistant microorganisms [6]. Critically ill patients are particularly prone to infections because of exposure to multiple invasive procedures compromising the anatomical barriers’ defenses, impairment of protective mechanisms such as cough reflex or acid gastric ambient by sedative drugs or stress-ulcer prophylaxis and the frequent impairment of the immune response induced by trauma, surgery, and sepsis. Furthermore, the use of broad-spectrum antibiotics, that is closely related to the development and spread of drug-resistant microorganisms, is really frequent in ICU clinical practice, with studies reporting a 30–60% rate of inappropriate or incorrect antibiotic prescriptions. For these reasons, nosocomial infections caused by MDR microorganisms are common in ICUs, frequently even more than in other departments [1, 3]. A number of studies have been performed to assess the burden of infection in critical illness. The Intensive Care Over Nations (ICON) audit showed that more than one-third of the patients develop an infection during their ICU stay [7]. The Extended Prevalence of Infection in Intensive Care (EPIC) II study showed that 51% of patients were considered to be infected while in ICU. The infection was of respiratory origin in 64% of cases. Staphylococcus aureus (20.5%) was the most frequent organism isolated, despite the overall predominance of Gramnegative organisms as a group: 62.2% (E. coli, Enterobacter spp., Klebsiella spp., Pseudomonas spp., and Acinetobacter) [8]. Antibiotic resistance is a serious problem in all parts of the world, including Asia-Pacific, Latin America, Middle East, Europe, and North America. In Europe, the European Antimicrobial Resistance Surveillance Network (EARS-Net) has provided European reference data on antimicrobial resistance for public health purposes since the program began in 1999. Over the last years, the proportion of K. pneumoniae and E. coli with resistance to fluoroquinolones, third-generation cephalosporins, aminoglycosides, and a combined resistance to all three antibiotic groups has increased significantly [9]. The recent “European Antimicrobial Resistance One Health ministerial conference 2016” highlighted the substantial antimicrobial resistance problem in Europe

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and for several antimicrobial group–bacterium combinations [10]. In general, lower resistance percentages are reported by countries in the north and higher percentages by countries in the south and east of Europe [10].

2.2

Infections and Resistance: Definitions

A group of international experts, brought together by a joint initiative between the European Centre for Disease Control and Prevention (ECDC) and the United States Centre for Disease Control and Prevention (CDC), was tasked with creating a standardized international terminology to describe acquired resistance profiles in multidrug-­resistant organisms [11]. MDROs have been divided into three categories depending on their resistance profile: 1. MDROs—nonsusceptible to at least 1 agent in 3 antimicrobial categories; 2. extensively drug-resistant (XDR) organisms—nonsusceptible to at least 1 agent in all but 2 or fewer antimicrobial categories; and 3. pan-drug-resistant (PDR) organisms—nonsusceptible to all agents in all antimicrobial categories. Moreover, a new, comprehensive recommendation on classification of infections caused by Gram-positive and emerging Gram-negative multidrug-resistant pathogens has been launched in 2012 in the consideration that E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp. (ESKAPE) pathogens account for more than 80% of infectious episodes in the ICU.  As this acronym seems to help to highlight the problem of MDR bacteria, some authors [12] claimed a change to “ESCAPE” is warranted (E. faecium, S. aureus, C. difficile, A. baumannii, P. aeruginosa, and Enterobacteriaceae) in order to highlight the importance of C. difficile and incorporate not only Enterobacter spp. but also other Enterobacteriaceae (or more modernly and widely Enterobacterales) because of the increasing levels of antibiotic resistance (including extended-spectrum β-lactamases, carbapenemases, and aminoglycoside resistance) and decreasing levels of fluoroquinolone susceptibility among these organisms.

2.3

MDR Gram Positive

MDR Gram-positive are major human pathogens, causing both healthcare- and community-associated infections. Among them, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and drug-­ resistant Streptococcus pneumoniae have been designated as serious public threats by the CDC [13]. Indeed, MRSA and VRE are leading causes of healthcare-­ associated infections in the United States, with conservative estimates suggesting they cause >12,000 deaths per year. Similarly, infections due to drug-resistant S. pneumoniae, the main cause of bacterial pneumonia and meningitis in adults, are estimated to cause 19,000 excess admissions and 7000 deaths per year in the United States alone [13]. Infections due to MRSA accounted for an estimated 148,727 infections and 7049 deaths in Europe in 2015 [2].

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Methicillin resistance is due to a modified penicillin-binding protein (PBP2a), which is not inhibited by any beta-lactam. MRSA phenotype is the most relevant from the clinical and the epidemiological points of view among staphylococci. In fact, MRSA infections have higher mortality and cause higher costs for the health system compared to methicillin-susceptible S. aureus (MSSA) [14]. MRSA is spread worldwide and prevalence is high in many countries, including Italy where it stands at about 40% [15]. Enterococci have a low virulence and are part of the intestinal flora but can provoke urinary tract infection (UTI), bacteremia, and endocarditis in vulnerable and immunocompromised patients; less frequently they are responsible, usually as copathogens, of intra-abdominal infections and surgical wound infections. Naturally resistant to cephalosporins, they can acquire genetic elements conferring resistance to penicillins, aminoglycosides, and glycopeptides (vancomycin-resistant enterococci, VRE). The European surveillance system EARS-Net indicates that the EU/ EEA population-weighted mean percentage of resistance to vancomycin in E. faecium among European countries increased from 10.4% in 2014 to 14.9% in 2017 [9]. Risk factors for VRE infection include diabetes, renal failure, cancer, prolonged hospital stay, proximity to a colonized or infected patient, previous treatment with broad-spectrum antibiotics (particularly vancomycin and cephalosporins). Treatment of Clostridium difficile infection with metronidazole or oral vancomycin has also been reported to increase the risk of acquiring VRE [16]. Finally, it should be reminded that patients colonized by VRE have a higher risk of bacteremia in case they are exposed to vancomycin, are immunocompromised, have relevant comorbidities, live in long-term care facilities, or have a VRE infection in another site [17].

2.3.1 MRSA Options for treating MRSA infections include the old drugs (vancomycin, teicoplanin, linezolid, daptomycin) and several new agents: the lipoglycopepetide dalbavancin and oritavancin, the new oxazolidinone tedizolid, the advanced-generation cephalosporins (ceftaroline and ceftobiprole), and the fluoroquinolone delafloxacin. The most recent guidelines for the treatment of MRSA infections are those released by the Infectious Diseases Society of America (IDSA) in 2011 [18]. According to the guidelines, vancomycin, linezolid, and daptomycin have all the highest level of evidence and recommendation for the treatment of skin and SSTIs, only daptomycin is rated AI for the treatment of bacteremia and endocarditis on native valve, while linezolid is rated II for MRSA pneumonia (as vancomycin), but the results of the Zephyr study have not been considered. According to the latter, mortality at the end of the study was significantly lower with linezolid among patients with MRSA nosocomial pneumonia [19]. For bone and joint infections, all the three drugs are rated BII. In case MRSA is isolated and susceptibility pattern is available, the treatment should be based on vancomycin MIC.  In case of MIC 60 years. If MRSA is unlikely, a beta-lactam should be preferred; otherwise an anti-MRSA drug should be selected according to local epidemiology of vancomycin MICs and site of infection. In case of severe sepsis or septic shock with renal impairment, the association of linezolid and daptomycin is an option, since vancomycin is slowly bactericidal and potentially nephrotoxic.

