Pharmacology in Noninvasive Ventilation 9783031446252, 9783031446269

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Noninvasive Ventilation. The Essentials Under the Auspices of the International Association of Non-invasive Mechanical Ventilation Series Editor: Antonio M. Esquinas Antonio M. Esquinas Bushra Mina Savino Spadaro Daniela Perrotta Francesco De Sanctis Editors

Pharmacology in Noninvasive Ventilation

Noninvasive Ventilation. The Essentials Series Editor Antonio M. Esquinas, Hospital Morales Meseguer Murcia, Spain

Nowadays, Noninvasive Ventilation (NIV) is widely accepted in medical practice. This Series, titled “Noninvasive Ventilation: Clinical and Practice,” is a culmination of extensive prior publications on the topic. It aims to define current clinical developments in NIV technologies, including equipment and ventilator modes, and provide practical recommendations primarily in Critical Care (CC), Pulmonary, Emergency, and Sleep Medicine. Building on previous publications, a group of experienced Editors and top international contributors aim to present new books that take a multidisciplinary approach and provide a comprehensive overview of Non-invasive Ventilation. The main goals of this Series are as follows: Establish a scientific reference for NIV clinical practice, covering pathophysiology, clinical indications, and evidence-based concepts. Present significant advances in CC, pneumology, anesthesiology, sleep medicine, pediatrics, and healthcare organization in acute and chronic respiratory failure. Analyze technological advancements and complementary procedures associated with NIV, such as aerosol therapy, humidification, and airway clearance, crucial for effective NIV techniques. Serve as a valuable teaching reference for healthcare professionals, including residents, consultants, and allied healthcare professionals, as well as undergraduate and postgraduate students and fellowship participants. The Series will produce focused thematic volumes, led by internationally recognized guest editors, providing comprehensive coverage of specific areas of NIV advancement in CC, emergency medicine, pulmonary, and sleep medicine.

Antonio M. Esquinas  •  Bushra Mina Savino Spadaro  •  Daniela Perrotta Francesco De Sanctis Editors

Pharmacology in Noninvasive Ventilation

Editors Antonio M. Esquinas Intensive Care Unit Hospital General Universitario Morales M Murcia, Murcia, Spain

Bushra Mina Medicine, Pulmonary Critical Care Medicine Northern Westchester Hospital Mount Kisco, NY, USA

Savino Spadaro Translational Medicine University of Ferrara Ferrara, Italy

Daniela Perrotta Anesthesiology and Pediatric Intensive Care Bambino Gesù Children’s Hospital Roma, Italy

Francesco De Sanctis Anesthesiology and Pediatric Intensive Care UOC ARCO Palidoro Bambino Gesù Children's Hospital Roma, Italy

ISSN 2948-2747     ISSN 2948-2755 (electronic) Noninvasive Ventilation. The Essentials ISBN 978-3-031-44625-2    ISBN 978-3-031-44626-9 (eBook) https://doi.org/10.1007/978-3-031-44626-9 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed 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 Paper in this product is recyclable.

Contents

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Noninvasive Ventilation and Pharmacology: Basic Physiological Interaction����������������������������������������������������������������   1 Ketki Deotale, Subrata Singha, and Jitendra Kalabandhe

Part I Pharmacological Clinical Indications in Adults 2

Aerosol Therapy—Noninvasive Ventilation and Bronchodilators Pharmacology��������������������������������������������������������  17 Elisabetta Roma and Barbara Garabelli

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 Humidification During Aerosol Therapy in NIV Patients����������������������  31 Manjush Karthika and Jithin K. Sreedharan

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 Medical Gas: Helium/Oxygen and Nitric Oxide Mixture in Noninvasive Ventilation ����������������������������������������������������������������������������  37 Madhuragauri Shevade and Rujuta Bagade

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 Noninvasive Mechanical Ventilation and Benzodiazepines, Indications, Monitoring, and Clinical Results����������������������������������������  47 Biljana Lazovic, Radmila Dmitrovic, Isidora Simonovic, and Antonio M. Esquinas

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Dexmedetomidine, Indications, Monitoring, and Clinical Results ����������������������������������������������������������������������������������  55 Bruno Matos Gomes

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Sedation, Ketamine, Indications, Monitoring, and Clinical Results ����������������������������������������������������������������������������������  61 Juan Pablo Valencia Quintero, Candela María Rodríguez Mejías, and Carlos Fernando Giraldo Ospina

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Sedation, Propofol, Indications, Monitoring, and Clinical Results ����������������������������������������������������������������������������������  69 Carlos Fernando Giraldo Ospina, Juan Pablo Valencia Quintero, and Candela M. Rodriguez Mejías

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Noninvasive Mechanical Ventilation: Locoregional Anesthesia������������  79 Matilde Mari, Riccardo La Rosa, and Savino Spadaro

10 Combined Acid-Base Abnormalities During Noninvasive Ventilation and Place of Acetazolamide ��������������������������������������������������  83 Burcu Öztürk Şahin and Gül Gürsel 11 Role  of Analgesics in Noninvasive Ventilation ����������������������������������������  93 Vincent E. DeRienzo and Brenton J LaRiccia 12 Cardiovascular  Drugs in Left Ventricular Failure During Noninvasive Mechanical Ventilation: Summary of Pharmacological Strategies ���������������������������������������������������������������������� 105 Arslan Ocal 13 Inhaled  Prostacyclin/Milrinone Therapy in Right Ventricular Failure: Implications for Noninvasive Mechanical Ventilation�������������� 117 João Oliveira Pereira, Pedro Nogueira, and Vânia Fernandes 14 Inhaled  Epoprostenol Pharmacology Therapy in Pulmonary Arterial Hypertension During Noninvasive Mechanical Ventilation������������������������������������������������������������������������������ 127 Afrah Obaidan and Hassan Althabet 15 Cardiovascular  Drugs, Left Ventricular Failure, and Implications in Noninvasive Mechanical Ventilation������������������������������ 133 Hugo Almeida, João Rodrigues, and Maria Pacheco 16 Antibiotic  Drugs and Noninvasive Ventilation: Indications, Classification and Clinical Results�������������������������������������� 141 Catarina Mendes Silva 17 Sleep  Breathing Disorders: Basic Pharmacology, Classification, and Clinical Trial Drugs �������������������������������������������������� 157 João Portela and Júlia Silva 18 Psychiatric  Pharmacology and Acute Respiratory Failure �������������������������������������������������������������������������������������������������������� 167 Omar Soubani, Ashika Bains, and Ayman O. Soubani 19 Psychiatric  Drugs. Neuroleptic Drugs in Noninvasive Mechanical Ventilation������������������������������������������������������������������������������ 181 Carrillo Andres, Guia Miguel, and Bayoumy Pablo 20 P  sychiatric Drugs. Toxicology: Respiratory Failure—Noninvasive Mechanical Ventilation���������������������������������������� 191 Omar Soubani, Ashika Bains, and Ayman O. Soubani

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21 Nutrition Drugs: Noninvasive Ventilation������������������������������������������������ 205 Hulya Yigit Ozay 22 B  ronchoscopy and Noninvasive Ventilation: Interface, Parameterization and Sedation���������������������������������������������� 213 Diana Moreira de Sousa and Margarida Afonso Part II Monitoring and Complications Pharmacology in Noninvasive Mechanical Ventilation 23 Monitoring  Practical Options: Pharmacology and Noninvasive Mechanical Ventilation������������������������������������������������������������������������������ 223 Ulku Sabuncu 24 Hemodynamic  Complications During Noninvasive Mechanical Ventilation and Pharmacology Interactions�������������������������������������������� 233 Daniela Nascimento Silva, Mariana Bessa Quelhas, and Ana Paula Valente da Silva Gonçalves 25 Pharmacology  During Noninvasive Mechanical Ventilation and Neurological Effects���������������������������������������������������������������������������� 243 Beatriz Rodríguez-Alonso, Daniel Encinas-Sánchez, and Moncef M. Belhassen-García Part III Pharmacological Clinical Indications in Pediatric Patients 26 A  erosol Therapy (Bronchodilators, Corticoids), Surfactant Therapy, Humidification, Oxygen, Nitric Oxide, and Heliox �������������������������������������������������������������������������������������������������� 251 Martino Pavone and Francesco De Sanctis 27 Sedation:  Benzodiazepines, Dexmedetomidine, Ketamine, Opiates�������������������������������������������������������������������������������������������������������� 257 Francesco De Sanctis 28 Anti-inflammatory Drugs: Glucocorticoids�������������������������������������������� 265 Serena Sinibaldi 29 Antihypertensive  Drugs for Pulmonary Hypertension, Cardiovascular Drugs for Right and Left Ventricular Failure �������������������������������������������������������������������������������������������������������� 277 Nicoletta Cantarutti and Rachele Adorisio 30 Neurologic Drugs (Anti-Epileptic, Anti-Dystonic)���������������������������������� 291 Susanna Staccioli

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31 Respiratory Distress (Dyspnea), Patient-­Ventilator Asynchrony, Sleep Disorder, Adjunct to Extubation, Do-Not-Intubate Patients�������������������������������������������������������������������������� 299 Martino Pavone 32 Cardiac  Pulmonary Edema, Chronic Heart Failure������������������������������ 307 Nicoletta Cantarutti and Rachele Adorisio 33 Adaptation-Intolerance,  Delirium in Agitated Patients. Neuromuscular Disorders: Breathing and Swallowing�������������������������� 315 Marcella Aversa and Susanna Staccioli 34 Gastrostomy Insertion, Bronchoscopy���������������������������������������������������� 323 Marcella Aversa and Daniela Perrotta Part IV Guide for Drugs Dose Clinical Practical Approach in Special NIV Indications 35 Pharmacology  Approach in Persistent Dyspnea and Noninvasive Ventilation Approach���������������������������������������������������� 333 Hatice Aslan Sirakaya 36 Sleep  Medicine Drugs: Classification and Clinical Results�������������������� 343 Inés Pérez Francisco and Ana Vallejo de la Cueva 37 Pharmacological  Therapy for the Management of Patient Ventilator Asynchrony During Noninvasive Ventilation������������������������ 359 Mohanchandra Mandal, Pradipta Bhakta, John Robert Sheehan, Brian O’Brien, and Dipasri Bhattacharya 38 D  elirium-Agitated Patients Undergoing Noninvasive Ventilation ���������������������������������������������������������������������������� 381 Ana Vallejo de la Cueva 39 Pharmacology  in Noninvasive Ventilation in Cardiac Pulmonary Edema ������������������������������������������������������������������������������������ 395 Serpil Öcal and Canan Esin Sağlam 40 Polytraumatized  Patients: Blunt Chest Trauma ������������������������������������ 407 Abhijit S. Nair and Antonio M. Esquinas 41 Pharmacology  in Noninvasive Ventilation in Do-Not-Intubate Patients and Palliative Medicine �������������������������������� 421 Élin Pinheiro Almeida, Daniela Nascimento Silva, and José Manuel Silva 42 Pre-oxygenation: Noninvasive Ventilation ���������������������������������������������� 433 Tanumoy Maulick, Gautam Modak, and Shameek Datta

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43 Adjunct  to Extubation-Noninvasive Mechanical Ventilation���������������� 443 Habib Md Reazaul Karim, Mussavvir Agha, and Antonio M. Esquinas 44 Pharmacology  in Acute COPD During Noninvasive Mechanical Ventilation������������������������������������������������������������������������������ 455 Mariana Bessa Quelhas and Daniela Nascimento Silva 45 Noninvasive  Ventilation and Upper Airway Obstruction in Neuromuscular Disease ���������������������������������������������������������������������������� 463 Alessandra Carneiro Dorça and Lívia Andreza de Macêdo Bezerra Alcântara

Abbreviations

ACE inhibitors Angiotensin converting enzyme inhibitors APACHE II Acute Physiology and Chronic Health Evaluation II ARDS Acute respiratory distress syndrome BiPAP Bi-level positive airway pressure BIS Bispectral index BVM Bag-valve mask BZDs Benzodiazepines CHF Chronic heart failure CNS Central nervous system CO2 Carbon dioxide COPD Chronic obstructive pulmonary disease CPAP Continuous positive airway pressure CPE Cardiogenic pulmonary edema CPET Cardiopulmonary exercise testing CT Computed tomography CTPA Computerized tomography pulmonary angiography DLCO Diffusing capacity for carbon monoxide EtN2 End-tidal nitrogen concentration EtO2 End-tidal oxygen concentration FAO2 Alveolar fraction of oxygen FiO2 Fraction of inspired oxygen FRC Functional residual capacity FVC Forced vital capacity GABA Gamma aminobutyric acid GCS Glasgow Coma Scale HFNC High-flow nasal cannula HFpEF Heart failure with preserved ejection fraction iCPET Invasive cardiopulmonary exercise testing ICU Intensive care unit IMV Invasive mechanical ventilation iNO Inhaled nitric oxide MAP Mean arterial pressure mMRC modified Medical Research Council NDMAD N-desmethyl adinazolam xi

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Abbreviations

NIV Noninvasive mechanical ventilation NIV Noninvasive ventilation NMA Network meta-analysis NO Nitric oxide NPPV Noninvasive positive pressure ventilation NRM Non-rebreathing mask NTG Nitroglycerin NT-pro BNP N-terminal pro-brain natriuretic peptide P:F Ratio PaO2:FiO2 Ratio PaO2 Partial pressure of arterial oxygen PCWP Pulmonary capillary wedge pressure PEEP Positive end expiratory pressure PFT Pulmonary function test PND Paroxysmal nocturnal dyspnea PPHN Persistent pulmonary hypertension of the newborn PVR Pulmonary vascular resistance RARs Rapidly adapting receptors RAS Reticular activating system RASS Richmond Agitation-Sedation scale RCT Randomized controlled trial RSI Rapid sequence induction RSS Ramsay scale SAPS Simplified Acute Physiology Score II SARs Slowly adapting receptors SAS Riker Sedation-Agitation scale THRIVE Transnasal humidified rapid insufflation ventilatory exchange

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Noninvasive Ventilation and Pharmacology: Basic Physiological Interaction Ketki Deotale, Subrata Singha, and Jitendra Kalabandhe

1.1 Introduction In recent years, the use of noninvasive ventilation (NIV) to manage respiratory failure has dramatically expanded, as it offers less dependency on invasive mechanical ventilation (IMV) and its associated complications such as upper respiratory airway trauma and haemorrhage and the use of muscle relaxants and sedative drugs that have been proven to hurt clinical outcomes [1, 2]. Nevertheless, this widespread use of NIV has allowed us to determine its application’s limits. Mask intolerance and agitation due to several factors such as anxiety, fear, pain, discomfort or claustrophobia may result in a patient’s refusal of ongoing NIV, leading to its discontinuation and subsequent requirement for endotracheal intubation [3]. In this regard, NIV failure is defined as the need for endotracheal intubation and has a high failure rate (up to 40%) [4, 5]. Failure of NIV is a significant issue because it is related to adverse clinical outcomes, such as increased mortality and the prolongation of mechanical ventilation [6]. Therefore, increasing attention is now being paid to understanding the possible factors responsible for NIV intolerance to improve patient comfort during NIV. According to Carlucci et  al., the rate of NIV discontinuation associated with patient refusal was up to 22% [7]. The NIV interface tolerance, anchor system, ventilatory settings, humidification, noise, patient position, psychological distress, anxiety, fear, pain and type and severity of the respiratory failure contribute to NIV intolerance. The underlying disease, haemodynamic instability, neurological status deterioration and poor patient-ventilator synchrony are some factors that also contribute to NIV intolerance/deterioration. Various interventional strategies to improve patient’s comfort and ensure the success of NIV include establishing a relationship K. Deotale · S. Singha (*) · J. Kalabandhe Department of Anesthesia and Critical Care, AIIMS Raipur, Raipur, Chhattisgarh, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_1

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Idenfying the sources of discomfort, such as agitaon, fear, pain, dyspnea, and the paent's unfulfilled dissasfacon.