2.3.2 Potential Role for the New Antibiotics Ceftaroline and ceftobiprole have anti-MRSA activity in addition to the spectrum of third-generation cephalosporins and might be useful in the treatment of pneumonia. Particularly, ceftobiprole is licensed for hospital-acquired pneumonia (excluding ventilator-associated cases). In fact, ceftobiprole has an anti-Pseudomonas activity close to that of ceftazidime, and in a randomized double-blind study, it showed cure rates comparable to those of ceftazidime plus linezolid in patients with HAP (excluding VAP) [20]. They share with the other cephalosporins a good safety profile, better than other anti-MRSA drugs. Dalbavancin’s main peculiarity is the very long half-life allowing an intravenous administration every week or even 2 weeks. It’s licensed for complicated SSTIs and its good penetration in the bone suggests a role in the management of osteomyelitis [21]. Therefore, its potential use in the setting of ICUs seems to be very limited. Tedizolid, licensed for SSTIs, has a good penetration in the epithelial lining fluid and has a potential role in the management of pneumonia. It seems to have a better safety profile compared to linezolid, particularly concerning bone marrow suppression [22]. Since such toxicity is more frequent after 10–14 days of treatment, which is generally considered an adequate duration of treatment for pneumonia, the cheaper linezolid is likely to remain the preferred option in the majority of cases; however, tedizolid might be appealing in patients that already have a significant reduction of blood cells. Delafloxacin is a new fluoroquinolone with enhanced activity against Gram-­ positive bacteria. Licensed for SSTIs, it’s being tested for pneumonia. Due to its peculiar chemical structure and mechanism of action with multiple bacterial targets, it’s thought to be less prone to the selection of resistance [23].

2.3.3 VRE Aminopenicillins are preferred over all other agents when enterococci are susceptible and patients can tolerate them. In case of endocarditis on native or prosthetic

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valve, an aminoglycoside or ceftriaxone should be added. Daptomycin and linezolid have demonstrated clinical efficacy against VREs. In case of UTI of the upper urinary tract or associated with bacteremia, daptomycin or linezolid is recommended. Quinupristin/Dalfopristin (Q/D) is reserved for selected cases of infection due to Enterococcus faecium resistant to vancomycin. In case of bacteremia or endocarditis due to vancomycin- and ampicillin-resistant strains, daptomycin and linezolid are preferable to Q/D, and none of the two has been demonstrated to be more effective in retrospective studies. Some authors suggest higher than standard doses of daptomycin, e.g., 10–12 mg/kg, should be considered in severe bloodstream infections due to VRE, to obtain a bactericidal effect; another possible strategy to enhance efficacy of daptomycin and prevent selection of resistance seems to be the combination with a beta-lactam, such as ampicillin, ceftriaxone, and, probably better, ceftaroline [24]. In case VRE strains are not highly resistant to aminoglycosides, these can be associated with daptomycin, linezolid, or Q/D, while in case of strains highly resistant to aminoglycoside (HLR), tigecycline, doxycyclyne, or rifampin can be an alternative as partner drug. In selected cases, daptomycin can represent an alternative to aminoglycosides for its rapid bactericidal activity, and the association with linezolid can be an option [25, 26]. Synergistic combinations are often warranted in complex infections of high inoculum and biofilms, while monotherapies are generally appropriate for uncomplicated infections. Although active against resistant enterococci, the pharmacokinetics, efficacy, and safety of tigecycline and quinupristin/dalfopristin can be problematical for severe infections. Recently, approved agents such as tedizolid and oritavancin have good in vitro activity against VRE, but clinical studies are lacking [27].

2.4

MDR Gram Negative

Evidence suggests that the prevalence of MDR Gram-negative bacteria is increasing worldwide [1–4]. Numerous risk factors can increase the likelihood of infection with resistant organisms, including: (1) prior antimicrobial therapy, especially with a broad-spectrum agent, in the preceding 90  days; (2) current hospitalization for 5 days; (3) a high prevalence of resistant organisms in a hospital environment; (4) immunosuppressive therapy; and (5) specific risk factors such as hospitalization for 2 days in the preceding 90 days, residence in a nursing home or long-term care facility, chronic dialysis within the preceding 30 days, home wound care or intravenous infusion therapy, and a family member with a resistant pathogen.

2.4.1 ESBL-Producing Enterobacteriaceae Resistance to third-generation cephalosporins among Enterobacteriaceae is generally mediated by the production of extended-spectrum beta-lactamase (ESBL). Therapeutic options are limited by the typically multiresistant phenotype of ESBL-­ producing Enterobacteriaceae and conditioned by the site and the severity of the infection. A timely and appropriate treatment is essential to reduce the mortality of

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these infections. Carbapenems represent the first choice in case of severe infections: meropenem 1–2 g IV tid and imipenem 1 g IV tid, in extended or continuous infusion after a loading dose. Ertapenem 1 g IV qd is a valid alternative because it has no activity against Pseudomonas spp and Acinetobacter spp, and therefore it does not apply selective pressure on nonfermenting Gram-negative bacteria and because it can be administered once daily [28]. However, data on clinical efficacy are more limited compared to imipenem and meropenem, and it is advisable to adopt it in case of not severe infections. Doripenem 500 mg IV tid in extended infusion has similar characteristics to meropenem and could represent an alternative, but data about its use against ESBL-producing bacteria are still scarce. Piperacillin/tazobactam 4.5 g IV tid or qid in extended or continuous infusion is a valid option when the microorganism is reported to be susceptible. The association with an aminoglycoside, if active, could offer an advantage. The extended infusion in 4  h, after a loading dose in 30  min, seems to guarantee a better pharmacodynamic profile against microorganisms with a MIC up to 16 mg/L [29]. However, recent results from a randomized clinical trial suggest that treatment with meropenem is associated with lower mortality compared to piperacillin/tazobactam, in patients with bacteremia due to ceftriaxone-resistant K.pneumoniae [30]. Ceftolozane/tazobactam, the combination of a new cephalosporine with an old beta-lactamase inhibitor, has been licensed for intra-abdominal and urinary tract infections and, more recently, pneumonia (HAP and VAP). This drug showed in vitro activity comparable to that of meropenem against E.coli and slightly inferior (but still superior to that of piperacillin/tazobactam and cephalosporins) against K.pneumoniae [31]. A wider use of this drug might be considered to spare carbapenems that have a high impact on the selection of resistant strains, such as carbapenemase-­producing Gram-negative bacteria. Tigecycline’s spectrum of activity includes Gram-negative producing ESBL and carbapenemase. It’s bacteriostatic, it does not reach adequate serum levels, but concentrates in the sites of infection, though not in the CNS and the urine. The slightly higher mortality among patients treated with tigecycline compared to those treated with other agents (difference of 1%) [32] suggests to limit the use of tigecycline to the registered indications (intra-abdominal infections, skin and soft-tissue infections), and in case it’s used against multiresistant Gram-negative bacteria, the association with other agents, such as colistin, fosfomycin, and carbapenems, as well as higher doses, such as 100 or 200 mg bid in large volumes to prevent nausea and vomit [33, 34], are advisable. Intravenous fosfomycin, at a dose of 12–24 g per day, may be an option in nonsevere infections, particularly in the setting of urinary tract infections, preferably in association with other agents, such as an aminoglycoside.

2.4.2 AmpC-Producing Enterobacteriaceae Ampicillinase C (AmpC) production is another mechanism of resistance to cephalosporins used by Enterobacteriaceae. This enzyme is naturally present in Enterobacter cloacae, and aerogenes, Citrobacter freundii, and Serratia

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marcescens and it’s spreading through plasmids to other bacteria, such as E. coli, K. pneumoniae, Salmonella enterica, and Proteus mirabilis. Differently by ESBL, AmpC is less active against fourth-generation cephalosporins such as cefepime, which is often active against AmpC-producers, but are not inhibited, or much less, by beta-­lactamase inhibitors, namely, clavulanic acid, sulbactam, and tazobactam. The efficacy of fourth-generation cephalosporins on AmpC-producers, however, can be impaired in case of severe infections with high bacterial mass, due to inoculum effect. In case of severe infection, therefore, a carbapenem is preferable [35].

2.4.2.1 Carbapenem-Resistant Gram Negative The increased use of carbapenems due to the spread of ESBL applied a selective pressure that induced an increase in carbapenem-resistance among nonfermenting Gram-negative, such as P. aeruginosa and A. baumannii, and more recently among Enterobacteriaceae. The main concern is at the moment the spread of carbapenem-­resistance in K. pneumoniae [2, 9]. Most common carbapenemase types include KPC (K. pneumoniae carbapenemase), more common among K. pneumoniae and less frequently detected in other Enterobacteriaceae and P. aeruginosa, OXA (oxacillinase), more common in A. baumannii and also found in Klebsiella spp and MBL (metallo-beta-lactamase), found in Enterobacteriaceae and nonfermenting Gram-negative [36]. Among these, KPC showed the capability of spreading very fast and it currently represents one of the main therapeutic challenges.

2.4.3 XDR P. aeruginosa XDR P. aeruginosa is resistant to carbapenems, all beta-lactams, fluoroquinolones, and often aminoglycosides. These strains are colistin-only susceptible (COS). Colistin is an old molecule necessarily rescued, although the experience about its use in clinical practice is quite scarce and out of date. It is usually used at the dose of two to three million units IV tid, possibly after a loading dose of nine million units, in an adult >75 kg. Administration once daily (nine million in 4 h) or twice a day (4.5 million bid) is recommended on the basis of pharmacokinetic data, but the risk of bacterial regrowth between too distant doses suggests caution. The scarce concentrations in the sites of infection and the relatively high MICs, even among strains still susceptible, strongly suggest the use of colistin in association with other drugs. Laboratory and clinical data suggest rifampin 600 mg IV or oral is a possible partner. However, the choice of the best combination of drugs should be based on synergy tests that the laboratory should perform in case of XDR clinical isolates. Other possible partners include injectable fosfomycin 3–6 g IV qid, aminoglycosides, for instance, amikacin 1 g IV qd, and in case of intermediate susceptibility or low-level resistance, carbapenems, in two- or three-drug combinations [33, 35]. These approaches are experimental and consequently require a strong collaboration between clinicians and microbiologists so that each case can contribute to the general debate.

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The new compound Ceftolozane/tazobactam has been demonstrated to have a good activity against P. aeruginosa, including MDR and XDR strains, and should always be tested on these strains [31]. Real-life experience suggests ceftolozane/ tazobactam can be effective in the treatment of serious infections due to Pseudomonas aeruginosa, including pneumonia, in this case at a dose double than standard [37]. Cefiderocol, a new siderophore cephalosporin, is promisingly active against carbapenem-­resistant Gram negative, including Enterobacteriaceae, A. baumannii, P. aeruginosa, and S. maltophilia [38].

2.4.4 XDR A. baumannii Usually, infections due to A. baumannii affect patients admitted in ICUs in epidemic clusters. Colonization is much more common than infection and it’s important to reserve treatment only to well-defined infections. This is quite simple for bacteremia, but much less for VAP. The phenotype of resistance of XDR A. baumannii is close to that of P. aeruginosa, with the relevant difference that more than 50% of the strains show relatively low MICs of tigecycline (2 mg/L). Also in case of XDR A. baumannii infection, monotherapy with colistin, and even worse, with tigecycline, is not recommended and an association of at least two drugs, for instance, colistin and tigecycline, is advisable. Amikacin, which is often reported to be active, often results to be antagonistic when combined with colistin [33]. Cefiderocol, due to its high in vitro activity, might have a significant impact in the management of A.baumannii infections [38].

2.4.5 K  PC-Producing K. pneumoniae and Other Carbapenemase-Producing Enterobacteriaceae (CRE) KPC-producing K. pneumoniae (KPC-KP) is currently spreading as an epidemic in many Countries, mostly in ICUs, but also in Neurorehabilitation, Internal Medicine, and Surgery wards due to the pathway of patients transferred from one ward to another and spreading the microorganism within the hospital. These outbreaks are also relevant for the mortality that seems to be higher than that caused by nonfermenting XDR Gram-negative. Risk factors for KPC-KP colonization include prolonged hospital stay and concomitant broad-spectrum antibiotic treatment. KPC-KP infections mainly affect vulnerable patients and often induce septic shock. The strategy to treat KPC-KP infection has been traditionally based on (a) higher doses, for instance, meropenem 2 g tid, tigecycline 100 mg bid, colistin nine million units as loading dose followed by 4.5 million units bid, (b) optimized administration, e.g., loading dose followed by extended infusion of carbapenems, and (c) combination therapy. In fact, combination therapy has demonstrated superiority in terms of mortality versus monotherapy [34, 39]. However, the wide use of carbapenems is among the reasons of the spread of MDR bugs and should be used in the treatment

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of CRE, in combination with other drugs, only when precise MICs are available and relatively low. Rapid and standardized tests aimed at studying the synergistic activity of different combinations of antibiotics are urgently needed. Recently introduced, Ceftazidime/avibactam, the association of an old third-­ generation cephalosporin with a new beta-lactamase inhibitor, can now be considered as first-line treatment for severe infections caused by these microorganisms, preferably in combination with a companion drug, such as an aminoglycoside, to increase bactericidal activity and prevent selection of resistance [40]. Although the best administration strategy has not yet been established, at least in most severe infections, a loading dose followed by extended or continuous infusion is probably advisable. In less severe, nonbacteremic infections, ceftazidime/avibactam can possibly be spared using tigecycline in the setting of abdominal infections, fosfomycin and aminoglycosides for UTIs. The association of gentamicin with colistin is generally not advisable because of the high risk of nephrotoxicity. Unfortunately, avibactam is not active against MBL, such as NDM enzymes. In such a case, aztreonam should be considered, since it is generally resistant to MBL, preferably in association with avibactam, or perhaps another beta-lactamase inhibitor, to protect it against other beta-lactamase, that often these strains produce in addition to MBL [41]. Again, a loading dose followed by extended or continuous infusion is probably the best administration strategy. A coformulation with avibactam will probably be available in the next future. Meanwhile, the combination with ceftazidime/avibactam is the only option. Cefiderocol showed a very promising in vitro activity against CRE, with very low resistance rates [42]. Other drugs, such as plazomicin, a new aminoglycoside, eravacycline, and combinations of carbapenems with other beta-lactamase inhibitors, namely, meropenem/vaborbactam and imipenem/relebactam, are about to be available and might contribute significantly to the management of these infections.

2.5

Empiric Therapy

The fundamental principle of antimicrobial therapy in these patients is the timeliness of the beginning of optimal initial antibiotic treatment (IAT) [34]. However, the increasing prevalence of MDR Gram-negative bacteria increases the chances of failure of the IAT, while an extended use of broad-spectrum antimicrobials may lead to further spread of resistance. Waiting for the results of cultures, recommendations for the initial management of patients with suspected Gram-negative infections include [6]: (1) careful assessment of the infectious state in terms of clinical severity and probability of Gram-­ negative MDR bacteria etiology; (2) assessment of previous bacterial colonization or of treatments that may have increased the likelihood of resistant organisms; (3) knowledge of local epidemiology; (4) early administration of an empirical antimicrobial therapy based on these considerations with subsequent adjustment based on

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21

the results from the microbiological laboratory. Depending on the suspected microorganism, an appropriate empirical IAT may include the combination of a broad-­ spectrum or anti-Pseudomonas cephalosporin plus an aminoglycoside, a beta-lactamase inhibitor combined with an aminoglycoside or a carbapenem. Although antibiotic-combination therapy regimens can lead to increased costs and adverse effects of drugs, the rationale for their use, at least at an early stage, is based on the possibility to take advantage of possible drug synergism, prevention (or delay) of drug resistance and widening of antimicrobial coverage when the risk of MDR organisms is high by using drugs with different mechanisms of action. Standard dosing regimens are often not adequate for critically ill patients due to some differences in pharmacokinetic/pharmacodynamic parameters characterizing ICU patients: an (a) increased volume of distribution and (b) increased renal clearance of antibiotics [43]. Initial antibiotic doses should therefore address the increased volume of distribution of antibiotics such that a large loading dose is required independent of subsequent clearances. If not, time to achieve adequate bacterial killing activity is delayed due to underdosing, which predisposes to the emergence of newly resistant bacterial strains. Once the results of the laboratory are available, the treatment regimen can be adapted and, possibly, de-escalated to the narrowest spectrum of activity. Notably, de-escalation of initial empirical therapy seems to be associated with lower mortality among patients’ sepsis and septic shock [44]. In the era of fast, automated nucleic acid amplification tests, the Microbiology lab is able to detect genes encoding for resistance mechanisms, e.g., carbapenemases, well before phenotypic susceptibility testing is available. On the basis of this information, the clinician can adjust therapy: for instance, supposing an Enterobacteriacea is isolated from blood culture and no genes for carbapenemases are detected, a carbapenem or ceftolozane/tazobactam, eventually in combination with an aminoglycoside, can be chosen; in case gene for KPC is detected, ceftazidime/avibactam, eventually in combination with an aminoglycoside, is probably the best option; in case gene for MBL is detected, ceftazidime/avibactam plus aztreonam is probably the most effective regime.