A structured evaluaon to determine the causes of paentrelated NIV failure.

Aempt nonpharmacological intervenons for NIV intolerance such as paent educaon in advance, sophrology, changing ill fi
ng mask or trying different interface, swiching to different venlatory se
ngs, addion of humidificaon and avoidance of disturbing variables like noise and ambient lighng.

If difficules connue, weigh the benefits of sedaon as a addendum/supplement to NIV.

Fig. 1.1  Clinical rationale/approach for the use of sedation in NIV

of collaboration with the patient, switching to another interface, changing the ventilatory setting (PSV, NAVA or PAV) and progressively increasing inspiratory pressure (thereby giving time for the patient to adapt), adopting interface rotation strategy, adding adequate humidification and controlling disturbing factors such as noise [8] (Fig. 1.1). Pharmacological measures, including analgo-sedative medications, can be a valuable option to avoid intubation when the above-listed non-­ pharmacological strategies prove unsuccessful.

1.1.1 Is It Necessary to Use Sedation During NIV? What Does the Literature Say? Sedation and analgesia can alleviate psychological distress and pain, improving NIV tolerance. Due to lack of evidence, sedation practices widely differ within and among specialities and geographic regions, and the physician’s clinical experience determines agent selection [9]. In 2015, an ancillary study conducted by Muriel et al. [10], using data from a prospective, international, multicentre observational trial of mechanically ventilated patients conducted in 322 ICUs from 30 countries [11], analysed the impact of analgesia and sedation on the risk of NIV failure. Patients who received at least 2 h of NIV as first-line ventilatory support at ICU admission were selected. They reported that about 19.6% of patients (162/842) received analgesia or sedation during NPPV; 8 patients received analgesia, 44 patients received sedation and 33 patients received both. Using a marginal structural model analysis, they observed no deleterious effect on NIV outcome when sedation

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or analgesia was used as a single agent; however, their simultaneous use was significantly associated with NIV failure, ICU mortality and 28-day mortality. The study did, however, have certain limitations. Another cross-sectional Web-based survey conducted by Devlin et al. identified that sedation was used in only ≤25% of patients receiving NIV [9]. Matsumoto et al. retrospectively evaluated the role of sedation in agitated patients treated with NIV after an episode of acute respiratory failure. Of the 155 of 3506 patients who received NIV, only 3.4% (81 patients with non-intubation code [DNI] and 39 non-­ DNI) were sedated intermittently or by continuous infusion. Risperidone or haloperidol for intermittent use and dexmedetomidine, midazolam or propofol for constant information were titrated as per RASS scores. The authors concluded that sedation is potentially helpful in avoiding NIV failure in both groups of patients (DNI and non-DNI) [12]. Several other observational studies and RCTs have also compared the efficacy and safety of sedatives during NIV, which will be discussed later in this chapter.

1.1.2 The Goal of Sedation in ICU Settings and During NIV or Does NIV Have an Impact on Sedation Goals? The goals of sedation in the intensive care unit (ICU) are to ensure analgesia and comfort, preserve natural sleep cycles and avoid disturbances such as ambient light and noise in a cooperative patient. Haemodynamic stability, preservation of metabolic homeostasis, muscular relaxation, preservation of diaphragmatic function, attenuation of the stress/immune response and the programmed withdrawal from sedation are also some of the goals which should not be different during NIV. Nonetheless, if NIV is being considered while progressing from intermittent mandatory ventilation to spontaneous breathing, there should be a gradual reduction in the use of sedation. While using sedation during NIV, firstly, we should avoid deep sedation and the respiratory depressant effects of various sedatives. Secondly, untoward effects of sedative drugs resulting in impairment of the upper airway should be considered, especially in patients with obstructive sleep apnoea [13].

1.2 Effects of Pharmacological Interventions on Physiology of NIV The level of acceptance and compliance with NIV depends on sedation, as cooperation can’t be expected from an insensate/deeply sedated patient or an agitated, anxious and disoriented patient. Hence, a sedation regime that brings the patient to calm, alert cooperation is demanded. However, considering the following physiological aspects in play, pharmacological intervention should be regarded as the last stage after the causal evaluation of NIV intolerance (Fig. 1.1).

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1.2.1 Is Sedation an Element/Component in the Success or Failure of NIV? 1.2.1.1 NIV Affects the Ventilatory Control Centre (VCC) A cluster of neurons in the brainstem known as the ventilatory control centre (VCC) controls the ventilatory pattern (tidal volume, frequency and inspiratory/expiratory ratio). As it facilitates gas exchange and unloads muscles, NIV significantly impacts the brainstem’s VCC. The VCC contains an intrinsic rhythm generator that receives inputs from chemoreceptors (i.e. PO2, PCO2 and pH receptors) in the great arteries and the fourth ventricle of the brain, as well as from mechanoreceptors (i.e. stretch and irritation receptors) in the thorax and ventilatory muscles. The VCC’s output regulates the intensity and timing of ventilatory and inspiratory muscle contractions. Cortical inputs (e.g. pain, anxiety, stress, the presence of an artificial airway and various central nervous system injuries) can also impact this pattern (loop gain), usually boosting overall ventilatory drive. Drugs like sedatives and opioids, as well as many other central nervous system ailments, can suppress the total ventilatory drive [14]. A patient’s sleep status can also influence these responses. 1.2.1.2 Sleep Status Sleep quality and regular sleep patterns are believed to affect the restoration of health in ICU settings. A study concluded that early sleep disturbances illustrated by an abnormal electroencephalographic way, disruption of the circadian sleep cycle and decreased rapid eye movement sleep have been associated with late NIV failure in elderly patients with acute hypercapnic respiratory failure [15]. Neurophysiological features of intravenous anaesthetic drugs and their relationships to rest have been studied in detail. Still, investigations of the differential effects of sedatives on electrophysiological dimensions of sleep are some areas/ points to ponder. Under these pretences, measures to alter the environment, such as minimising noise, ambient lighting and other disturbances, should be considered before using sedatives. 1.2.1.3 Patient-Ventilator Asynchrony and Sedation Data obtained from a small cohort of 48 patients undergoing chronic NIV at home detected an increased incidence of ineffective efforts (IE) during sleep compared to an awake state. Consequently, these observations can be hypothetically considered in the ICU setting involving NIV and sedation. A clinical challenge with NIV (and invasive ventilation) occurs with minimal ventilator settings but a vigorous patient effort resulting in potentially harmful transpulmonary pressures and volumes. In these scenarios, reversible causes of a robust inspiratory action such as pain, acidosis and anxiety must be addressed. However, beyond that, managing such patients without any apparent reason becomes an issue/difficult [16]. Some authors suggest that an inappropriate, excessive respiratory drive should be blunted with sedatives or opioids to prevent self-induced lung injury. On the contrary, others believe that self-induced lung injury is controversial and that sedative drugs should be avoided to ease the ventilator withdrawal process.

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1.2.1.4 Respiratory Drive and Timing Sedation and analgesia have different depressive effects on respiratory function depending on the drug’s choice and dose, its sedative or analgesic effects and the recipient’s sensitivity and metabolic capacity. Two classes of drugs have been used most frequently in some studies examining the clinical use of sedatives in patients receiving NIV or, more accurately, in patients failing NIV for interface intolerance: both GABAergic agonists such as midazolam or propofol and opiates such as morphine or remifentanil may blunt the respiratory centre’s output. The electrical activity of the diaphragm (EAdi) can be considered a direct measure of respiratory drive and timing close to assessing respiratory centres, which permits a better understanding of patient-ventilator interaction. By implementing EAdi monitoring, it was proven that propofol substantially interferes with patient-ventilator synchrony in pressure support ventilation (PSV) at doses inducing deep sedation during MIV [17]. Propofol decreased neural drive and effort during PSV and neurally adjusted ventilator assistance (NAVA) while preserving the respiratory timing. On the contrary, a reduction of the respiratory drive was not seen during continuous infusion of opioids. Still, detrimental effects on respiratory timing were observed when airway occlusion pressure was at 0.1 s (P 0.1) (surrogate of EAdi) [18, 19] or even when EAdi was measured directly [20]. Even though these results were obtained during invasive ventilation, they suggest caution when using the same sedation strategies and dosages during NIV, especially in light of the lack of data on other sedation side effects, particularly haemodynamic instability, which may be a severe problem in COPD patients who are typically older and have significant comorbidities such as cor pulmonale or other cardiovascular diseases. 1.2.1.5 Underlying Disease It should be noted that the likelihood of NIV success seems to be related to the underlying disease in patients with hypoxic respiratory failure rather than to the degree of hypoxia. For example, acute respiratory distress syndrome or community-­ acquired pneumonia forewarns NIV failure, as does the lack of oxygenation improvement after an hour on NPPV. There is no substantial evidence that sedation will be beneficial in these situations where the response rate to NIV is intrinsically poor. On the contrary, initiating sedation in these situations may lead to failure of NIV due to underlying pathology and thus ultimately delaying MIV when necessary. Also, sedation does not avert any of the contraindications to NIV [21]. Nava and Ceriana [22] divided NIV failure into three groups, namely, immediate (< 1 h after initiation), early (1–48 h) and late (>48 h), and identified predictors of failure for each time segment. Factors responsible for immediate NIV failure included “intolerance, agitation and patient-ventilator asynchrony”, for which “judicious sedation” is recommended but not described in detail. 1.2.1.6 Experienced Staff Patient acceptance and compliance are the critical factors for the success of NIV, and staff proficiency and competence play a vital role in achieving that. The NIV training and experience of the clinician team partly determine whether the patient

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will succeed with NPPV or, instead, require intubation. Greater clinician-team NPPV experience and expertise are associated with a higher percentage of patients achieving NIV than a less-experienced clinician team [22]. Intensivists and nurses in ICUs are well-versed in administering sedatives and analgesics. Because of the varying sensitivities and rates of metabolism among patients, dosing these medicines can be complex. As a precaution, sedation and analgesia should be delivered by trained personnel at the minimal doses necessary to build tolerance while avoiding oversedation. This should be done in an environment where ECG and oximetry tracings can be examined constantly, at the very least. Several sedation scales are available to help guarantee that the dose of sedation is kept to a minimum, but their use requires experienced personnel.

1.2.2 Specific Situations Where Sedation During NIV Is Beneficial Specific guidelines for NIV [2] acknowledge indications for which there is compelling or even persuasive (Grade 2B or better) evidence for the benefit of sedation during NIV is relatively small and may be summarised as follows: Acute respiratory failure in the forms of: • Exacerbation of chronic obstructive pulmonary disease (acute-on-chronic) with acidotic and hypercapnic components • Acute respiratory failure in immunocompromised patients • Respiratory failure that is secondary to cardiogenic pulmonary oedema not arising from shock or acute coronary syndrome As an adjunct to extubation (in higher centres) for: • Patients with COPD • Patients who are at a high risk of recurrent respiratory failure Most candidates for sedation during NIV are expected to come from these categories and share some presenting features. As seen earlier, discomfort, anxiety, agitation, pain, dyspnoea, delirium and the disappointed expectations of the patient are pivotal in many cases to failure of NIV and hence also to the decision to use sedation in NIV.

1.2.2.1 Agitation and Delirium Patients already agitated before tracheal extubation are the first group to consider. Managing agitated and restless patients presenting with severe respiratory distress can be challenging. Failure of compliance with NIV calls for unwanted endotracheal intubation. Administration of a sedative drug should be preceded by a thorough evaluation of the causes of anxiety. Anxiety caused by a decrease or change in sedative regimen is diagnosed after all other stress causes have been excluded.

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Some prospective observational studies reported the efficacy of sedatives for agitated patients with acute respiratory failure undergoing NIV [23–27]. The effects of delirium in NIV patients require immediate care. A comprehensive study indicated a high prevalence of fever in NIV patients (37%), connected to a significantly higher chance of failure. The evidence on which these conclusions were founded, on the other hand, was labelled as poor quality [28]. There is currently weak evidence for dexmedetomidine use in delirium management.

1.2.2.2 Dyspnoea The second group of patients could well be those who are dyspnoeic and apprehensive, with dyspnoea being related to extubation delays. In a report published by the American Thoracic Society, dyspnoea’s neuro(patho)physiology and clinical features were explored in depth [29]. Dyspnoea was characterised based on the quality of the dyspnoea experience, the stimuli that elicited it and the afferent neural pathways that mediate it. It’s important to emphasise that dyspnoea has an affective component that may be distinguished from the sensory dimension and modulated independently [30]. This highlights the necessity of recognising and evaluating the anxiety element of dyspnoea. The patient’s participation is required, and any existing sedation regimen must be modified to meet that requirement. Single-item evaluations of severity of discomfort or unpleasantness, as well as multi-item scales of emotional responses such as anxiety, can be used to explore the affective dimension of dyspnoea. As a result, sedation may be beneficial in cases where NIV is recommended, and meticulous examination indicates anxiety, dyspnoea with a high affective dimension or delirium as roadblock/hurdle to successful implementation.

1.2.3 Analgesics and Sedatives Are Preferably Used During NIV When the non-pharmacological strategies have failed, analgo-sedation schemes can be employed to manage agitation during NIV. Given the pathophysiology of an NIV failure, the selection of sedative drug depends upon three factors: the upper airway patency, respiratory depression and the affective aspect of dyspnoea. Agitation can be due to fear, anxiety, pain, lack of sleep, fever and hypoxia. To counteract musculoskeletal pain and subsequent stiffening of the chest wall and diaphragm, analgesic drugs such as acetaminophen, nonsteroidal anti-inflammatory drugs or opioid can be administered [31]. Physicians can choose sedative drugs when the cause for agitation is anxiety or intolerance. The rate of NIV failure could be reduced by implying a sedation strategy [32]. Irrespective of the sedation plan adopted, sedation assessment is vital during NIV through subjective scales like RASS (Richmond agitation-sedation scale) [12] or tools like the bi-spectral index and entropy. A sedation assessment at regular time intervals allows to achieve the desired sedation target and avert oversedation [33].