2.6

Duration of Therapy

The optimal duration of antibiotic therapy remains controversial but has significantly decreased over the past two decades, since an excessively long duration is recognized as one of the main reasons of inappropriateness in antibiotic therapy. In ventilator pneumonia, a shorter treatment course of 7–8 days has been validated, even though for some specific pathogens or clinical situations a longer treatment course may still be recommended [1]. For complicated intra-abdominal infection, a treatment course of 4 days may also be acceptable when septic shock is not present [45]. Serial biomarkers such as procalcitonin can also help to accurately identify patients appropriate for shorter courses of antibiotics [46].

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 ole of Additional Therapies in Gram-Negative MDR/ R XDR Bacteria Septic Shock

Early identification of the causing agent, appropriate antibiotic therapy, and prompt volemic resuscitation in shocked patients are the cornerstones for the treatment of sepsis caused by MDR germs. However, given the increasing clinical and therapeutic burdens caused by antibiotic resistance and the high prevalence of immune suppression in patients with MDR infection, many experts and opinion makers consider the use of additional therapies reasonable in critically ill patients [6]. The use of adjunctive therapies for restoring immune function seems to be very promising but, unfortunately, sound evidence is not yet available. Waiting for the results of the ongoing trials, in patients with sepsis by MDR/XDR infections the capability of immune response should be carefully monitored by appropriate biomarkers. New emerging drugs focused on modifying the inflammatory response are currently being investigated for the treatment of septic shock. Immunomodulatory therapy for sepsis includes inflammatory cytokines, cellular receptors, nuclear transcription factors, coagulation activators, and apoptosis regulators. There are various therapies based on monoclonal antibodies that block inflammatory mediators and receptors, agents that block or eliminate bacterial products, modulators of immune function and immunostimulatory molecules. They have shown promising results in animal tests and are currently at various stages of clinical evaluation. This is an approach based on the more modern concept of “precision” or “personalized” medicine. An example of “personalized medicine in sepsis management” is the potential benefit of beta blockers infusion in the subset of patients with tachycardia [47, 48].

2.8

Prevention and Control of MDR Infections in the ICU

Infection control measures, pivotal for reducing the spread of Gram-negative MDR organisms in hospitals, include the implementation of specific guidelines for the early detection of resistant organisms (e.g., screening for rectal colonization), educational programs for hand hygiene and monitoring of hand hygiene protocols application, timely alert systems, and strict isolation procedures when resistant microorganisms are isolated [6, 33]. Since microorganism resistance patterns may vary from center to center, effective surveillance is important to continuously evaluate the state of bacterial resistance in specific departments. Antimicrobial stewardship programs should be implemented to ensure the appropriate use of antibiotics. A recent meta-analysis evaluated the relative effectiveness of strategies for the prevention of Gram-negative MDR bacteria infections in ICU patients [3]. Forty-two studies (5 randomized controlled trials and 37 observational studies) and 62,068 patients were included in the analysis. The meta-analysis showed that a multifaceted strategy consisting of standard care, antimicrobial stewardship, accurate environmental cleansing, and source control actions was the most effective intervention to prevent the acquisition of MDR Gram-negative germs.

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23

Antimicrobial Stewardship

Institution of an antimicrobial stewardship program (AMS) seems to be an effective strategy and is strongly recommended in ICUs with a high prevalence of MDR bacteria with the aim of fighting drug resistances, improving patient outcomes, and reducing health-care costs [49]. Key issues of AMS programs are halting antibiotics in patients without infection and selection of the appropriate drug for empirical therapy that, as general rules, depends on clinical conditions of the patient, source of infection, local antimicrobial susceptibility patterns, patient microbiological history, and previous therapy. Moreover, use of adequate dosages, early de-escalation of empirical broad-spectrum antibiotics focusing the treatment on the isolated microorganism, switching to monotherapy whenever possible, and a short course of therapy are also fundamental elements of AMS in critically ill patients. An AMS program in ICUs should include also full-time Infectious Disease physicians and clinical pharmacists with infectious disease training in reducing antimicrobial use. A close relationship with the Microbiology Laboratory is mandatory in case of severe infections due to MDR microorganisms: all the phases of processing have to be fastened and results promptly communicated and tailored strategies such as additional susceptibility tests, synergy testing, and bactericidal activity of the serum must be considered. Also, prospective audit and feedback of antimicrobial prescriptions, therapeutic drug monitoring, formulary restrictions, use of local antibiograms, and partnership with infection prevention services, when available, are important parts of the package.

References 1. Kollef M, Bassetti M, Francois B, et  al. The intensive care medicine research agenda on multidrug-­ resistant bacteria, antibiotics, and stewardship. Intensive Care Med. 2017;43:1187–97. 2. Cassini A, Högberg LD, Plachouras D, et  al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis. 2019;19(1):56–66. Epub 2018 Nov 5. https://doi.org/10.1016/S1473-3099(18)30605-4. 3. Bassetti M, Righi E. New antibiotics and antimicrobial combination therapy for the treatment of gram-negative bacterial infections. Curr Opin Crit Care. 2015;21:402–11. 4. Teerawattanapong N, Kengkla K, Dilokthornsakul P, et al. Prevention and control of multidrug-­ resistant gram-negative bacteria in adult intensive care units: a systematic review and network meta-analysis. Clin Infect Dis. 2017;64:S51–60. 5. Hawkey PM, Warren RE, Livermore DM, et al. Treatment of infections caused by multidrug-­ resistant gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/ Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother. 2018;73:iii2–iii78. 6. Tosi M, Roat E, De Biasi S, Munari S, et al. Multidrug resistant bacteria in critically ill patients: a step further antibiotic therapy. J Emerg Crit Care Med. 2018;2:103. 7. Vincent JL, Marshall JC, Amendys-Silva SA, et al. Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir Med. 2014;2:380–6.

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8. Vincent J, Rello J, Marshall J, et  al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–9. 9. European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2010. p. 2017. 10. http://www.consilium.europa.eu/en/press/press-releases/2016/06/17-epsco-conclusions-antimicrobial-resistance/. Visited April 2019. 11. Magiorakos A-P, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18:268–81. 12. Peterson LR. Bad bugs, no drugs: no escape revisited. Clin Infect Dis. 2009;49:992–3. 13. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States. http://www.cdc.gov/drugresistance/threat-report-2013/index.html. Visited April 2019. 14. Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and economic burden of antimicrobial resistance. Expert Rev Anti Infect Ther. 2008;6:751–63. 15. Malacarne P, Boccalatte D, Acquarolo A, et al. Epidemiology of nosocomial infection in 125 Italian intensive care units. Minerva Anestesiol. 2010;76:13–23. 16. Al-Nassir WN, Sethi AK, Li Y, et al. Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob Agents Chemother. 2008;52:2403–6. 17. Salgado CD. The risk of developing a vancomycin-resistant Enterococcus bloodstream infection for colonized patients. Am J Infect Control. 2008;36:S175.e5–8. 18. Liu C, Bayer A, Cosgrove SE, et  al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011;52:285–92. 19. Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, McGee WT, Reisman A, Chastre J.  Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012;54(5):621–9. Epub 2012 Jan 12. https://doi.org/10.1093/cid/cir895. 20. Awad SS, Rodriguez AH, Chuang YC, Marjanek Z, Pareigis AJ, Reis G, Scheeren TW, Sánchez AS, Zhou X, Saulay M, Engelhardt M. A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia. Clin Infect Dis. 2014;59(1):51–61. Epub 2014 Apr 9. https://doi.org/10.1093/ cid/ciu219. 21. Dunne MW, Puttagunta S, Sprenger CR, Rubino C, Wart S, Baldassarre J. Extended-duration dosing and distribution of Dalbavancin into bone and articular tissue. Antimicrob Agents Chemother. 2015;59(4):1849–55. Prepublished online 2015 Jan 5. Published online 2015 Mar 11. https://doi.org/10.1128/AAC.04550-14. 22. Lodise TP, Fang E, Minassian SL, Prokocimer PG. Platelet profile in patients with acute bacterial skin and skin structure infections receiving tedizolid or linezolid: findings from the phase 3 ESTABLISH clinical trials. Antimicrob Agents Chemother. 2014;58(12):7198–204. https:// doi.org/10.1128/AAC.03509-14. 23. Tulkens PM, Van Bambeke F, Zinner SH.  Profile of a novel anionic Fluoroquinolone-­ Delafloxacin. Clin Infect Dis. 2019;68(Supplement_3):S213–22. https://doi.org/10.1093/cid/ ciy1079. 24. Munita JM, Murray BE, Arias CA.  Daptomycin for the treatment of bacteraemia due to vancomycin-­resistant enterococci. Int J Antimicrob Agents. 2014;44(5):387–95. Epub 2014 Sep 2. https://doi.org/10.1016/j.ijantimicag.2014.08.002. 25. Yadav G, Thakuria B, Madan M, Agwan V, Pandey A.  Linezolid and vancomycin resistant enterococci: a therapeutic problem. J Clin Diagn Res. 2017;11:GC07–11. 26. Rivera AM, Boucher HW.  Current concepts in antimicrobial therapy against select gram-­ positive organisms: methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, and vancomycin-resistant enterococci. Mayo Clin Proc. 2011;86:1230–43.