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1.2.3.1 Opioids Opioids are the most commonly used analgesic/sedative during NIV.  Physicians efficiently use this drug class because of its combined effect of analgesia and sedation, especially if the cause of an NIV intolerance is unclear. Despite being an excellent analgesic, opioids as a single sedative agent should be restricted due to their respiratory depressive effect, which is undesirable in patients receiving partial ventilatory support like NIV. Opioids such as morphine, fentanyl, remifentanil and sufentanil have been studied over the past two decades to facilitate NIV tolerance. Opioids provide analgesia by mainly activating μ1-receptor and its mild effect on μ2- and δ-receptors which, on the other hand, are also involved in respiratory drive depression. Fentanyl and morphine provide adequate analgesia at the cost of the reduced respiratory drive as they act on all receptor subtypes. Further, after a long-­ term continuous infusion, they also risk accumulation exacerbating respiratory depression. However, the literature shows one study depicting that intravenous morphine infusion improved NIV compliance in a case of acute pulmonary oedema caused by heart failure [34]. Sufentanil, a synthetic opioid acting specifically on μ1-receptors, proves interesting for continuous infusion in ICU patients as its context-­sensitivity half-life is seven times lower than fentanyl, reducing the risk of accumulation. One pilot study suggested continuous infusion of sufentanil at 0.2–0.3 μg/kg/h resulting in awake sedation without any adverse effects in critically ill patients on partial respiratory support [19]. Two European studies have demonstrated the curative use of remifentanil for NIV intolerance in respiratory failure and rendered its use safe and effective during NIV [27, 35]. A recent cohort study by Hao et al. revealed that remifentanil and dexmedetomidine have similar efficacy in managing moderate to severe NIV intolerance [36]. 1.2.3.2 Benzodiazepines Even though benzodiazepines are the most used sedative agent, they are barely studied for NIV tolerance. Benzodiazepines do not possess analgesic properties and also increase the risk of delirium; hence, they are avoided in elderly patients with agitation. However, a case report demonstrates the successful use of lorazepam during NIV in severe asthma exacerbation [37]. With the limited available data/with the scarce studies available, the risk-benefit aspect of benzodiazepines during NIV is not clear/defined yet. However, drugs such as midazolam can be opted for where anxiety is the apparent reason for NIV intolerance, provided facilities for close monitoring of respiratory parameters/status are available. 1.2.3.3 Propofol Propofol seems an exciting option for sedation during NIV due to its rapid pharmacokinetics. However, propofol can adversely affect gas exchange, breathing patterns and respiratory drive in proportion to its infusion rate. It is also known to cause hypotension and apnoea. However, some studies demonstrate propofol as a potential safe agent when used with a target-controlled infusion during NIV [26, 38].

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1.2.3.4 Dexmedetomidine Among other sedative drugs, dexmedetomidine possesses the lowest risk of depression in the respiratory centres and does not affect the upper airway patency. Several studies show that dexmedetomidine can be safely used in paediatric patients with respiratory failure to facilitate NIV tolerance [39–42]. Although dexmedetomidine can cause bradycardia and hypotension, this drug has successfully improved patient-­ ventilator synchrony in patients with acute respiratory failure [23, 43]. It may also be a helpful sedative agent facilitating the induction of NPPV in patients with severe asthma [24]. Dexmedetomidine needs fewer dose adjustments than midazolam and is also superior for maintenance of sedation than benzodiazepines [44, 45]. However, in the literature, one study done by Devlin et al. (with a small sample size of 33) failed to show a beneficial effect of dexmedetomidine on NIV intolerance, although overall, we could say that dexmedetomidine is comparatively safe and probably effective during NIV. 1.2.3.5 Ketamine Data are insufficient, but theoretically, ketamine is a good choice. Patients should go to their pleasant places in their minds. Ketamine provides analgesia, sedation and amnesia depending upon the dosing. As opposed to opioids, ketamine retains pharyngeal and laryngeal protective reflexes while preserving functional residual capacity, minute ventilation and tidal volume. It lowers airway resistance and increases lung compliance, so it is less likely to produce respiratory depression. Haemodynamically, ketamine increases heart rate and blood pressure due to its sympathomimetic effect, which may help manage respiratory failure in patients with hypotension [46]. However, ketamine can produce hypersalivation and emergence reactions, stimulating anxiety in a mentally unprepared patient. To date, very few case reports are available discussing the use of ketamine during NIV. Some case reports and small studies show the physiological benefits of ketamine in the setting of asthma. Despite insufficient evidence, Kiureghian et  al. described the adjuvant use of NIV and intravenous ketamine to avoid MIV in a patient with severe exacerbation of asthma [47]. Verma et al. reported that a ketamine-induced dissociative state in patients with acute decompensated heart failure facilitated NIV management in an otherwise uncooperative patient allowing NIV to be effective [48]. In the future, extensive series and trials need to establish the use of ketamine-induced sedation in agitated, uncooperative patients to enable compliance with NIV and to compare ketamine with other sedatives during NIV for a better understanding. We suggest it should be used with caution in this subset of patients. In the light of current evidence, given the paucity of well-controlled studies investigating the ICU sedation regimens during NIV, it is ambivalent about pointing to a single sedative agent optimal for every patient. Some important factors to be assessed before selecting an apt sedative agent are the cause of NIV intolerance, allergies, comorbidities and respiratory and haemodynamic status. Ideally, an agent should be able to resolve NIV intolerance without respiratory compromise.

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1.3 Conclusion While sedation is not mandatory, the present limited data suggests that sedation during NPPV is safe and feasible; a more widespread application should await the results of more extensive observational studies or randomised clinical trials. As emergency physicians, our goal should be to avoid intubating patients and to put them on mechanical ventilation when other options may be attempted. With the continued rise of NIV as a therapeutic tool, a more systematic approach to administering sedatives is required. Fresh research into prescribing patterns (and the reasoning underpinning them) is desirable: a study of the effects of switching sedatives would also be illuminating. Ways of sedation when NIV is delivered on standard wards are undocumented; this is another area that deserves more attention/subject to further studies (Table 1.1). Table 1.1  Advantages and disadvantages of sedatives used during NIV Drugs Remifentanil

Propofol Midazolam

Dexmedetomidine

Ketamine

Advantages –  Do not accumulate –  Can be easily titrated – Hepatic of renal dysfunction do not alter its metabolism – Favourable pharmacokinetic profile –  Good efficacy –  Haemodynamic stability

– Provide anxiolysis, sedation and analgesia –  No respiratory depression – Superior to midazolam for sedation with fewer dose adjustments – Provides analgesia, sedation and amnesia – Produces less respiratory depression

Disadvantages –  Nausea and vomiting –  Chest wall rigidity

–  Hypotension and apnoea – In critically ill patients who are obese, with low albumin levels, or have renal failure, accumulation can occur – Increased risk of delirium and agitation –  Bradycardia and hypotension – Caution in haemodynamic instability

– Hypersalivation and emergency reactions stimulating anxiety – Insufficient data for use during NIV

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19. Conti G, Arcangeli A, Antonelli M, et al. Sedation with sufentanil in patients receiving pressure support ventilation has no effects on respiration: a pilot study. Can J Anaesth (Journal canadien d’anesthesie). 2004;51(5):494–9. https://doi.org/10.1007/BF03018315. 20. Costa R, Navalesi P, Cammarota G, et al. Remifentanil effects on respiratory drive and timing during pressure support ventilation and neurally adjusted ventilatory assist. Respir Physiol Neurobiol. 2017;244:10–6. https://doi.org/10.1016/J.RESP.2017.06.007. 21. Glossop AJ, Shepherd N, Bryden DC, Mills GH. Non-invasive ventilation for weaning, avoiding reintubation after extubation and in the postoperative period: a meta-analysis. Br J Anaesth. 2012;109(3):305–14. https://doi.org/10.1093/BJA/AES270. 22. Nava S, Ceriana P.  Causes of failure of noninvasive mechanical ventilation. Respir Care. 2004;49(3):295. 23. Akada S, Takeda S, Yoshida Y, et al. The efficacy of dexmedetomidine in patients with noninvasive ventilation: a preliminary study. Anesth Analg. 2008;107(1):167–70. https://doi. org/10.1213/ANE.0B013E3181732DC2. 24. Takasaki Y, Kido T, Semba K.  Dexmedetomidine facilitates induction of noninvasive positive pressure ventilation for acute respiratory failure in patients with severe asthma. J Anesth. 2009;23(1):147–50. https://doi.org/10.1007/S00540-­008-­0712-­5. 25. Huang Z, Sheng CY, Li YZ, Yun LJ. Dexmedetomidine versus midazolam for the sedation of patients with non-invasive ventilation failure. Intern Med. 2012;51(17):2299–305. https://doi. org/10.2169/internalmedicine.51.7810. 26. Clouzeau B, Bui HN, Vargas F, et  al. Target-controlled infusion of propofol for sedation in patients with non-invasive ventilation failure due to low tolerance: a preliminary study. Intensive Care Med. 2010;36(10):1675–80. https://doi.org/10.1007/s00134-­010-­1904-­7. 27. Rocco M, Conti G, Alessandri E, et al. Rescue treatment for noninvasive ventilation failure due to interface intolerance with remifentanil analgosedation: a pilot study. Intensive Care Med. 2010;36(12):2060–5. https://doi.org/10.1007/s00134-­010-­2026-­y. 28. Charlesworth M, Elliott MW, Holmes JD. Noninvasive positive pressure ventilation for acute respiratory failure in delirious patients: understudied, underreported, or underappreciated? A systematic review and meta-analysis. Lung. 2012;190(6):597–603. https://doi.org/10.1007/ S00408-­012-­9403-­Y. 29. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185(4):435. https://doi.org/10.1164/RCCM.201111-­2042ST. 30. von Leupoldt A, Ambruzsova R, Nordmeyer S, Jeske N, Dahme B.  Sensory and affective aspects of dyspnea contribute differentially to the Borg Scale’s measurement of dyspnea. Respiration. 2006;73(6):762–8. https://doi.org/10.1159/000095910. 31. Nava S, Ceriana P. Patient-ventilator interaction during noninvasive positive pressure ventilation. Respir Care Clin N Am. 2005;11(2):281–93. https://doi.org/10.1016/J.RCC.2005.02.003. 32. Ni YN, Wang T, Yu H, Liang BM, Liang ZA. The effect of sedation and/or analgesia as rescue treatment during noninvasive positive pressure ventilation in the patients with Interface intolerance after extubation. BMC Pulm Med. 2017;17(1):125. https://doi.org/10.1186/ S12890-­017-­0469-­4. 33. Ergan B, Nasilowski J, Winck JC.  How should we monitor patients with acute respiratory failure treated with noninvasive ventilation? Eur Respir Rev. 2018;27(148):170101. https:// doi.org/10.1183/16000617.0101-­2017. 34. Nakayama M, Ishii A, Yamane Y. Novel strategy of noninvasive positive pressure ventilation by intravenous morphine hydrochloride infusion for acute cardiogenic pulmonary edema: two case reports. J Cardiol. 2006;48(2):109–14. 35. Constantin JM, Schneider E, Cayot-Constantin S, et al. Remifentanil-based sedation to treat noninvasive ventilation failure: a preliminary study. Intensive Care Med. 2007;33(1):82–7. https://doi.org/10.1007/S00134-­006-­0447-­4. 36. Hao GW, Luo JC, Xue Y, et al. Remifentanil versus dexmedetomidine for treatment of cardiac surgery patients with moderate to severe noninvasive ventilation intolerance (REDNIVIN):

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a prospective, cohort study. J Thorac Dis. 2020;12(10):5857. https://doi.org/10.21037/ JTD-­20-­1678. 37. Cappiello JL, Hocker MB.  Noninvasive ventilation in severe acute asthma. Respir Care. 2014;59(10):e149–52. https://doi.org/10.4187/RESPCARE.02730. 38. Clouzeau B, Bui HN, Guilhon E, et  al. Fiberoptic bronchoscopy under noninvasive ventilation and propofol target-controlled infusion in hypoxemic patients. Intensive Care Med. 2011;37(12):1969–75. https://doi.org/10.1007/S00134-­011-­2375-­1. 39. Shein SL. Dexmedetomidine during noninvasive ventilation: different acuity, different risks? Pediatr Crit Care Med. 2018;19(4):373–5. https://doi.org/10.1097/PCC.0000000000001453. 40. Shutes BL, Gee SW, Sargel CL, Fink KA, Tobias JD. Dexmedetomidine as single continuous sedative during noninvasive ventilation: typical usage, hemodynamic effects, and withdrawal. Pediatr Crit Care Med. 2018;19(4):287–97. https://doi.org/10.1097/PCC.0000000000001451. 41. Venkatraman R, Hungerford JL, Hall MW, Moore-Clingenpeel M, Tobias JD. Dexmedetomidine for sedation during noninvasive ventilation in pediatric patients. Pediatr Crit Care Med. 2017;18(9):831–7. https://doi.org/10.1097/PCC.0000000000001226. 42. Piastra M, Pizza A, Gaddi S, et al. Dexmedetomidine is effective and safe during NIV in infants and young children with acute respiratory failure. BMC Pediatr. 2018;18(1):282. https://doi. org/10.1186/S12887-­018-­1256-­Y. 43. DeMuro J, Mongelli M, Hanna A. Use of dexmedetomidine to facilitate non-invasive ventilation. Int J Crit Illn Inj Sci. 2013;3(4):274. https://doi.org/10.4103/2229-­5151.124161. 44. Huang Z, Chen YS, Yang ZL, Liu JY. Dexmedetomidine versus midazolam for the sedation of patients with non-invasive ventilation failure. Intern Med. 2012;51(17):2299–305. https://doi. org/10.2169/INTERNALMEDICINE.51.7810. 45. Senoglu N, Oksuz H, Dogan Z, Yildiz H, Demirkiran H, Ekerbicer H. Sedation during noninvasive mechanical ventilation with dexmedetomidine or midazolam: a randomized, double-­ blind, prospective study. Curr Ther Res Clin Exp. 2010;71(3):141. https://doi.org/10.1016/J. CURTHERES.2010.06.003. 46. Erstad BL, Patanwala AE. Ketamine for analgosedation in critically ill patients. J Crit Care. 2016;35:145–9. https://doi.org/10.1016/J.JCRC.2016.05.016. 47. Kiureghian E, Kowalski JM.  Intravenous ketamine to facilitate noninvasive ventilation in a patient with a severe asthma exacerbation. Am J Emerg Med. 2015;33(11):1720.e1–2. https:// doi.org/10.1016/J.AJEM.2015.03.066. 48. Verma A, Snehy A, Vishen A, Sheikh WR, Haldar M, Jaiswal S. Ketamine use allows noninvasive ventilation in distressed patients with acute decompensated heart failure. Indian J Crit Care Med. 2019;23(4):191. https://doi.org/10.5005/JP-­JOURNALS-­10071-­23153.

Part I Pharmacological Clinical Indications in Adults

2

Aerosol Therapy—Noninvasive Ventilation and Bronchodilators Pharmacology Elisabetta Roma and Barbara Garabelli

What is inhalation therapy? In summary, it is the most effective way of administering drugs for most respiratory diseases. The history of aerosol therapy dates back to 4000 years ago, when the leaves of Atropa belladonna and Datura stramonium were smoked in special pipes to relieve asthma attacks. It was only at the end of the nineteenth century that Sales created the first vaporizer for inhaling drugs, consisting of a large glass ampoule. In the mid-­ twentieth century, the first dry powder inhalers and then the first pre-dosed sprays were made. The advantages of this route of administration can be summarized as follows: (a) The drug is delivered directly to the target organ. (b) Topical bioavailability of the drug. (c) Systemic diffusion decreased. (d) Need for lower dosages. (e) Quick and powerful therapeutic action. (f) Lower side effects compared to systemic administration. The aerosol is a system consisting of multiple particles, solid or liquid, which are so small that they are stably suspended in a gaseous medium, generally air, but sometimes also oxygen. Factors affecting the deposition of inhalant drugs are: E. Roma (*) The NeMO Centre, Niguarda Hospital, Milan, Italy e-mail: [email protected] B. Garabelli AOU Maggiore della Carità, University Hospital, Novara, Italy e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_2

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18 Table 2.1  Particle sizes of the aerosol that are able to reach each anatomical region

Table 2.2  Inhalation devices available on the market

E. Roma and B. Garabelli Nasal cavities, pharynx, larynx Trachea Bronchi and lungs Terminal bronchioles Alveolar canals and pulmonary alveoli

Over 30 μm 20–30 μm 10–20 μm 3–10 μm 40% aerosol deposition during heated humidification through ventilator circuits [21–24]. The effects of humidification on aerosol delivery and deposition vary based on the system used, the medication dosage, and the placement of inhaler/aerosol device in the circuit. There required a balance between the administration of aerosol medications and the disconnection of the circuit or the interruptions in ventilation; hence, T-piece adaptors for the small-volume nebulizers and spacers for metered-dose inhalers were introduced by various manufacturers. It is recommended to connect these accessories always while circuiting the ventilator and to be used as and when required. Nevertheless, it is reported that heated humidifiers generate moisture, and it tends to get collected in the spacers, as in water trap, and it can be up to 5 mL in a few hours [25]. Some of the studies addressed the subject area, focusing on different approaches such as the use of different aerosol delivery devices, placement of the aerosol devices, increasing the fill volume, types of circuit, switching off the humidifiers, etc. Aerosol delivery (salbutamol) in COPD patients, who were on NIV at humidified and non-humidified conditions, was studied, using devices such as a vibrating mesh nebulizer, jet nebulizer, and metered-dose inhaler with spacer. Although the vibrating mesh nebulizer stood superior in terms of drug delivery and deposition, no significant difference was observed in the salbutamol content of the urine samples, between the humidified and dry conditions, when comparing these three devices [26]. Fill volume of aerosol medicines against various humidification states was compared in vibrating mesh and jet nebulizers. The humidification conditions were heated humidification, humidification with no-heat, and no-heat and

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non-­humidification. The different fill volumes were 1, 2, and 4 mL of normal saline diluted with 5000 μg salbutamol. The total inhaled doses of these fill volumes compared between the devices with diverse humidification conditions were similar, drawing the conclusion that humidification has no effect on fill volumes of aerosol medications [27]. Other aspects considered were the types of circuits used and the humidification impact on the aerosol medications. It was reported by a group of authors that humidification has no significant impact on aerosol medications, delivered through vibrating mesh or jet nebulizers, while using single-limb circuit in NIV [28]. A recent in vitro study concluded that there was no difference in the delivery of aerosol medicines during NIV, when compared in a dry or humidified condition, through single-limb circuit with different nebulizer positions. Regarding NIV dual-­ limb circuit, the aerosol delivery was lower with humidification only when the nebulizer was positioned at a humidifier inlet, compared to a dry setting [29]. The placement of aerosol devices is important to optimize drug delivery. While using a single-limb circuit with a non-vented mask, the aerosol delivery will be higher if the nebulizer is placed 15 cm from the exhalation valve toward the patient’s side compared to all other positions. However, in the dual-limb humidified circuit with a non-vented mask, the aerosol delivery will be optimal if the nebulizer is placed 15 cm from the Y-piece in the inspiratory limb, compared to other positions as in practice [29]. HME is efficient in humidification and an alternate for heated humidifiers. However, the HME can filter the aerosol drug particles, hence significantly reducing the drug delivery. Hence, irrespective of invasive or noninvasive ventilation, it is recommended to remove the HME from the circuit during aerosol treatments [30].

3.4 Conclusion There is still a paucity of literature when it comes to the debate of humidification and its impact on aerosol delivery in NIV patients. Many articles published in the last three decades support the dramatic reduction of aerosol delivery in humidified conditions. But with the evolution of new technology and outcome of in vitro studies, the current literature suggests that humidification has only a minimal or no impact on the deposition of aerosol medications. This chapter concludes with the following recommendations. 1. Humidification is recommended for NIV patients. 2. Active humidification is advised for NIV patients, considering better tolerance and comfort. 3. Switching off the heated humidifiers during aerosol therapy is not recommended. 4. Passive humidification such as HME is not recommended for NIV patients.

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References 1. Nava S, Navalesi P, Conti G.  Time of non-invasive ventilation. Intensive Care Med. 2006;32(3):361–70. 2. Chiumello D, Chevallard G, Gregoretti C. Non-invasive ventilation in postoperative patients: a systematic review. Intensive Care Med. 2011;37(6):918–29. 3. Dhand R.  Aerosol therapy in patients receiving noninvasive positive pressure ventilation. J Aerosol Med Pulm Drug Deliv. 2012;25:63–78. 4. Dhand R. Basic techniques for aerosol delivery during mechanical ventilation. Respir Care. 2004;49:611–22. 5. Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet. 2011;377:1032–45. 6. Williams R, Rankin N, Smith T, Galler D, Seakins P.  Relationship between the humidity and temperature of inspired gas and the function of the airway mucosa. Crit Care Med. 1996;24:1920–9. 7. American Association for Respiratory Care, Restrepo RD, Walsh BK. Humidification during invasive and noninvasive mechanical ventilation: 2012. Respir Care. 2012;57(5):782–8. 8. Kakkar RK, Berry RB. Positive airway pressure treatment for obstructive sleep apnea. Chest. 2007;132:1057–72. 9. Wiest GH, Lehnert G, Bruck WM, Meyer M, Hahn EG, Ficker JH.  A heated humidifier reduces upper airway dryness during continuous positive airway pressure therapy. Respir Med. 1999;93:21–6. 10. Holland AE, Denehy L, Buchan CA, Wilson JW. Efficacy of a heated passover humidifier during noninvasive ventilation: a bench study. Respir Care. 2007;52(1):38–44. 11. Chiumello D, Chierichetti M, Tallerini F, et al. Effect of a heated humidifier during continuous positive airway pressure delivered by a helmet. Crit Care. 2008;12(2):R55. 12. Schuman S, Stahl CA, Möller K, Priebe HJ, Guttmann J. Moisturizing and mechanical characteristics of a new counter flow type heated humidifier. Br J Anaesth. 2007;98(4):531–8. 13. Kacmarek R.  Noninvasive positive pressure ventilation. Egan’s fundamentals of respiratory care. 9th ed. St. Louis, MO: Mosby Elsevier; 2009. p. 1091–114. 14. Pelosi P, Severgnini P, Selmo G, et  al. In vitro evaluation of an active heat-and-moisture exchanger: the Hygrovent gold. Respir Care. 2010;55(4):460–7. 15. Jaber S, Chanques G, Matecki S, Ramonatxo M, Souche B, Perrigault PF, Eledjam JJ. Comparison of the effects of heat and moisture exchangers and heated humidifiers on ventilation and gas exchange during non-invasive ventilation. Intensive Care Med. 2002;28:1590–4. 16. Lellouche F, Maggiore SM, Deye N, Taille S, Pigeot J, Harf A, Brochard L.  Effect of the humidification device on the work of breathing during noninvasive ventilation. Intensive Care Med. 2002;28:1582–9. 17. Lellouche F, Maggiore SM, Lyazidi A, et  al. Water content of delivered gases during non-­ invasive ventilation in healthy subjects. Intensive Care Med. 2009;35:987–95. 18. Esquinas A, Nava S, Scala R, et al. Intubation in failure of noninvasive mechanical ventilation: preliminary results (abstract). Am J Respir Crit Care Med. 2008;177:A644. 19. Thille AW, Bertholon JF, Becquemin MH, Roy M, Lyazidi A, Lellouche F, et al. Aerosol delivery and humidification with the boussignac continuous positive airway pressure device. Respir Care. 2011;56:1526–32. 20. Richards GN, Cistulli PA, Ungar RG, Berthon-Jones M, Sullivan CE. Mouth leak with nasal continuous positive airway pressure increases nasal airway resistance. Am J Respir Crit Care Med. 1996;154:182–6. 21. Diot P, Morra L, Smaldone GC.  Albuterol delivery in a model of mechanical ventilation. Comparison of metered-dose inhaler and nebulizer efficiency. Am J Respir Crit Care Med. 1995;152:1391–4.

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22. Fink JB, Dhand R, Duarte AG, Jenne JW, Tobin MJ.  Aerosol delivery from a metered-­ dose inhaler during mechanical ventilation. An in vitro model. Am J Respir Crit Care Med. 1996;154:382–7. 23. Fink JB, Dhand R, Grychowski J, Fahey PJ, Tobin MJ. Reconciling in vitro and in vivo measurements of aerosol delivery from a metered-dose inhaler during mechanical ventilation and defining efficiency-enhancing factors. Am J Respir Crit Care Med. 1999;159:63–8. 24. O’Riordan TG, Palmer LB, Smaldone GC.  Aerosol deposition in mechanically ventilated patients. Optimizing nebulizer delivery. Am J Respir Crit Care Med. 1994;149:214–9. 25. Hess DR. Aerosol therapy during noninvasive ventilation or high-flow nasal cannula. Respir Care. 2015;60:880–91. 26. Mohsen M, Elberry AE, Salah Eldin A, Hussein RR, Abdelrahim EM.  Effects of heat and humidification on aerosol delivery during auto-CPAP noninvasive ventilation. Arch Pulmonol Respir Care. 2017;3(1):11–5. 27. Saeed H, Mohsen M, Fink JB, et  al. Fill volume, humidification and heat effects on aerosol delivery and fugitive emissions during noninvasive ventilation. J Drug Deliv Sci Technol. 2017;39:372–8. 28. Saeed H, Mohsen M, Salah Eldin A, Elberry AA, Hussein RR, Rabea H, Abdelrahim ME. Effects of fill volume and humidification on aerosol delivery during single-limb noninvasive ventilation. Respir Care. 2018;63(11):1370–8. 29. Tan W, Dai B, Xu DY, Li LL, Li J. In-vitro comparison of single limb and dual limb circuit for aerosol delivery via noninvasive ventilation. Respir Care. 2022;67(7):807–13. 30. Ari A, Fink JB. Factors affecting bronchodilator delivery in mechanically ventilated patients. Nurs Crit Care. 2010;15(4):192–203.

4

Medical Gas: Helium/Oxygen and Nitric Oxide Mixture in Noninvasive Ventilation Madhuragauri Shevade and Rujuta Bagade

4.1 Introduction Medical-grade gases have been used for a long time to treat various respiratory diseases. Chronic respiratory diseases remain at the forefront, leaving patients with many issues due to these diseases. Oxygen is widely used in critical scenarios for patients with hypoxia-inducing medical conditions. Apart from oxygen, other gases are also used for specific purposes. Helium was discovered in 1868 and has been used in medicine since then [1]. The combination of heliox was first used in the 1930s for divers to reduce the decompression sickness related to diving [1]. Meanwhile, the inhaled use of nitric oxide (NO) for cardiorespiratory diseases, although it was discovered in the 1980s, was only seen in the 1990s [2]. Over the years, the use of various medical gases has gained more clarity with increasing evidence in favor or against their use. These gases were delivered through delivery devices such as masks as well as in combination with noninvasive ventilation. This chapter highlights the use of medical gas mixtures, namely, heliox and nitric oxide, in Noninvasive Ventilation.

M. Shevade (*) Chest Research and Training Pvt. Ltd, Pune, India Symbiosis Center for Research and Innovation, Faculty of Health Sciences, Symbiosis International (Deemed) University, Pune, India R. Bagade S.L. Raheja Hospital (A Fortis Associate), Mumbai, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_4

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4.2 Heliox Gas Mixture 4.2.1 Helium-Oxygen Combination Heliox is a combination of helium and oxygen. Helium is an inert, colorless, odorless noble gas found in the earth’s atmosphere. It is a very light gas with a density lighter than air. Oxygen is a colorless, odorless gas that helps in the sustenance of lives on the earth. After nitrogen, almost 21% of the atmosphere is made up of oxygen. It is considered as a drug and is used to treat chronic diseases and during medical emergencies. The combination of helium and oxygen is used to support the respiration of patients who have a difficulty in breathing. It is administered through a gas blender in three combinations depending on the concentration of each gas. The three combinations are 80% oxygen to 20% helium, 70% oxygen to 30% helium, or 60% oxygen to 40% helium [1]. The primary purpose of using this combination is to oxygenate and ventilate patients who have increased airway resistance. Apart from that, the use of heliox therapy affects ventilation in many positive ways. It helps in the reduction of the work of breathing of the patients. Due to its density and laminar flow, it decreases the peak pressures that are needed for the flow. The diffusion capacity improves and there is better carbon dioxide elimination in patients. With improved gas exchange and increased expiratory flow, the patients have an overall reduction in the dyspnea. For patients with obstruction requiring inhaled medication, the drug deposition is better when administered with heliox [3].