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27. Mercuro NJ, Davis SL, Zervos MJ, Herc ES. Combatting resistant enterococcal infections: a pharmacotherapy review. Expert Opin Pharmacother. 2018;19:979–92. 28. Mody RM, Erwin DP, Summers AM, et  al. Ertapenem susceptibility of extended spectrum beta-lactamase-producing organisms. Ann Clin Microbiol Antimicrob. 2007;6:6. 29. Kaufman SE, Donnell RW, Hickey WS.  Rationale and evidence for extended infusion of piperacillin-­tazobactam. Am J Health Syst Pharm. 2011;68:1521–6. 30. Harris PNA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320(10):984–94. 31. Sader HS, Farrell DJ, Castanheira M. Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12). J Antimicrob Chemother. 2014;69(10):2713–22. 32. Tasina E, Haidich AB, Kokkali S, Arvanitidou M. Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. Lancet Infect Dis. 2011;11:834–44. 33. Cerceo E, Deitelzweig SB, Sherman BM, Amin AN. Multidrug-resistant gram-negative bacterial infections in the hospital setting: overview, implications for clinical practice, and emerging treatment options. Microb Drug Res. 2016;22:412–31. 34. Cunha BA.  Pharmacokinetic considerations regarding tigecycline for multidrug-resistant (MDR) Klebsiella pneumoniae or MDR Acinetobacter baumannii urosepsis. J Clin Microbiol. 2009;47:1613. 35. Bassetti M, Carnelutti A, Peghin M. Patient specific risk stratification for antimicrobial resistance and possible treatment strategies in gram-negative bacterial infections. Expert Rev Anti Infect Ther. 2017;15:55–65. 36. Miriagou V, Cornaglia G, Edelstein M, et al. Acquired carbapenemases in gram-negative bacterial pathogens: detection and surveillance issues. Clin Microbiol Infect. 2010;16:112–22. 37. Bassetti M, Castaldo N, Cattelan A.  Ceftolozane/tazobactam for the treatment of seri ous Pseudomonas aeruginosa infections: a multicentre nationwide clinical experience. Int J Antimicrob Agents. 2019;53(4):408–15. 38. Zhanel GG, Golden AR, Zelenitsky S, et  al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant gram-negative bacilli. Drugs. 2019;79(3):271–89. 39. Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, Losito AR, Bartoletti M, Del Bono V, Corcione S, Maiuro G, Tedeschi S, Celani L, Cardellino CS, Spanu T, Marchese A, Ambretti S, Cauda R, Viscoli C, Viale P, ISGRI-SITA (Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva). Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a ­multicentre study. J Antimicrob Chemother. 2015;70(7):2133–43. Epub 2015 Apr 21. https:// doi.org/10.1093/jac/dkv086. 40. Tumbarello M, Trecarichi EM, Corona A, et  al. Efficacy of Ceftazidime-Avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniae Carbapenemase-­ producing K. pneumoniae. Clin Infect Dis. 2019 Jan 18;68(3):355–64. 41. Emeraud C, Escaut L, Boucly A, et al. Aztreonam plus Clavulanate, Tazobactam or Avibactam for treatment of infections caused by Metallo-β-lactamase-producing gram-negative bacteria. Antimicrob Agents Chemother. 2019;63(5):e00010–9. 42. Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore cephalosporin, cefiderocol, against carbapenem-nonsusceptible and multidrug-­ resistant isolates of gram-negative bacilli collected worldwide in 2014 to 2016. Antimicrob Agents Chemother. 2018;62:e01968–17. https://doi.org/10.1128/AAC.01968-17. 43. Roberts JA, Taccone FS, Lipman J.  Understanding PK/PD.  Intensive Care Med. 2016;42:1797–800. 44. Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernández-Delgado E, Herrera-Melero I, Ortiz-Leyba C, Márquez-Vácaro JA. De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic

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3

The Diaphragmatic Dysfunction Paolo Formenti, Valentina De Giorgis, and Davide Chiumello

Contents 3.1  Introduction  3.2  The Diaphragm 3.3  Anatomy and Respiratory Function 3.4  Diaphragmatic Dysfunction and Fatigue 3.5  Invasive Evaluation of Diaphragmatic Function 3.6  Noninvasive Evaluation of Diaphragmatic Function: The Ultrasound 3.7  Diaphragmatic Displacement 3.8  Thickness and Thickening Fraction 3.9  Conclusion References

3.1

 27  28  28  29  31  31  31  33  36  36

Introduction

Discontinuing mechanical ventilation is a key moment in the recovery of critically ill patients as it enhances the process of rehabilitation and reduces the morbidities associated (ventilator-induced lung injury—VILI, ventilator-induced diaphragm dysfunction—VIDD, ventilation-associated pneumonia—VAP) [1–3].

P. Formenti Department of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo, San Paolo University Hospital, Milan, Italy V. De Giorgis Department of Health Sciences, University of Milan, Milan, Italy D. Chiumello (*) San Paolo Hospital, Intensive Therapy Department, University of Milan, Milan, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 D. Chiumello (ed.), Practical Trends in Anesthesia and Intensive Care 2019, https://doi.org/10.1007/978-3-030-43873-9_3

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Weaning from mechanical ventilation could be delayed by the combined actions of cardiovascular, abdominal, neuromuscular, and psychic pathologies [4].

3.2

The Diaphragm

The respiratory system is formed essentially by two components, the gas exchanger (the lung) and a mechanical pump that creates the in or out airflow from the lung (the thoracic cage and the associated muscles) [5]. These two components are interdependent and act in combination to allow a normal function of the respiratory system. The respiratory muscles are peculiar in comparison with the other muscles: 1. They are the unique skeletal muscles fundamental for life; in continuous contraction and so the most used skeletal muscles [6, 7]; 2. They are under both voluntary and involuntary control; 3. They must face elastic and resistive loads, whereas the other skeletal muscles face mostly inertia [5]. Respiratory muscles represent only 3% of body weight but constitute a durable system with a strong functional reserve and a remarkable adaptation capacity to the pathophysiological requests of the organism.