4.2.2 Disease Conditions in Which It Is Helpful Heliox can be used in all age groups right from adults to neonates [4]. As mentioned above, helium is a less dense gas. It is used with oxygen when the requirement for oxygen increases in the patient. The less dense gas travels in a laminar flow and easily reaches all the sections of the lungs including the smaller airways. This makes it easier or less cumbersome for the patients to breathe in and out. The combination of heliox was used to lessen the breathing difficulties of patients with upper airway obstruction. Lung protective strategies of using heliox therapy are known. It improves patient outcomes and makes the patient a little more comfortable while breathing. Patients with croup, epiglottitis, and laryngitis were treated with heliox therapy [1, 4, 5]. It is also used in patients with lower respiratory tract issues such as asthma, COPD, cystic fibrosis, etc. [6, 7]. In patients with asthma and COPD, there is inflammation and airflow limitation causing obstruction in the airways. For patients with COPD, there is mucus production that further leads to obstruction. All this gives rise to increased resistance in the airways. Thus, patients find it difficult to breathe. To reduce the patient’s work of breathing, heliox gas therapy through a noninvasive medical gas delivery device is considered effective in managing these patients. This gas mixture is especially important during acute

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flare-­ups and exacerbations. Heliox therapy is also used in patients who have upper airway obstruction. Heliox therapy can also be delivered to patients with increased work of breathing through a noninvasive mechanical ventilator.

4.2.3 Use of Helium Oxygen in NIV Without a ventilator, heliox is delivered by medical gas delivery devices such a non-­ rebreather (NRB) mask. While the method to deliver the heliox may slightly differ based on the ventilator that is used, what is described next are the general steps required to deliver heliox gas mixture through a noninvasive ventilator. Ensure that you have made the necessary connections and set the ventilator to deliver a gas mixture of helium and oxygen. You should set the oxygen as 100% on the ventilator when connected to the heliox blending source to ensure that the correct amount is being delivered since the ventilator does not know any better and will take all the gas from the source that is connected: in this case, it is the heliox. This is to ensure that the ventilator delivers the set amount appropriately. Once the other values are set as per the requirement, it is important to set the alarms correctly. Since helium is a lighter gas, the pressures detected by the ventilator will be low and a low-pressure alarm may be triggered. The pressures decrease by half when heliox is used. Thus, the alarms including the tidal volume, minute ventilation, and pressures must be set correctly. Typically, heliox mixtures are delivered through gas tanks or cylinders. Hence, it is important to note the rate of emptying while it is being delivered to the patient. Depending on the ventilator, the circuits that can be used are different. If the circuit is a single limb and has a port for exhalation, that leak will empty the cylinder faster. Hence, one must always have backup cylinders available for patient use. Connections differ for different ventilators. Make sure you select the appropriate setting on the vent when heliox is connected. Make sure all sensors are calibrated according to the requirements of the ventilator. The flowmeter is not regulated for heliox. So, the flow rate that is set is different than what the patient is actually getting. The patient is getting more than what is set because of the less density. Hence, to know the actual flow, one must use the conversion factor. The conversion factor for 80-20 is 1.8, 70-30 1.6, and 60-40 is 1.4 and use an appropriate blender for gas delivery [8]. The use of heliox with NIV in children has been studied in a small group and has shown positive results for acute bronchiolitis not treatable with usual therapy [5].

4.3 Nitric Oxide: A Selective Pulmonary Vasodilator Besides oxygen and helium-oxygen, nitric oxide (NO), which is a potent vasodilator, is the other medical gas that is administered.

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4.3.1 Chemistry of Nitric Oxide Nitric oxide (NO) is a colorless, nonflammable, and tasteless and an odorless gas with a very short half-life. NO is also a potent pulmonary vasodilator and is slightly soluble in water [9].

4.3.2 Pulmonary Effects of Inhaled Nitric Oxide 4.3.2.1 Pulmonary Vasodilation NO, when administered through inhalation in very low concentrations (5–80 ppm), rapidly diffuses across the alveolar-capillary membrane and bounds to hemoglobin and hence has little effect on the systemic circulation. The therapeutic goal of NO is enhancing the arterial oxygenation, improving the pulmonary blood flow, and decreasing the pulmonary vascular resistance. A number of studies suggest that inhaled nitric oxide (iNO) plays an important role in treating pulmonary hypertension in the pediatric as well adult group of patients [10, 11]. Hence, inhaled nitric oxide has been used to treat persistent pulmonary hypertension of the newborn (PPHN), meconium aspiration, bronchopulmonary dysplasia, refractory hypoxemia, and hypertension-associated congenital heart disease in infants. In adults and children, it has been used to alleviate pulmonary hypertension (see Table 4.1) [12].

Table 4.1  Indications for inhaled nitric oxide therapy

Indications for inhaled nitric oxide therapy  • Refractory hypoxemic respiratory failure  • Persistent pulmonary hypertension of the newborn  • Primary pulmonary hypertension  • Respiratory distress syndrome  • Pulmonary hypertension after cardiac surgery  • Meconium aspiration  • Bronchopulmonary dysplasia  • Acute pulmonary embolism  • Congenital diaphragmatic hernia  • Pulmonary hypertension associated with ARDS in adults

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20 PPM

PaO2 < 10 mmHg

Discontinue / ↑ to 40 ppm

PaO2 > 10 mmHg

Wean FiO2 to 0.6 (every 2 hourly before weaning iNO)

20-10-5-4-3-1-@ 4-6 hours interval with ABG, 30 min after each wean

Fall in PaO2 >10% from previous successful wean or PaO2 < 50 mmHg - dose escalation to double the existing dose

Fig. 4.1  Initiation and weaning of iNO therapy

4.3.3 Dosing The therapeutic dose of iNO required for the desired effect i.e., improving hypoxia and reducing the PVR both in the neonatal and the adult set of patients is usually low between 2 to 20 ppm. The patients can be initiated at a dose of 20 ppm (parts per million) and thereafter titrated in accordance with the patient’s oxygenation status and depending on the tolerance. See Fig. 4.1.

4.3.4 Assessment of Response to iNO Assess the response after initiating a patient on iNO for about 30–60 min. A positive response is marked by an increase in PaO2 (partial pressure of arterial oxygen) of ≥20 mmHg, or an increase in the SpO2 by 10%, or by a decrease in the FiO2 (fraction of inspired oxygen) requirement by about 20%.

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A partial response is categorized by an increase in the PaO2 by about 15–20%, or an increase in the oxygen saturation by about 5–10%, and a decrease in the FiO2 requirement by about 10–20%.

4.3.5 iNO Delivery Through NIV Nitric oxide can be delivered in conjunction with the high-flow nasal cannula (HFNC). Nitric oxide when delivered though HFNC nullifies the need for mechanical ventilation (MV) and its associated disastrous effects, reduces the need for sedation, and prevents complications associated with MV such as ventilator-associated pneumonia, critical illness myopathy, and polyneuropathy, reduces the need for prolonged use of supplemental oxygen, reduces the number of days for hospitalization, etc. Studies have shown that when HFNC + iNO therapy was given to the patients, there was an increase in the survival rates when compared to NO delivery through MV and a decrease in the need for mechanical ventilation. Hypoxemia is the leading cause of respiratory failure, leading the patient to end up on a mechanical ventilator. This can be avoided to some extent by correcting the hypoxemia by the addition of iNO to the high-flow nasal delivery of O2. Other benefits associated with the delivery of iNO through HFNC include the following: the patients remain conscious, can maintain their airway, and clear their secretions. Furthermore, there is a reduced need for inotropes, as mechanical ventilation often leads to hemodynamic instability [13]. iNO can also be delivered noninvasively through nasal CPAP with a set CPAP of about 5–8 cm H2O and FiO2 which is titrated according to the patient’s O2 saturation. One limiting factor associated with the delivery of iNO through NIV is the leaks [14]. Choosing the appropriate interface is important to achieve the best results.

4.3.5.1 Nitric Oxide in Neonates Persistent Pulmonary Hypertension of the Newborn Pulmonary hypertension in newborns may be caused by premature closure of the ductus arteriosus, idiopathic pneumonia, meconium aspiration, prematurity, or lung hypoplasia [15]. PPHN occurs when pulmonary vascular resistance remains elevated after birth which causes right-to-left shunting of blood across the patent ductus arteriosus and the foramen ovale, leading to severe hypoxemia. iNO in this group of patients causes an increase in the blood flow without causing hypotension [16]. Inhaled nitric oxide significantly increases oxygenation in preterm and term infants with PPHN. Hypoxemic Respiratory Failure Inhaled nitric oxide (iNO) has proven benefits when used in conjunction with endotracheal intubation and mechanical ventilation in treating patients with pulmonary artery hypertension and hypoxemic respiratory failure in the neonates. However, the

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delivery of nitric oxide with noninvasive nasal continuous positive airway pressure (CPAP) is used to avoid the complications associated with mechanical ventilation (MV) [6]. There is reported evidence of the safe and effective delivery of iNO in preterm and term infants with the nasal CPAP [11]. The use of iNO delivered through bubble nasal CPAP in the term and preterm newborns with hypoxemic respiratory failure showed improved oxygenation with a reduced requirement of supplemental O2 [17]. Administering high levels of oxygen in premature neonates can have adverse effects. The cardiopulmonary transition at birth from uterine to extrauterine life involves a series of events wherein there is a drop of pulmonary vascular resistance and an increase in peripheral vascular resistance. These cardiovascular changes at birth are facilitated by mediators. NO, a potent vasodilator, regulates the pulmonary vascular tone and accelerates the fluid clearance from the alveoli. During resuscitation of preterm neonates in addition to ventilation and administration of supplemental O2, iNO can be used as an adjunct to expedite pulmonary vasodilation by decreasing the pulmonary vascular resistance, improving the V/Q mismatch, increasing the pulmonary blood flow, and reducing exposure to high levels of supplemental O2, thereby nullifying the harmful effects associated with it [18].

4.3.6 Toxicity and Adverse Effects • The toxic effects of nitric oxide are due to its oxidative effects caused by the chemical by-products, namely, nitrogen dioxide (NO2), which are produced upon exposure to O2. NO2 causes toxic effects to the respiratory tract, altered surfactant function, pulmonary edema, genotoxic alterations, and tissue injury. The toxic effects of NO following inhalation occur due to the formation of NO2 [2]. The safety limit for exposure to NO2 is set at 5 ppm. It is thereby advisable to monitor inline the NO2 concentration when administering inhaled nitric oxide therapeutically. • iNO can combine with hemoglobin forming nitrosyl hemoglobin which oxidizes to methemoglobin (MetHb). Nitric oxide has a higher affinity toward hemoglobin than that of carbon monoxide. Excessive amount of methemoglobin leads to tissue hypoxia. This causes a shift in the oxygen dissociation curve to the left, thereby inhibiting the release of O2. The symptoms of hypoxia (fatigue, dyspnea) usually appear when the MetHb levels are above 15% [2]. These high levels of MetHb can alter and give false pulse oximetry readings. It is therefore always advisable to keep on monitoring the MetHb levels with the help of an arterial blood gas analysis. If the MetHb levels are high, reduce the iNO dose or methylene blue can be given. • iNO can also interact with the humidity in the circuit. Nitric oxide reacts with water (H2O) to form nitric acid. So, keep the water out of the circuit.

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4.3.7 Weaning from iNO Therapy Withdrawal of iNO can cause hypoxemia and pulmonary hypertension due to the rebound effect; therefore, withdrawal from the iNO must be done carefully to prevent the rebound effect. Weaning assessment should be done after 4 h from the initiation of the therapy. If the oxygen (FiO2) requirement is less than 60%, weaning should ideally be considered. When weaning the iNO dose, cut the dose down to half every four hours, e.g., if the dose is at 20 ppm, get it down to 10 ppm and wait and assess for weaning failure. Weaning failure is defined as: 1. An increase in the FiO2 requirement by more than 20% 2. A decrease in the oxygen saturation by more than 5%. If there is a weaning failure, return to the previous dose of iNO and wait for 4 hours before reattempting weaning. The NO level should be reduced to the lowest possible dose (≤5 ppm). The patient should be hemodynamically stable and should be requiring low levels of inspired O2 (FiO2 < 40%) and a positive end-expiratory pressure of ≤5 cm H2O. The patient must be preoxygenated for some time before the withdrawal of inhaled nitric oxide [19]. After tapering the dose to a 5 ppm, further tapering of the dose should be done by 1 ppm every 2 h. Once the iNO therapy has been discontinued, close monitoring is a must to avoid increased pulmonary artery pressure and hypoxemia following the withdrawal.

4.4 Conclusion Respiratory diseases have everlasting effects on the patients and their health-related quality of life. Medical gas therapy has been used since ages to treat patients with refractory hypoxia. However, it is only limited to oxygen therapy. Recent advances and researches have shown proven benefits of heliox and nitric oxide therapy in treating both adult and neonatal groups of patients. Heliox therapy helps in treating patients with chronic respiratory diseases, whereas inhaled nitric oxide therapy, which is considered a selective pulmonary vasodilator therapy, helps in reducing pulmonary vascular resistance and treating patients with chronic hypoxemic failure. Although these medical gases are preferably administered through the invasive mode, the noninvasive method of delivery of these medical gases is equally effective and less invasive and almost nullifies the other disastrous effects associated with bypassing the natural airway of the patient.

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References 1. Hess DR, Fink JB, Venkataraman ST, Kim IK, Myers TR, Tano BD. The history and physics of heliox. Respir Care. 2006;51(6):608–12. 2. Weinberger B. The toxicology of inhaled nitric oxide. Toxicol Sci. 2001;59(1):5–16. 3. Goode ML, Fink JB, Dhand R, Tobin MJ.  Improvement in aerosol delivery with helium-­ oxygen mixtures during mechanical ventilation. Am J Respir Crit Care Med. 2001;163:109–14. Available at www.atsjournals.org. 4. Gupta VK, Cheifetz IM. Heliox administration in the pediatric intensive care unit: an evidence-­ based review. Pediatr Crit Care Med. 2005;6(2):204–11. Available at https://journals.lww.com/ pccmjournal/Fulltext/2005/03000/Heliox_administration_in_the_pediatric_intensive.16.aspx. 5. Martinón-Torres F.  Non-invasive ventilation with helium-oxygen in children. J Crit Care. 2012;27(2):220.e1–9. Available at https://www.sciencedirect.com/science/article/pii/ S0883944111002334. 6. Abroug F, Ouanes-Besbes L, Hammouda Z, Benabidallah S, Dachraoui F, Ouanes I, et  al. Non-invasive ventilation with helium–oxygen mixture in hypercapnic COPD exacerbation: aggregate meta-analysis of randomized controlled trials. Ann Intensive Care. 2017;7:59. 7. Tassaux D, Jolliet P, Roeseler J, Chevrolet JC.  Effects of helium-oxygen on intrinsic positive end-­ expiratory pressure in intubated and mechanically ventilated patients with severe chronic obstructive pulmonary disease. Crit Care Med. 2000;28(8):2721. Available at https://journals.lww.com/ccmjournal/Fulltext/2000/08000/ Effects_of_helium_oxygen_on_intrinsic_positive.6.aspx. 8. Fink J.  Opportunities and risks of using heliox in your clinical practice. Respir Care. 2006;51(6):651–60. 9. Fukuto JM.  Chemistry of nitric oxide: biologically relevant aspects. Adv Pharmacol. 1995;34:1–15. 10. Ozturk E. Use of inhaled nitric oxide in pediatric cardiac intensive care unit. Arch Turk Soc Cardiol. 2016;44(3):196–202. 11. Lindwall R, Blennow M, Svensson M, Jonsson B, Berggren-Boström E, Flanby M, et al. A pilot study of inhaled nitric oxide in preterm infants treated with nasal continuous positive airway pressure for respiratory distress syndrome. Intensive Care Med. 2005;31(7):959–64. 12. Hess DR, MacIntyre NR, Galvin WF, Mishoe SC, Adams AB. Respiratory care: principles and practice. 2nd ed. Jones & Bartlett Learning: Burlington; 2011. p. 254. 13. Kiran Shekar A, Varkey S, Cornmell G, Parsons L, Tol M, Siuba M, et al. Feasibility of non-­ invasive nitric oxide inhalation in acute hypoxemic respiratory failure: potential role during the COVID-19 pandemic. Nitric Oxide. 2020;116:35–7. https://doi.org/10.1101/2020.05.1 7.20082123. 14. DiBlasi RM, Dupras D, Kearney C, Costa E, Griebel JL. Nitric oxide delivery by neonatal non-invasive respiratory support devices. Respir Care. 2015;60(2):219–30. 15. Ichinose F, Roberts JD, Zapol WM. Inhaled nitric oxide. Circulation. 2004;109(25):3106–11. 16. Kinsella J.  Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet. 1992;340(8823):819–20. 17. Sahni R, Ameer X, Ohira-Kist K, Wung JT. Non-invasive inhaled nitric oxide in the treatment of hypoxemic respiratory failure in term and preterm infants. J Perinatol. 2017;37(1):54–60. 18. Sekar K, Szyld E, McCoy M, Wlodaver A, Dannaway D, Helmbrecht A, et al. Inhaled nitric oxide as an adjunct to neonatal resuscitation in premature infants: a pilot, double blind, randomized controlled trial. Pediatr Res. 2020;87(3):523–8. 19. Kacmarek RM, Stoller JK, Heuer AJ.  Fundamentals of respiratory care. Amsterdam: Elsevier; 2019.

5

Noninvasive Mechanical Ventilation and Benzodiazepines, Indications, Monitoring, and Clinical Results Biljana Lazovic, Radmila Dmitrovic, Isidora Simonovic, and Antonio M. Esquinas

5.1 Introduction Benzodiazepines (BZDs) are a group of medications that are used as anxiolytics and hypnotics. Their history traces back to 1961 when chlordiazepoxide was unintentionally created at the Hoffmann-La Roche Laboratory as a consequence of an accidental chemical reaction. Thousands of chemicals have been created and evaluated, but only roughly 20 have entered clinical trials, according to statistics from the literature. Midazolam, diazepam, lorazepam, oxazepam, alprazolam, nitrazepam, clonazepam, bromazepam, and many others are routinely used [1]. BZDs were the most often prescribed medications in the United States in 2007, with over 112 million prescriptions issued. BZDs are being used to treat a variety of conditions, including anxiety, insomnia, spasticity caused by central nervous system (CNS) disorders, muscle relaxation, and epilepsy. They are also utilized intraoperatively due to their amnesic and anxiolytic qualities, although these features become unwanted side effects in almost all other therapeutic situations [2]. In this topic, we will discuss the mechanism of action, novel BZDs, and the use of these medications in sedation during noninvasive ventilation (NIV).

B. Lazovic (*) · R. Dmitrovic · I. Simonovic Department of Pulmonology, University Clinical Center “Zemun”, Belgrade, Serbia A. M. Esquinas Intensive Care Unit, Hospital General Universitario Morales Meseguer, Murcia, Spain © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_5

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5.2 The Mechanism of Action Gamma-aminobutyric acid (GABA) is the most prevalent neurotransmitter in the central nervous system (CNS), having significant concentrations in the cortex and limbic system. GABA is an inhibitory neurotransmitter that lowers neuron excitability. GABA receptors are classified into three categories: A, B, and C.  BZDs operate as GABA-A receptor positive allosteric modulators. The GABA-A receptor complex is made up of five glycoprotein subunits, each of which has a multitude of isoforms. The GABA-A receptors are made up of two α subunits, two β subunits, and 1 one subunit (Fig. 5.1). It is important to note that each receptor complex contains two GABA-binding sites but only one BZD-binding site, which is located in a specific pocket at the pairing of the α and γ subunits. BZDs bind to pockets formed by the aforementioned subunits, causing a conformational shift in the GABA-A receptor, which then causes a change in the GABA-A chloride channel, resulting in cell hyperpolarization and an inhibitory impact throughout the CNS [3]. Based on α1 subunit isoform and clinical impact, the BZDs’ receptor has been classified into different categories. The BZD type 1 receptor is abundant in the cortex, thalamus, and cerebellum, and its activation is responsible for sedative effects, anterograde amnesia, and part of diazepam’s anticonvulsive properties. Type 2 receptors are abundant in the limbic system, motor neurons, and dorsal horns of the spinal cord. Anxiolytic effects are accomplished by activating receptors in the limbic system, whereas muscular relaxation is accomplished by activating receptors in the motor neuron and spinal cord [4].

GABA site Barbiturate site barbiturates etomidate etazolate

General anaesthetics propofol steroids halothane ethanol

CI

Benzodiazepine site benzodiazepines non-benzodiazepines

agonists antagonists inverse agonists

Subsynaptic membrane

Fig. 5.1  GABA receptor with target sites. Available from http://ccforum.com/content/12/S3/S4/ figure/F1

Short to intermediate half-life Alprazolam High (80) (xanax) Bromazepam High (70) (lectopam) Clonazepam High (85) (klonopin) Lorazepam (ativan) High (85) Oxazepam (serax) Very high (97)

Desalkylflurazepam: very high (97)

Flurazepam (dalmane)

1–4

None None None None

18–50 10–20 5–15

1–6 (intramuscular, 1–1.5; sublingual, 1) 1–4

1–2

1–2

1–2 (injection: intramuscular, 0.5–1.5; intravenous, within 0.25) (sterile emulsion: intramuscular, >2; intravenous, 0.13–0.25) (rectal gel: 1.5) 0.5–1

0.5–2

0.5–4

Time to peak plasma concentration (h)

None

Desalkylflurazepam (47–100) N-1-hydroxyethylflurazepam (2–4)

Desmethylchlordiazepoxide (18) Demoxepam (14–95) Desmethyldiazepam (40–120) Oxazepam (5–15) Desmethyldiazepam (40–120) Oxazepam (5–15) Desmethyldiazepam (40–120) Temazepam (8–15) Oxazepam (5–15)

Major active metabolites (half-life in h)

6.3– 26.9 8–19

2.3

20–80

30–100

Very high (96)

Desmethyldiazepam: very high (95–98) Very high (98)

5–30

Protein binding (%)

Clorazepate (tranxene) Diazepam (valium)

Drug Long half-life Chlordiazepoxide (librium)

Half-­ life range (h)

Table 5.1  BZDs used in clinical practice. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/

(continued)

Renal Renal; fecal

Renal (5.0 mg/kg) increasing the risk of vomiting and slightly increasing the risk of apnea and recovery agitation [11]. Thus, there is no apparent benefit to using 1 mg/kg IV rather than 2 mg/kg IV or to using 3 mg/kg IM rather than 4–5 mg/kg IM, except perhaps a slightly faster recovery with the lower dose [12]. Clinicians should consider simply using the higher dose because ketamine is less consistently effective with lower doses. During the 1970s, anesthesiologists typically administered much higher ketamine doses (7–15 mg/kg IM) than those advocated now, and a systematic review identified no apparent difference in adverse event profiles between the higher and more standard dosing. In the meta-analysis, sub-dissociative ketamine (>3 mg/kg IM) demonstrated fewer airway and respiratory adverse effects relative to full dissociative dosing;

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however, such low doses are inadequate for most painful procedures and showed a higher incidence of recovery agitation. No such association was found for IV dosing. The IM and IV routes display a similar risk of airway and respiratory adverse events and clinically important recovery agitation [13]. However, the IM route is associated with a higher rate of vomiting and a longer recovery, and thus the literature supports a preference for IV administration in settings in which venous access can be obtained rapidly with minimal upset. The simple and inexpensive IM route may be preferable in other settings, and the IV route is also advantageous for lengthy procedures (more than 20 min) in that it permits convenient repeated dosing. IV access is also preferred for adults in the event of a clinically important unpleasant recovery reaction because of occasional. The minimum dose at which the dissociative state can be reliably achieved in children is 1.5 mg/kg IV, and common loading doses are 1.5–2.0 mg/kg. Repeated incremental doses of 0.5–1.0 mg/kg may be administered to prolong sedation. Dissociative dosing in adults is typically 1.0 mg/kg, with half doses repeated as needed [14]. Although a distinct feature of ketamine is the preservation of spontaneous respirations, the notable exception is when ketamine is administered rapidly IV. Transient respiratory depression and apnea have been reported 1–2 min after rapid IV administration, presumably from unusually high central nervous system levels. Accordingly, evidence is suggestive that IV ketamine is administered for 30–60 s [15]. Delayed respiratory depression past the period of initial drug administration has not been reported, except when attributable to co-administered agents.

7.5 Results Small randomized studies of patients with burns suggest that during painful procedures, oral ketamine provides better analgesia than dexmedetomidine or the combination of midazolam, acetaminophen, and codeine (e.g., dressing changes) [16]. Another review suggested a reduction in opioid consumption postoperatively [17]. Data from well-designed randomized controlled trials are needed to determine a clear role of ketamine in procedural sedation/analgesia and ICU analgesia. • Airway complications: When used for procedural sedation in major procedures involving the posterior pharynx (e.g., endoscopy) or when used for patients with an active pulmonary infection or disease (including upper respiratory disease or asthma), the use of ketamine increases the risk of laryngospasm. Patients with a history of airway instability, tracheal surgery, or tracheal stenosis may be at a higher risk of airway complications. The American College of Emergency Physicians (ACEP) considers these situations relative contraindications for the use of ketamine [18]. The manufacturer recommends against the use of ketamine alone in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree; mechanical stimulation of the pharynx should be avoided, whenever possible, if ketamine is used alone.

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• Increased intracranial pressure: Some consider the use of ketamine in patients with CNS masses, CNS abnormalities, or hydrocephalus a relative contraindication due to multiple reports that ketamine may increase intracranial pressure in these patients; use caution, especially at higher doses [18]. However, assuming adequate ventilation, some evidence suggests that ketamine has minimal effects on intracranial pressure and may even improve cerebral perfusion and reduce intracranial pressure [19]. • Respiratory depression: Rapid IV administration or overdose may cause respiratory depression or apnea. Resuscitative equipment should be available during use.

7.5.1 Monitoring Parameters Heart rate, BP, respiratory rate, transcutaneous O2 saturation, and emergence reactions; cardiac function (continuously monitored in patients with increased BP or cardiac decompensation); LFTs, alkaline phosphatase, and gamma-glutamyl transferase (baseline and then at periodic intervals), if continuous IV infusion, monitor BP at baseline and then hourly. Vital signs and pain levels should be monitored at 30 min and 60 min post-dose.

References 1. Dorandeu F. Happy 50th anniversary ketamine. CNS Neurosci Ther. 2013;19:369. 2. Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966;45:29–40. 3. Rogers R, Wise RG, Painter DJ, Longe SE, Tracey I. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging. Anesthesiology. 2004;100:292–301. 4. Plourde G, Baribeau J, Bonhomme V. Ketamine increases the amplitude of the 40-Hz auditory steady state response in humans. Br J Anaesth. 1997;78:524–9. 5. Morse Z, Kaizu M, Sano K, Kanri T.  BIS monitoring during midazolam and midazolam-­ ketamine conscious intravenous sedation for oral surgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:420–4. 6. Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88:82–8. 7. Sawynok J. Topical and peripheral ketamine as an analgesic. Anesth Analg. 2014;119:170. 8. Mion G, Granry JC, Villevieille T. Nuove applicazioni della ketamina nell’anesthesia moderna (Capitolo 33). In: Ezio R, editor. Anestesia generale e clinica, tomo I. 2nd ed. Torino: UTET; 2004. p. 515–31. 9. Lugli AK, Yost CS, Kindler CH. Anesthetic mechanisms: update on the challenge of unraveling the mystery of anaesthesia. Eur J Anaesthesiol. 2009;26:807. 10. Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54:158–68. 11. Krauss B, Green SM.  Sedation and analgesia for procedures in children. N Engl J Med. 2000;342:938–45.

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12. Shah A, Mosdossy G, McLeod S, et al. A blinded, randomized controlled trial to evaluate ketamine/propofol versus ketamine alone for procedural sedation in children. Ann Emerg Med. 2011;57:425–33. 13. Sener S, Eken C, Schultz CH, et  al. Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial. Ann Emerg Med. 2011;57:109–14. 14. Miner JR, Gray RO, Bahr J, et al. Randomized clinical trial of propofol versus ketamine for procedural sedation in the emergency department. Acad Emerg Med. 2010;17:604–11. 15. Pena BMG, Krauss B.  Adverse events of procedural sedation and analgesia in a pediatric emergency department. Ann Emerg Med. 1999;34:483–90. 16. Kundra P, Velayudhan S, Krishnamachari S, Gupta SL.  Oral ketamine and dexmedetomidine in adults’ burns wound dressing–a randomized double blind cross over study. Burns. 2013;39:1150. 17. Patanwala AE, Martin JR, Erstad BL. Ketamine for analgosedation in the intensive care unit: a systematic review. J Intensive Care Med. 2017;32:387. 18. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57(5):449–61. 19. Quibell R, Fallon M, Mihalyo M, Twycross R, Wilcock A. Ketamine. J Pain Symptom Manag. 2015;50(2):268–78. https://doi.org/10.1016/j.jpainsymman.2015.06.002.

8

Sedation, Propofol, Indications, Monitoring, and Clinical Results Carlos Fernando Giraldo Ospina, Juan Pablo Valencia Quintero, and Candela M. Rodriguez Mejías

8.1 Introduction Propofol is one of the most used drugs during anesthetic procedures and in critical care for the induction and maintenance of general anesthesia. In addition to its short duration, it is one of the most preferred drugs for sedation in assisted ventilation in intensive care units, and also for diagnostic and surgical procedures, alone or in combination with local or regional anesthesia [1]. The use of noninvasive ventilation (NIV) in critical and intensive care has greatly expanded in recent decades in response to evidence of its benefits as a means of reducing reliance on invasive ventilation (i.e., with tracheal intubation) and associated complications and for the treatment of acute respiratory failure. More acute respiratory care units (ARCU) are currently being created to care for those respiratory patients with an intermediate severity level where drugs for sedation and NIV induction are increasingly being implemented and adapted; for now these units are still in a phase of evolution [2].