3.3

Anatomy and Respiratory Function

The diaphragm is the main inspiratory muscle. It constitutes 0.5% of body weight in an adult norm type [8] with an area of 900 cm2 [9, 10]. The phrenic nerve provides the motor innervation with fibers from C3, C4, C5; the sensory innervation related to the tendon center is afferent, as well to the phrenic nerve, whereas peripheral zones are afferent to intercostal nerves from T5 to T12. The diaphragm is a membranous muscle formed by a not contractile central area (the tendon center), which constitutes about 15/20% of its surface, and two muscle portions, the costal and crural diaphragm [11]. In humans, the fibers of the costal portion are inserted at the level of the xiphoid process of the sternum and the upper margins of the lower six ribs. From their insertions, the costal fibers run cranially in direct contact with the rib cage and they are apposed to the inner aspect of the lower rib cage. On the contrary, the fibers of the crural portion are inserted at the level of the anterolateral portion of the first three lumbar vertebrae and on the aponeurotic arcuate ligament [12]. The ability of different portions of the muscle to generate force was studied through the evaluation of diaphragm regional thickness: one of the costal portions resulted in 40% higher cross-sectional area than the crural portion [13]. It is important to remember that there is a high regional difference in the same costal portion [14, 15]. Thus, we can observe an increasing thickness from the tendon center

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toward the insertion [16]. We can state that there is no uniformity in the capacity of the diaphragmatic fibers to generate force. For instance, in a healthy human, an elliptical cylinder surmounted by a dome-shaped portion composes the overall shape of the diaphragm. The dome corresponds to the central tendon, while the cylinder portion is mostly formed by fibers in direct contact with the inner rib cage, the so-called zone of apposition (ZOA) [16, 17]. In adults in an upright position, ZOA represents about 30% of the surface of the rib cage. However, the shortening of fibers as a consequence of the diaphragmatic contraction reduces this component. This is equal to an average of 1.5 cm during normal breathing in a healthy human [12]. Therefore, as previously explained, the ZOA is the component that modifies its geometry much more while the dome has a caudal excursion, with relation to its rib insertions without a substantial modification in its shape and dimensions. This pattern of contraction, actually similar to a piston inside a cylinder, shows a simplistic exemplification of the movement of the diaphragm during inspiratory breathing and its way to determine an increase in lung volumes.

3.4

Diaphragmatic Dysfunction and Fatigue

The diaphragm, like the other skeletal striated muscles, is subject to fatigue, so its capacity to manage heavy works under excessive strain is limited in time. However, it can tolerate resistive loads lower than 40% of the maximal load for an indefinite time [18]. The definition of diaphragmatic fatigue is the loss of capacity to produce a constant force with the repetition of action, reversible upon rest [19]. The etiology of muscle fatigue is due to a deficit of signal generation between the central nervous system and peripheral contractile system. We can classify the respiratory muscles fatigue into three types: –– central fatigue, –– “high-frequency” peripheral fatigue –– “low-frequency” peripheral fatigue. In central fatigue, the muscle’s capacity to produce force in repeated contractions is reduced due to nervous output reduction. Peripheral fatigue derives from the inability of the neuromuscular junction or the downstream portions to produce force in response to direct electrical stimulation, and it can be classified as “high frequency” or “low frequency” based on the force-frequency curve after fatigue. All these three processes can be active simultaneously in the presence of increased respiratory resistive load. The relative importance of each of them depends on how long the respiratory load is maintained and on other physiological variables such as the nutritional status, the arterial pressure, and respiratory gas exchange parameters. Fatigue is not a single event, but it is a process that occurs when the muscle is subject to an unsustainable load in time. A sequence of modifications takes place along the way from the generation of the signal to the production of force.

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3.4.1 Diaphragmatic Dysfunction The term “diaphragmatic dysfunction” refers to a range of clinical evidences ranging from partial deficit in generating force (weakness) to the total loss of diaphragmatic function (paralysis) [20, 21]. It is a condition often undiagnosed but that should be taken into account while approaching patients affected by dyspnea [22, 23]. There are conditions that predispose the development of this functional defect such as inflammatory or metabolic diseases, trauma and surgery, mechanical ventilation, mediastinal masses, myopathies, neuropathies, diseases that cause pulmonary hyperinflation [21, 24], involving the muscle unilaterally or bilaterally. Unilateral diaphragmatic dysfunction is not usually associated with symptoms at rest, while it may result in a reduction of exercise capacity or, rarely, causes orthopnea [25, 26]. Comorbidities such as obesity, neuromuscular degenerative diseases, cardiopathy, and/or pulmonary diseases can affect more extreme symptomatology. Bilateral diaphragmatic paralysis or a severe generalized muscle weakening is more commonly symptomatic. Patients can complain of dyspnea at rest or during exercise, orthopnea, fragmented or not restful sleeping due to nocturnal hypoventilation with consequent hypersomnia, depression, morning headache, and fatigue [27, 28]. Other complications are the development of subsegmentary atelectasis and lower respiratory tract infections [29]. In the Intensive Care Unit, common causes of diaphragmatic dysfunction and weakness are the critical illness polyneuropathy (CIP) and the myopathies [30], especially in patients with sepsis, multiorgan failure, hyperglycemia. These events should be regarded as potential causes of weaning failure. Disuse atrophy can occur after a brief ventilation period or after curarization. It comes from atrophy of both fast- and slow-twitch muscle fibers. Moreover, malnutrition, dysoniae such as hypophosphatemia, hypomagnesemia, hypokalemia, hypocalcemia, thyroid dysfunction, and long-lasting dependence on mechanical ventilation are all predisposing factors communally present in ICU patients [31, 32]. The combination of a diaphragmatic weakness along with any process causing an increase in respiratory work (such as pneumonia, pulmonary edema, atelectasis, bronchospasm, pleural effusion) can exceed the contractile capacities of a weaker diaphragm and determine for the patient an extended period of mechanical ventilation. As far as the role of mechanical ventilation in the development of diaphragmatic dysfunction is concerned, the very existence of loss of ability to generate inspiratory force called “Ventilation-induced Diaphragmatic Dysfunction” (VIDD) is proved [33, 34]. This condition not only affects the diaphragm but also involves the rest of respiratory muscles [35, 36]. The pathophysiology of VIDD has been studied mainly in an animal model, although recently different studies have investigated this condition in humans, starting from brain-death donors [37], to ICU patients with different pathological conditions [38]. Other mechanisms seem to be involved in VIDD such as the reduction of diaphragmatic blood flow, the increase in oxidative stress, and the upregulation of cytokine cascades also active in sepsis (IL-6, TNF-α, IL-1β).

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Invasive Evaluation of Diaphragmatic Function

Diaphragmatic function can be studied with different techniques divided into invasive and noninvasive. The currently available tools for invasive assessment of electrical activity of muscle are the diaphragm electromyography and the phrenic nerve stimulation; other less invasive technique are represented by the measurement of pleural and abdominal pressures, which allow to perform different variables such as the work of breathing (WOB), the transpulmonary pressure (Ptp), the transdiaphragmatic pressure (Pdi), and the esophageal and diaphragmatic pressure-time product (PTPes − PTPdi) [39]. Invasive methods also include those indices that can be derived directly from patients on mechanical ventilation, such as P0.1 and Pmusc index (PMI).

3.6

 oninvasive Evaluation of Diaphragmatic Function: N The Ultrasound

Bedside ultrasound has become a routine device used in clinical practice in the Intensive Care Unit [40, 41]. The ultrasound examination of the diaphragm includes mainly two methods: the study of its excursion with the respiratory acts (displacement) [42, 43] and the evaluation of its thickness at ZOA [44, 45].

3.7

Diaphragmatic Displacement

The evaluation of diaphragmatic displacement requires the use of a convex 3.5–5 MHz probe, positioned at the subcostal level on the medium midclavicular line or anterior axillary line. The probe is directed medially, dorsally, and toward the subject’s head in a way that the delivered ultrasound beam hits, with a straight angle, the posterior third of the hemi diaphragm under study (Fig.  3.1a, b). The procedure first involves the identification of a good-quality ultrasound image in bidimensional mode (B-mode) using the window provided by the liver on the right and by the spleen on the left (Fig. 3.1c). Once a good image is obtained, the M-mode is used in order to display the movement of the diaphragm along the exploration line, which must be perpendicular to the image of the diaphragm in B-mode. Tables 3.1 and 3.2 show the normal values ​​for the displacement of right and left diaphragm, for men and women. During a normal respiratory act, the diaphragm moves in inspiration in a cranial–caudal direction, approaching the ultrasound probe positioned at the subcostal level, while in expiration, it moves away from the probe itself. Such displacements are visualized in M-mode as positive deflections in inhalation and negative deflections in exhalation. Further measurable parameters are the speed of shortening of the diaphragm (in cm/s), the time of inspiration (Tinsp, in seconds), and the total time of the respiratory cycle (Ttot, in seconds).