8.2 Indications A desirable sedation should facilitate mechanical ventilation and sleep, allay anxiety, release pain and delirium, and alleviate physiologic responses to stress including tachycardia, shortness of breath, and hypertension without depressing respiration or hypoxic drive and cough reflex. C. F. Giraldo Ospina (*) Minimal Invasive Surgery, Hospital Regional Universitario de Málaga, Málaga, Spain J. P. Valencia Quintero · C. M. Rodriguez Mejías Intensive Care Unit, Hospital Universitario Virgen de la Nieves, Granada, Spain © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_8

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The regimens of sedation and analgesic that clinicians prefer to use may improve patients’ comfort and tolerance and be quite varied during NIV. It is reported that benzodiazepines, propofol, and opiates are the most often selected for NIV in patients with ARF [3]. Propofol is an intravenous anesthetic that is used for procedural sedation, during monitored anesthesia care, or as an induction agent for general anesthesia. It may be administered as a bolus or an infusion or some combination of the two. The formula contains soybean oil, glycerol, egg lecithin, and a small amount of the preservative EDTA. Like most general anesthetic agents, the mechanism of action for propofol is poorly understood but thought to be related to the effects on GABA-mediated chloride channels in the brain. Propofol may work by decreasing dissociation of GABA from GABA receptors in the brain and potentiating the inhibitory effects of the neurotransmitter. This, in turn, keeps the channel activated for a longer duration resulting in an increase in chloride conductance across the neuron causing a hyperpolarization of the cell membrane making it harder for a successful action potential to fire [4]. Sedation of mechanically ventilated patients in intensive care is commonly used, and the administration of propofol as a continuous infusion is recommended. But thanks to its properties of rapid action and short duration, diagnostic techniques are implemented in patients who require NIV. Due to the specific pharmacodynamic and pharmacokinetic parameters of propofol, the use of goal-controlled infusion (TCI) is a relevant option for this type of short procedure [5].

8.2.1 Pulmonary Intervention Techniques In hypoxemic patients, it has been shown that performing fibrobronchoscopy (FBC) under noninvasive ventilation (NIV) can preserve oxygenation [6, 7] (Fig. 8.1). The

Fig. 8.1  Respiratory Department. Regional University Hospital of Málaga. Performing fibrobronchoscopy in a patient with hypoxemic respiratory failure, with NIV (V60), introducing a FBC through the facial mask membrane port

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Fig. 8.2 Respiratory Department. Regional University Hospital of Málaga. Paco Paez, MD. Performing EBUS in a patient for the diagnosis of mediastinal lymphadenopathies, with NIV (V60), introducing FBC through the naso-buccal mask

recent French consensus on NIV recommends performing FBC under NIV in patients with acute hypoxemic respiratory failure. Nevertheless, this procedure remains uncomfortable [7–11]. In addition, the patient’s agitation may lead to desaturation and compromise the realization of FBC [6]. The use of propofol in patients with NIV is more associated with patients with pulmonary disease who require some diagnostic or therapeutic procedure. This is the case of patients with severe COPD, with exacerbation crises, who require electrical cardioversion procedures due to an episode of atrial fibrillation with high ventricular response, and patients on NIV who require a diagnosis by means of EBUS (endobronchial ultrasound) (Fig.  8.2) of mediastinal adenopathies (lung cancer, lymphoproliferative syndrome, sarcoidosis) or bronchoscopy for the placement of endobronchial valves [8–10]. In this context, the implementation of NIV can avoid orotracheal intubation during the placement of endobronchial valves, which makes this a safe procedure in patients with poor cardiopulmonary function.

8.2.2 Digestive Endoscopic Techniques The use of propofol has been described in patients with NIV during non-respiratory procedures, as support during an upper gastrointestinal endoscopy for placement of

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a percutaneous gastrostomy (PG) in a patient with amyotrophic lateral sclerosis (ALS) bulbar type. In general, placement of a GP is a relatively safe procedure. However, sedation of varying degrees is frequently required, which could lead to introducing the risk of respiratory compromise in patients with a forced vital capacity (FVC) of less than 50%, and the risk of aspiration, because the pharynx is temporarily anesthetized. The application of NIV during PG placement offers a safe means of promoting the nutritional status of ALS patients with low FVC [8].

8.2.3 Transesophageal Echocardiogram (TEE) In patients with a cardiac history and orthopnea who require a transesophageal echocardiogram (TEE), the use of NIV may reduce the need for deep sedation or general anesthesia. It has been documented and reported the use of NIV associated with TEE in severely orthopneic patients with aortic stenosis [9] through a modified face mask, as well as performing aortic valve replacement or percutaneous aortic valve replacement, without technical problems or respiratory or hemodynamic complications. NIV associated with TEE can avoid orotracheal intubation and the need for general anesthesia. To provide sedation during diagnostic and surgical procedures, the dose and rate of administration should be adjusted based on clinical response. Most patients will require 0.5–1 mg/kg body weight administered over 1–5 min for induction of sedation. Maintenance of sedation can be achieved by progressively adjusting the propofol infusion to the desired level of sedation. Generally 1.5–4.5 mg/kg body weight/h is needed. In case it is necessary to rapidly increase the intensity of sedation, the infusion can be supplemented by bolus administration of 10–20  mg (1–2  ml of Propofol Sandoz 10 mg/ml). In patients over 55 years of age and patients with grades III and IV of SAA, it may be necessary to reduce the speed of sedation and the dose.

8.3 Monitoring Although propofol is one of the safest anesthetic drugs, it requires an understanding of its neurological, respiratory, and cardiovascular effects in order to determine its control and monitoring guidelines.

8.3.1 Central Nervous System Effects Propofol causes a dose-dependent decreased level of consciousness and can be used for moderate sedation to general anesthesia. This decreased sensorium may lead to loss of protective airway reflexes, and propofol should not be used in any patient unless they are appropriately fasting. The American Society of Anesthesiologists’

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(ASA) NPO guidelines should be used as a template for the duration of fast following varying oral intake. In addition to depression of cognition, propofol will cause a decrease in cerebral blood flow, intracranial pressure, and cerebral oxygen consumption. Propofol causes increased latency and decreased amplitude during somatosensory evoked potential monitoring and, at higher doses, can lead to burst suppression and even an isoelectric EEG. In rat models, propofol has neuroprotective effects on the brain and will decrease oxidative damage and apoptosis. It also has been shown to cause transient excitatory phenomena such as choreiform movements and opisthotonus (abnormal posturing caused by spasm of the muscles) after injection. Propofol has also been shown to suppress seizure activity in the brain and is seldom used off-label to treat refractory status epilepticus. Propofol exerts antiemetic actions on the brain, which helps reduce postoperative nausea and vomiting. Although this mechanism is still unknown, it is believed to be due to a direct depressant effect on the chemoreceptor trigger zone and vagal nuclei.

8.3.2 Cardiovascular Effects Propofol causes vasodilation by inhibiting sympathetic vasoconstrictor activity along with mild depression of myocardial contractility, which accounts for the hypotension often seen when administered. This effect can be substantial with a profound reduction in the mean arterial pressure, especially when propofol is administered as a bolus. Caution should be used in hypovolemic or in catecholamine-­ depleted patients [12].

8.3.3 Respiratory Effects Propofol causes dose-dependent respiratory depression due to the inhibition of the hypercapnic ventilatory drive. This respiratory depression is potentiated by concurrent use of other sedative agents (benzodiazepines, opioids, central acting alpha two agonists, or other anesthetic medications). An induction dose of propofol will cause apnea. Propofol has also been seen to cause a low incidence of bronchospasm in asthmatic patients.

8.3.4 Additional Monitoring Requirements/Precautions Propofol can cause profound cardiovascular and respiratory depression and will ultimately end in general anesthesia if given in large enough doses. For this reason, any practitioner who administers propofol must be qualified to care for a patient who is at any level of sedation (ranging from moderate sedation to general anesthesia). Emergency equipment must be readily available and in good working order. At

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a minimum, the ASA recommends monitoring of oxygenation, circulation, ventilation, and temperature for all anesthetics. Appropriate anesthesia personnel must be continually present during all anesthetic cases requiring general anesthesia, monitored anesthesia care, or a regional anesthetic. Rescue equipment should include a bag valve mask, two sources of oxygen (centrally supplied or cylinders), laryngoscopes, endotracheal tubes of differing sizes, laryngeal mask airways, a crash cart with appropriate ACLS medications, and a defibrillator. The ASA guidelines for NPO status should be followed for any patient receiving an anesthetic since the loss of protective airway reflexes carries the risk of gastric content aspiration [13]. Propofol can cause profound cardiovascular and respiratory depression and will ultimately end in general anesthesia if given in large enough doses. For this reason, any practitioner who administers propofol must be qualified to care for a patient who is at any level of sedation (ranging from moderate sedation to general anesthesia). Emergency equipment must be readily available and in good working order. At a minimum, the ASA recommends monitoring of oxygenation, circulation, ventilation, and temperature for all anesthetics. Appropriate anesthesia personnel must be continually present during all anesthetic cases requiring general anesthesia, monitored anesthesia care, or a regional anesthetic [14]. Rescue equipment should include a bag valve mask, two sources of oxygen (centrally supplied or cylinders), laryngoscopes, endotracheal tubes of differing sizes, laryngeal mask airways, a crash cart with appropriate ACLS medications and a defibrillator. The ASA guidelines for NPO status should be followed for any patient receiving an anesthetic since the loss of protective airway reflexes carries the risk of gastric content aspiration [6]. The physicochemical properties of propofol could allow diffusion across the alveolocapillary membrane and a measurable degree of pulmonary propofol elimination. The authors tested this hypothesis and showed that propofol can be quantified in expiratory air and that propofol breath concentrations reflect blood concentrations. This could allow real-time monitoring of relative changes in the propofol concentration in arterial blood during total intravenous anesthesia. Some research has been publishing measured gas-phase propofol using a mass spectrometry system based on ion–molecule reactions coupled with quadrupole mass spectrometry which provides a highly sensitive method for online and offline measurements of organic and inorganic compounds in gases. In a first sequence of experiments, the authors sampled blood from neurosurgery patients undergoing total intravenous anesthesia and performed propofol headspace determination above the blood sample using an autosampler connected to the mass spectrometry system. In a second set of experiments, the mass spectrometry system was connected directly to neurosurgery patients undergoing target-controlled infusion via a T piece inserted between the endotracheal tube and the Y connector of the anesthesia machine, and end-expiratory propofol concentrations were measured online [15]. A close correlation between propofol whole blood concentration and propofol headspace was found (range of Pearson r, 0.846–0.957; P < 0.01; n 6).

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End-­expiratory propofol signals mirrored whole blood values with close intraindividual correlations between both parameters (range of Pearson r, 0.784–0.985; n 11) [15]. Ion–molecule reaction mass spectrometry may allow the continuous and noninvasive monitoring of expiratory propofol levels in patients undergoing general anesthesia.

8.3.5 Computer-Assisted Personalized Sedation (CAPS) The SEDASYSw (Ethicon Endo-Surgery, Cincinnati, OH) is the first computer-­ assisted personalized sedation system to receive US FDA approval. It was developed to allow mild-to-moderate propofol sedation to be delivered by nonanesthesiologists [16]. It consists of a full monitoring array (electrocardiography, noninvasive blood pressure, pulse oximetry, capnography) and also the aforementioned ARM. In addition, there is a propofol infusion pump, with the infusion rate selected by the proceduralist. The system is designed to stop propofol delivery if monitoring detects apnea or an unresponsive [17]. An adaptive neuro-fuzzy inference system has been recently described that can predict which effect site concentration pairs of propofol and remifentanil result in a particular range of processed EEG values and a desired level of sedation without applying stimulation to the patient. The noxious stimulation response index has been described which, using the propofol and remifentanil effect site concentrations, predicts who will respond to noxious stimulation with more accuracy than physiologic or electroencephalographic parameters [18].

8.4 Clinical Results The usefulness of NIV as support in minimally invasive procedures in high-risk patients may represent a valid and safe option, and reduce the need for orotracheal intubation and its complications, in addition to shortening ICU stay and reducing mortality. The most recent Cochrane review on the place of NIV as a weaning strategy for intubated adults with respiratory failure reported that only one of the studies they identified used a standardized sedation protocol before or after initiation of NIV and argued that the role of sedation as a co-intervention requires specific investigation in future trials [19]. Parte del uso de la sedación en la VNI parece ser empírico y quizás no esté estructurado., sobre todo, parece estar poco investigado. To date, it is still not known what the optimal strategy of sedation and analgesic for patients who suffer from ARF and are treated with NIV is [20]. More clinical trials and standardization of sedation protocols are required, with propofol to apply a consistent and predefined NIV.

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References 1. Keenan SP, Sinuff T, Burns KE, Muscedere J, Kutsogiannis J, Mehta S, Cook DJ, Ayas N, Adhikari NK, Hand L, Scales DC, Pagnotta R, Lazosky L, Rocker G, Dial S, Laupland K, Sanders K, Dodek P, Canadian Critical Care Trials Group/Canadian Critical Care Society Noninvasive Ventilation Guidelines Group. Clinical practice guidelines for the use of noninvasive positive-pressure ventilation and noninvasive continuous positive airway pressure in the acute care setting. CMAJ. 2011;183:E195–214. 2. Torres A, Ferrer M, Blanquer JB, Calle M, Casolivé V, Echave JM.  Grupo de Trabajo de Cuidados Respiratorios Intermedios de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Arch Bronconeumol. 2005;41(9):505–12. 3. Hilbert G, Clouzeau B, Bui HN, Vargas F. Sedation during non-invasive ventilation. Minerva Anestesiol. 2012;78(7):842–6. https://doi.org/10.1016/j.annfar.2012.04.0247. 4. Antkowiak B, Rammes G. GABA(A) receptor-targeted drug development-new perspectives in perioperative anesthesia. Expert Opin Drug Discovery. 2019;14(7):683–99. 5. Conti G, Ranieri VM, Costa R, Garratt C, Wighton A, Spinazzola G, Urbino R, Mascia L, Ferrone G, Pohjanjousi P, Ferreyra G, Antonelli M. Effects of dexmedetomidine and propofol on patient-ventilator interaction in difficult-to-wean, mechanically ventilated patients: a prospective, open-label, randomised, multicentre study. Crit Care. 2016;20:206. 6. Clouzeau B, Bui H-N, Guilhon E, Grenouillet-Delacre M, Leger MS, Saghi T, Pillot J, Filloux B, Coz S, Boyer A, Vargas F, Gruson D, Hilbert G. Fiberoptic bronchoscopy under noninvasive ventilation and propofol target-controlled infusion in hypoxemic patients. Intensive Care Med. 2011;37:1969–75. 7. Antonelli M, Pennisi MA, Conti G, Bello G, Maggiore S, Michetti V, Cavaliere F, Meduri G. Fiberoptic bronchoscopy during noninvasive positive pressure ventilation delivered by helmet. Intensive Care Med. 2003;29:126–9. 8. Chertcoff M, Blasco M, Borsini E, Iriart H, Soto J, Chertcoff F. Utilización de la ventilación mecánica no invasiva en situaciones especiales. Reporte de serie de casos. Rev Am Med Resp. 2013;3:162–8. 9. Guarracino F, Cabrini L, Baldassarri R, et al. Non-invasive ventilation aided transoesophageal echocardiography in high risk patients: a pilot study. Eur J Echocardiogr. 2010;11:554–6. 10. Frank C, Sciurba MD, Armin Ernst MD, Felix JF, Herth MD, for the VENT Study Research Group. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010;363:1233–44. 11. Scala R, Naldi M, Maccari U. Early fiberoptic bronchoscopy during non-invasive ventilation in patients with decompensated chronic obstructive pulmonary disease due to community acquired- pneumonia. Crit Care. 2010;14:R80. 12. Li S, Lei Z, Zhao M, Hou Y, Wang D, Xu X, Lin X, Li J, Tang S, Yu J, Meng T. Propofol inhibits ischemia/reperfusion-induced cardiotoxicity through the protein kinase C/nuclear factor erythroid 2-related factor pathway. Front Pharmacol. 2021;12:655726. 13. Ferrier DC, Kiely J, Luxton R. Propofol detection for monitoring of intravenous anaesthesia: a review. J Clin Monit Comput. 2022;36:315–23. 14. Brohan J, Goudra BG. The role of GABA receptor agonists in anesthesia and sedation. CNS Drugs. 2017;10:845–56. 15. Hornuss C, Praun S, Villinger J, Dornauer A, Moehnle P, Dolch M, Weninger E, Chouker A, Feil C, Briegel J, Thiel M, Schelling G. Real-time monitoring of propofol in expired air in humans undergoing total intravenous anesthesia. Anesthesiology. 2007;106:665–74. 16. Urman RD, Maurer WG. Computer computer-assisted personalized sedation: friend or foe? Anesth Analg. 2014;119:207–11. 17. Sheahan CG, Mathews DM. Monitoring and delivery of sedation. Br J Anaesth. 2014;113:37–47. 18. Luginbuhl M, Schumacher PM, Vuilleumier P, et  al. Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction. Anesthesiology. 2010;112:872–80.