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a

b

c

d

Fig. 3.1  Diaphragmatic displacement. (a) Ultrasound probe positioned at the left subcostal space to detect the diaphragm displacement. (b) Probe position allows a perpendicular projection of ultrasound using the hepatic and spleen acoustic windows. (c) B-mode ultrasound allows to detect the anatomical position of the diaphragm (hyperecogenic line) and the liver (d) M-mode view of diaphragm displacement Table 3.1  Right diaphragmatic displacement values in male and female subjects Variables Quiet breathing Sniffing breathing Sigh

Male (cm) 1.8 ± 0.3 (1.1–2.5) 2.8 ± 0.6 (1.8–4.4) 7 ± 1.1 (4.7–8.2)

Female (cm) 1.6 ± 0.3 (1–2.2) 2.6 ± 0.5 (1.6–3.6) 5.7 ± 1 (3.6–7.7)

P 0.9 [5, 15, 20–22, 30], whereas its presence results in muscle weakness, hypoventilation, upper airways obstruction, frequent causes of hypoxic/hypercapnic postoperative complications) [25–29]. Strategies aimed at PORC prevention should include [7, 8, 17, 18, 20, 30]: 1 . use of short- or intermediate-action NMBAs, 2. neuromuscular monitoring when NMBAs are used [5] 3. TOF titration of the degree of neuromuscular blockade according to surgical needs: deep block should be if not mandatory for the type of surgery. A major question is nowadays the real necessity of deep block. 4. Assessment of the degree of neuromuscular block at the end of surgery and consequent response. (a) TOFr > >Antagonization. (b) TOFr >0.9 (=1) no indication for antagonists. It must be noted that residual curarization (TOF  3. Atropine 0.01 mg/kg is strongly advised.

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6. VEC and ROC have a specific antagonist, sugammadex, which can be administered after TOF count >1 (otherwise, wait until TOF count >3 for neostigmine) [31]. 7. a recent consensus [16] proposed to wait 15 min before extubation after neostigmine administration with a TOF >3 (or 10 min for a TOF count >4), at the end of sevoflurane-based anesthesia. In case of propofol infusion and TOF count >3, a 5-min interval after neostigmine ensures safe extubation. Extubation requires TOFr >0.9 after spontaneous resolution of muscle blockade or antagonists action: ACEIs (acetylcholine-esterase inhibitors) are neostigmine, pyridostigmine, edrofonium (the first is still the drug most extensively used in anesthesia and intensive care), and sugammadex, which is the only selective agent capable of steroidal NMBA antagonization [5, 7, 8, 17, 18, 31].

4.6.1 Acetylcholinesterase Inhibitors (ACEIs) [5, 7, 8, 17, 18] ACEIs increase the amount of ACh at NMJ level; ACh acts as a NMBA competitor on nAChRs restoring muscle activity. Duration of action of neostigmine ranges between 60 and 120 min. Furthermore, ACEIs effects are also directed on muscarinic receptors, potentially leading to clinically relevant parasympaticomimetic effects (mainly bradycardia). Atropine or glycopirrolate must always be available to treat bradycardia. For the (usual) neostigmine dose of 0.03 mg/kg, atropine average dosage is 1 mg. In case of use of glycopyrrolate, 0.2 mg is administered every 1 mg neostigmine. Increased doses may be required if maximum neostigmine doses (0.07 mg/kg, very seldom used, and with relevant possible adverse effects) are used. In case of sevoflurane-based anesthesia and rocuronium as NDNMBA, median reversal time from TOFc 3 to TOFr >0.9 was 15  min (7–43), after neostigmine administration, 9.7 (5.1–7.4) minutes after TOFc >4 and 5 min when propofol was used as the main anesthetic agent. Unavailability of neuromuscular monitoring equipment forces the anesthetist to clinically (subjectively) assess the degree of functional muscular recovery, although this subjective evaluation is prone to errors. It must be emphasized that in case of deep block (PTC >1 TOFc 0) neostigmine is ineffective.

4.6.2 Sugammadex (SUG) [5, 7, 8, 17, 18, 31, 32] Sugammadex is a modified gamma-cyclodextrin specifically designed to “encapsulate” free-circulating aminosteroidal nondepolarizing muscle relaxants. The highest affinity is documented for rocuronium; SUG does not have any effect on SCh, ATR, or CIS. Free molecules of ROC are “captured” by SUG and free ROC concentration rapidly decreases, creating a gradient between neuromuscular junction and plasma, where they are encapsulated by the gamma-cyclodextrin [17]. Rapid and efficient antagonization results in prompt recovery of neuromuscular transmission. Recovery

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of muscle function is significantly more rapid with SUG than neostigmine. SUG dosage must be based on the level/degree of blockade and to the lean/ideal body weight [17]: 1 . for deep block (1–2 PTC) 4 mg/kg dose leads to TOF > 0.9 in 5 min, 2. intermediate level of block (TOFc 2–4) 2  mg/kg dose ensures TOFr >0.9  in 3–5 min, 3. in emergency situations (impossible endotracheal intubation, impossible ventilation after muscle paralysis), a dose of 16 mg/kg dose completely reverses muscular blockade in 3 min. Hence, rocuronium at 1.2 mg/kg dose in rapid sequence intubation or in case of complex intubations can be completely, safely, and rapidly reversed. SUG is not devoid of side effects, including hypersensitivity (5%), anaphylaxys (1:1000–1:20000), and bradycardia [32, 33]. Problematic could be the (re)-use of aminosteroidal agents within a short intermediate period of time after administration. Specifically addressing the problem of reintubation shortly after reversal with SUG, a practical option supported by clinical studies and quoted by Murphy et al. could be the use of rocuronium 1.2 mg/kg, able to produce onset of the neuromuscular block within 3  min (if SUG was administered 5  min before), and within 1.5  min (if SUG was used 30  min before) [17, 32]. Aminosteroidal NDNMBAs should not be used within 5 min of SUG administration (in this specific setting ATR or CIS or SCh should be considered) [32]. Special attention should be reserved for the so-called special populations. In patients suffering from neuromuscular disorders, the use of neostigmine could be problematic because of the risk of muscle weakness. Instead, the use of aminosteroidal compounds reversed by the usual doses of SUG has been successfully reported in many clinical cases; studies in larger series are awaited, but the option has a good rationale [17]. SUG, not recommended in case of severe renal failure, has been successfully used in mild-to-­ moderate renal dysfunction; in case of severe renal impairment, the ROC-SUG complex is removed by high flux hemodialysis. In case of hepatic dysfunction, the use of SUG was possible; the reversal of neuromuscular block, longer than in healthy patients, was faster and safer than with ACEIs [17]. Kinetic and dynamic profiles are minimally affected in the elderly patient and in the pediatric population [32].

4.7

Future Perspectives [7, 8, 34–36]

New molecules are required to have adequate potency to allow clinically reasonable doses, rapid onset, although this may affect potency, rapid clearance, and metabolism (compatible with potency and rapid onset), with inactivation pathways that are hopefully independent from end-organ function/failure; in other words, a safer profile [32, 34, 35]. According to possible side effects, hemodynamic stability, absence of hypersensitivity/anaphylaxis, and absence of airways alterations are

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key. In recent years a very promising compound, rapacuronium, was withdrawn from the market in the USA because of interaction with M2 and M3 bronchial receptors leading to bronchospasm [34]. Fumarates are a new NMBA class that may meet these needs. Among Fumarates, Gantacurium and CW002 are worth to be mentioned; chloride atom on gantacurium is key to increase the rate of inactivation (degradation) in the presence of l-cysteine, the new essential molecule in reversal of these agents [34, 35]. Gantacurium is an ultrashort-acting NMBA, characterized by rapid onset and intermediate potency (ED95 0.19 mg/kg,) being inactivated by hydrolysis; a reaction with l-cysteine can speed up the degradation process. This inactivation mechanism is innovative (spontaneous hydrolysis plus l-cysteine) and occurs in 2–3 min. Ideal conditions for intubation are achieved in 60–90 s using 0.3–0.4 mg/kg (ED95 1.5–2) and could be even shorter using 0.5 mg/ kg (ED95 × 5). High doses may result in histamine liberation. Blockade antagonization with l-cysteine enables TOF recovery in 2–3 min. Marketing has been hampered by complexity in production operations and side effects [35, 36]. Still under animal experimentation, but promising, seems to be CW 1759–50—a new ultrashort NDBA.  Compared to gantacurium, the clinical profile has been defined “superior”; changes in mean arterial pressure and heart rate were less and degradation with l-cysteine very rapid [36]. As recently assessed by Murrel and Savarese [34], the perfect blocking agent, ultrashort acting, provided with the most favorable dynamic and kinetic profiles, with the best safety profile, completely reversible at any time point of blockade and able to offer the same conditions provided by SCh (but devoid of the SCh side effects!) has to be found, as yet. Quite surprisingly, SCh, conceived in 1952, is still the basis of comparison. Promising compounds such as Fumarates and related molecules and l-cysteine reversal are now under intense studies. According to Murrel and Savarese [34], these molecules will have a considerable role in the very next future of our everyday clinical practice. Conflicts of Interests  Andrea De Gasperi received fees and travel reimbursements for lectures from MSD.

References 1. Barash P, Bieterman K, Hersey D. Game changers: the 20 most important anesthesia articles ever published. Anesth Analg. 2015;120:663–70. 2. Griffith HR, Johnson GE.  The use of curare in general anesthesia. Anesthesiology. 1942;3:414–20. 3. Brull SJ, Kopman AF.  Current status of neuromuscular monitoring. Anesthesiology. 2017;126:173–90. 4. Beecher HK, Todd DP. A study of the deaths associated with anesthesia and surgery: based on a study of599548 anesthesias in ten institutions 1948-1952, inclusive. Ann Surg. 1954;140:2–35. 5. Naguib M, Brull SJ. Johnson KB conceptual and technical insights into the basis of neuromuscular monitoring. Anaesthesia. 2017;72(Suppl. 1):16–37. 6. Pandit JJ, Andrade J, Bogod DG, et al. Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland. The 5th National Audit Project (NAP5) on

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a­ ccidental awareness during general anaesthesia: summary of main findings and risk factors. Br J Anaesth. 2014;69:1089–101. 7. Renew JR, Naguib M. Clinical use of neuromuscular blocking agents in anesthesia. UptoDate; June 2019. 8. Naguib M, Lien CA, Meistelman C. Pharmacology of neuromuscular blocking drugs. Chapter 34. In: Miller RD, Eriksson LI, Fleisher L, Kornish JPW, Cohen M, Young WL, editors. Miller’s anesthesia. 8th ed. Amsterdam: Elsevier; 2015. p. 958–94. 9. Sury MR, Palmer JH, Cook TM, Pandit JJ. The state of UK anaesthesia: a survey of National Health Service activity in 2013. Br J Anaesth. 2014;113:575–84. 10. Lee LA, Athanassoglou V, Pandit JJ. Neuromuscular blockade in the elderly patient. J Pain Res. 2016;9:437–44. 11. Higgs A, McGrath BA, Goddard C, Rangasami J, Suntharalingam G, Gale R, Cook TM.  Guidelines for the management of tracheal intubation in the critically ill adult. Br J Anaesth. 2018;120:323–52. 12. Pandit JJ, Irwin MG.  Airway management in critical illness: practice implications of new Difficult Airway Society guidelines. Anaesthesia. 2018;73:544–8. 13. Berg H, Roed J, Viby-Mogensen J, et  al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand. 1997;41:1095–103. 14. Hristovska AM, Duch P, Allingstrup M, Afshari A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Rev. 2017;8:CD012763. 15. Ortega R, Brull JS, Prielipp R, Gutierrez A, De La Cruz R, Conley MC. Monitoring neuromuscular function. N Engl J Med. 2018;378:e6. 16. Naguib M, Brull JS, Kopman AF, Hunter JM, Fülesdi B, Arkes HR, et al. Consensus statement on perioperative use of neuromuscular monitoring. Anesth Analg. 2018;127:71–80. 17. Murphy GS, deBoer HD, Eriksson LI, Miller RD.  Reversal (antagonism) of neuromuscular blockade. Chap 35. In: Miller textbook of anesthesia. 8th ed. Amsterdam: Elsevier; 2014. p. 996. 18. Haberer JP. Farmacologia clinica dei Curari. EMC dicembre 2017 I-36-355 A-10 (Italian edition of the original EMC French Edition). 19. Martyn JAJ.  Neuromuscular physiology and pharmacology. Chapter 18. In: Miller RD, Eriksson LI, Fleisher L, Kornish JPW, Cohen M, Young WL, editors. Miller’s anesthesia. 8th ed. Amsterdam: Elsevier; 2015. p. 423–43. 20. Miorisoluzione, monitoraggio neuromuscolare e antagonismi. Buone Pratiche Cliniche SIAARTI. www.siaarti.it. Accessed 28 Mar 2018. 21. Murphy GS.  Neuromuscular monitoring in the perioperative period. Anesth Analg. 2018;126:464–8. 22. Baillard C. Monitoraggio della curarizzazione. EMC 2011–36-390-A-10 (Italian edition of the original EMCFrench Edtion). 23. Marsch SC, Steiner L, Bucher E, Pargger H, Schumann M, Aebi T, et al. Succinylcholine vs rocuronium for rapid sequenve intubation in intensive care: a prospective randomized controlled trial. Crit Care. 2011;15:R199. 24. Murphy GS, DeBoer HD, Eriksonn LI, Miller RD.  Reversal of neuromuscular blockade. Chap 35. In: Miller RD, Eriksson LI, Fleisher L, Kornish JPW, Cohen M, Young WL, editors. Miller’s anesthesia. 8th ed. Amsterdam: Elsevier; 2015. p. 995–1027. 25. Viby-Mogensen J, Jorgensen BC, Ording H.  Residual curarization in the recovery room. Anesthesiology. 1979;50:539–41. 26. Butterly A, Bittner EA, George E, Sandberg WS, Eikermann M, Schmidt U, et al. Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge. Br J Anaesth. 2010;105:304–9. 27. Fortier LP, McKeen D, Turner K, de Médicis É, Warriner B, Jones PM, Chaput A, Pouliot JF, Galarneau A. The RECITE study: a Canadian prospective, multicenter study of the incidence

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5

Extracorporeal Circulation in Acute Respiratory Failure: High Flow Versus Low Flow Alessio Caccioppola, Valentina Galanti, Sara Froio, Silvia Coppola, and Davide Chiumello

Contents 5.1  Introduction  5.2  General Principles of Treatment 5.3  History 5.4  Techniques 5.5  Indications and Contraindications 5.6  Complications 5.7  Managing Considerations 5.8  Conclusions References

5.1

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Introduction

Extracorporeal circulation is considered a life-saving therapy for patients affected by acute respiratory distress syndrome. In this text, we will describe its history, its increasing spread, and its role in acute respiratory failure in different ways.

A. Caccioppola · V. Galanti Department of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo, San Paolo University Hospital, Milan, Italy Department of Health Sciences, University of Milan, Milan, Italy S. Froio · S. Coppola Department of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo, San Paolo University Hospital, Milan, Italy D. Chiumello (*) San Paolo Hospital, Intensive Therapy Department, University of Milan, Milan, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 D. Chiumello (ed.), Practical Trends in Anesthesia and Intensive Care 2019, https://doi.org/10.1007/978-3-030-43873-9_5

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Acute respiratory failure (ARF) is characterized by sudden occurrence of a severe impairment of gas exchange in terms of both the oxygen (O2) delivery in the blood and the ability to remove carbon dioxide (CO2). ARF is one of the most common causes of admission in intensive care unit (ICU) and more than half of patients admitted in ICU develop ARF during hospitalization. The mortality rate is higher than 34%, and it increases significantly according to age, preexisting comorbidities, and the presence of shock or multiorgan failure [1–3]. One of the causes of ARF is acute respiratory distress syndrome (ARDS), which represents the most severe expression of ARF, the etiology may be pulmonary or extrapulmonary (i.e., sepsis, trauma, pancreatitis) [4]. Since its first description in 1967 [5], ARDS has been redefined several times. According to the last Consensus Conference, ARDS is defined by occurrence, within a week from a known clinical injury, of acute arterial hypoxemia (PaO2/FiO2 ≤300) measured with a minimal end-expiration pressure (PEEP) of 5 cmH2O, along with the presence of bilateral radiographic opacities not entirely explained by cardiac failure or fluid overload [6]. ARDS is classified as: • Mild (200 12-13%

Stop fluid

yes

SVV/PPV>12-13% Check SVV/PPV every 10 min

MAP70  years, alcohol abuse, scoring