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19. Yeung J, Couper K, Ryan EG, Gates S, Hart N, Perkins GD.  Non-invasive ventilation as a strategy for weaning from invasive mechanical ventilation: a systematic review and Bayesian meta-analysis. Intensive Care Med. 2018;44(12):2192–204. 20. Wang X, Meng J. Butorphanol versus propofol in patients undergoing noninvasive ventilation: a prospective observational study. Int J Gen Med. 2021;14:983–92.

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Noninvasive Mechanical Ventilation: Locoregional Anesthesia Matilde Mari, Riccardo La Rosa, and Savino Spadaro

Patients with preexisting serious pulmonary disease are at a high risk of developing postoperative respiratory complications [1]. Locoregional anesthesia may be a safer option in such patients, since the administration of local anesthetics may allow anesthesia and analgesia for surgical procedures avoiding the need for mechanical ventilation. Nevertheless, even though the additional effects on sympathetic innervation may be favorable on different organs, the impact of epidural anesthesia on lung function is still unclear [2]. Providing anesthesia without a ventilatory support may avoid mechanical irritation caused by endotracheal intubation; anyway, that aspect should be offset by an increased bronchial reactivity due to an uncontrolled vagal tone following sympathicolysis and by the epidural motor blockade of respiratory muscles [3]. Particularly, the extension of the motor blockade is mainly determined by the height of the insertion of the catheter for epidural anesthesia and to a lesser extent by the concentration of the local anesthetic. In low thoracic and lumbar epidural anesthesia, for example, the vital capacity (VC) reduction is not clinically relevant [4]; on the contrary, higher thoracic (dermatomes T1–T5) epidural administration of local anesthetics alters lung function and leads to a greater reduction of VC and forced expiratory volume in one second (FEV1) due to a direct motor blockade of intercostal muscles [5]. Even so, patients with asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation with bronchial hyperreactivity and reversible or nonreversible airway obstruction; in these cases, general anesthesia can lead bronchospasm up to life-threatening complications. Consequently, surgical procedures performed under regional anesthesia are associated with fewer M. Mari (*) · R. La Rosa · S. Spadaro (*) Department of Translational Medicine, University of Ferrara, Ferrara, Italy e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_9

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respiratory complications avoiding airway irritation as compared with the same procedures under general anesthesia. However, many patients with severe chronic obstructive pulmonary disease cannot lie flat and may therefore need general anesthesia and positive pressure ventilation if the surgery requires the lithotomy position with a significant degree of head-down tilt. That is the reason why patients with respiratory failure may benefit from the combined use of locoregional anesthesia and noninvasive mechanical ventilation (NIMV), which is an accepted treatment for chronic and acute respiratory failure and has been used increasingly to avoid tracheal intubation and the resulting complications by combining pressure support and positive end-expiratory pressure [6]. Candidates for NIMV should be able to protect their own airway, to cough and to swallow their own secretions. Even if NIMV is most commonly performed in ICU, it is also used for preoxygenation and postoperative recovery in patients with respiratory issues following major surgery [7, 8]. The intraoperative use of NIMV is rarely reported, but some cases have been described particularly in obstetrics and gynecological surgery. In a case report showed by Erdogan et al. [9], a morbidly obese and asthmatic pregnant woman with respiratory distress and pulmonary edema secondary to severe preeclampsia was managed with spinal anesthesia and perioperative NIMV (BiPAP) for emergency caesarean delivery. In that case, spinal anesthesia was selected due to the prediction of difficult intubation and perioperative pulmonary dysfunction, in addition to the risk of uncontrolled hypertension secondary to preeclampsia during both intubation and extubation. Since neuraxial anesthesia too would interfere with the mechanics of breathing, perioperative NIMV was administrated. In this way, the combined use of NIMV with neuraxial anesthesia has resulted in favorable maternal and fetal outcomes. Ferrandière et  al. [10] showed the beneficial effects of NIMV in correcting hypoxemia in severe COPD during spinal anesthesia. A morbidly obese patient with severe COPD underwent transurethral resection of the prostate under spinal anesthesia in the lithotomy position. During surgery, hypoxemia and an important decrease of forced vital capacity were observed, and a large decrease in diaphragmatic excursion (- 30%) was confirmed by performing an M-mode sonographic study of the diaphragm in the operating room. In order to correct the deterioration in forced vital capacity and resultant hypoxemia and alveolar hypoventilation, they initiated NIMV without oxygen supplementation and that resulted in an improvement of diaphragm kinetics marked by sonography. In that case, NIMV proved to be a more effective treatment of hypoxemia and hypercapnia than oxygen supplementation, demonstrating that a possible mechanism of hypoxemia may be a diaphragmatic dysfunction. Bapat et al. [11] reported the case of a patient with severe chronic obstructive pulmonary disease who underwent local resection of a carcinoma of the rectum under spinal anesthesia. As the surgical procedure required the patient to be in the lithotomy position, but preoperative assessment showed that he could not lie flat, they decided to apply continuous positive airway pressure with a face mask during

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spinal anesthesia to help him to tolerate the position comfortably and to facilitate breathing during surgery. Usually, patients with severe COPD who cannot lie flat are considered unsuitable for regional anesthesia in a head-down lithotomy position, but the use of CPAP made it possible for that patient. In conclusion, by avoiding tracheal intubation, muscle relaxation, and general anesthesia, NIMV could be of particular interest for patients with conditions predisposing to difficult or prolonged weaning from mechanical ventilation, and the combination with neuraxial anesthesia may be a valuable management strategy in selected patients with acute or chronic respiratory failure requiring surgery.

References 1. Wong DH, Weber EC, Schell MJ, Wong AB, Anderson CT, Barker SJ. Factors associated with postoperative pulmonary complications in patients with severe chronic obstructive pulmonary disease. Anesth Analg. 1995;80:276–84. 2. Basse L, Raskov HH, Hjort Jakobsen D, Sonne E, Billesbølle P, Hendel HW, Rosenberg J, Kehlet H. Accelerated postoperative recovery programme after colonic resection improves physical performance, pulmonary function and body composition. Br J Surg. 2002;89(4):446–53. 3. Groeben H. Epidural anesthesia and pulmonary function. J Anesth. 2006;20:290–9. 4. Freund FG, Bonica JJ, Ward RJ, Akamatsu TJ, Kennedy WF. Ventilatory reserve and level of motor block during high spinal and epidural anesthesia. Anesthesiology. 1967;28:834–7. 5. Sundberg A, Wattwil M, Arvill A. Respiratory effects of high thoracic epidural anaesthesia. Acta Anaesthesiol Scand. 1986;30:215–7. 6. Liesching T, Kwok H, Hill NS. Acute applications of noninvasive positive pressure ventilation. Chest. 2003;124:699–713. 7. Thys F, Delvau N, Roeseler J, et al. Emergency orthopaedic surgery under noninvasive ventilation after refusal for general anaesthesia. Eur J Emerg Med. 2007;14:39–40. 8. El-Khatib MF, Kanazi G, Baraka AS. Noninvasive bilevel positive airway pressure for preoxygenation of the critically ill morbidly obese patient. Can J Anesth. 2007;54:744–7. 9. Erdogan G, Okyay DZ, Yurtlu S, Hanci V, Ayoglu H, Koksal B, Turan IO.  Non-invasive mechanical ventilation with spinal anesthesia for cesarean delivery. Int J Obstet Anesth. 2010;19:438–55. 10. Ferrandière M. Non-invasive ventilation corrects alveolar hypoventilation during spinal anesthesia. Can J Anaesth. 2006;53(4):404–8. 11. Bapat PP, Anderson JA, Bapat S, Sule A. Use of continuous positive airway pressure during spinal anaesthesia in a patient with severe chronic obstructive pulmonary disease. Anaesthesia. 2006;61:1001–3.

Combined Acid-Base Abnormalities During Noninvasive Ventilation and Place of Acetazolamide

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Burcu Öztürk Şahin and Gül Gürsel

10.1 Introduction Noninvasive mechanical ventilation (NIV) and invasive mechanical ventilation (MV) are frequently used treatment modalities in patients with respiratory failure (RF). Although NIV is used in patients with all kinds of respiratory failure, the diseases in which it is most useful and included in the standard treatment regimen are chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS), and heart failure. NIV also increases oxygenation in acute hypoxemic respiratory failure and reduces dyspnea by reducing the work of breathing. According to the development time of respiratory failure, as acute, chronic, or acute on chronic basis, isolated or combined acid-base abnormalities accompany the picture. Well-known and appropriate treatment of these acid-base abnormalities may increase the success of treatment in these patients. Hypercapnic respiratory failure is a complex condition that causes acid-base imbalance by affecting the physiological processes of many organs and systems in the body. For a given increase in carbon dioxide, the only way to minimize the resulting acidemia is to create metabolic alkalosis through urinary ion excretion mechanisms [1]. In hypoxic and hypercapnic COPD patients, fluid homeostasis is impaired by the avid retention of sodium and water. This may be explained by other pathophysiological mechanisms, including increased sodium retention in the kidneys and B. Öztürk Şahin (*) Gazi University School of Medicine Department of Pulmonary Disease, Ankara, Turkey G. Gürsel Division of Critical Care, Gazi University School of Medicine Department of Pulmonary Disease, Ankara, Turkey e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_10

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associated edema, partially right heart failure (cor pulmonale), and renal and hormonal abnormalities [2]. The sudden decrease in ventilation in hypercapnic COPD exacerbations causes acute respiratory acidosis or worsens preexisting chronic respiratory acidosis. Due to the frequency of comorbidities and associated multidrug therapy in these patients, mixed acid-base and hydro-electrolyte disorders are becoming increasingly common, especially in critically ill and elderly populations [3].

10.2 Causes of Acid-Base Abnormalities That May Occur During NIV Respiratory failure is defined as acute if it occurs within hours or days, and as chronic if it develops within weeks or months. Acute respiratory failure may develop without a previous underlying respiratory system disease, or it may develop based on chronic respiratory failure. In chronic hypercapnic respiratory failure, excess CO2 is compensated by bicarbonate retained by the kidneys. However, when there is a sudden deterioration in the clinical condition of the patient, the kidneys do not have enough time for compensation by holding more HCO3 and acute respiratory failure develops on a chronic basis. With NIV, significant improvement in gas exchange is achieved in the early and late periods in chronic lung diseases. Although the studies have differences in terms of the patient profile, the severity of the disease, and the NIV method applied, an average of 0.06 increase in arterial blood pH value, 9  mmHg decrease in PaCO2 value, and 8 mmHg increase in PaO2 value are reported in acute applications [4–6].

10.2.1 Respiratory Acidosis It is the clinical picture where the pH value is below 7.35 and the PaCO2 value is above 45 mmHg. The main mechanism is the decrease in CO2 excretion because of alveolar hypoventilation and the increase in the CO2 value in the blood. Respiratory acidosis can be acute or chronic. Compensation for respiratory events occurs metabolically. In acute respiratory acidosis, HCO3−1 mEq/L increases for every 10 mmHg increase in PaCO2. In chronic respiratory acidosis (>24-h duration), HCO3−4 mEq/L increases for every 10 mmHg increase in PaCO2. The increase in HCO3− is called metabolic compensation. For this, the kidneys come into play; the H+ ion is expelled and the HCO3− ion is retained. Metabolic compensation occurs slowly and optimally occurs in 2–5 days [7]. In simple acid-base disorders, both PaCO2 and HCO3− move in the same direction (both rise in respiratory acidosis and metabolic alkalosis and fall in both respiratory alkalosis and metabolic acidosis). The opposite movement of HCO3− and PaCO2 is indicative of a mixed acid-base disturbance.

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10.2.2 Metabolic Alkalosis Respiratory acidosis and metabolic alkalosis are the main acid-base disorders seen in patients who need mechanical ventilation. Metabolic alkalosis is common in patients with respiratory failure [8]. Metabolic alkalosis can be caused by many conditions encountered during ICU stays, including a diuretic or glucocorticoid use, vomiting or nasogastric suctioning, and permissive hypercapnia induced by lung protective strategies. Metabolic alkalosis is an acid-base disorder frequently seen in critically ill patients, characterized by a high serum pH level due to increased plasma bicarbonate (HCO3−) retention and often associated with high mortality and morbidity [9, 10]. Metabolic alkalosis attenuates respiratory central drive performance by reducing the stimulatory effects of hypercapnia and impairs oxygenation mainly due to a shift to the left of the dissociation curve of oxyhemoglobin. It may also suppress cardiac output and favor cardiac arrhythmias and metabolic disturbances such as hypokalemia and hypophosphatemia. All mechanisms induce hypoventilation and can lead to respiratory failure [6]. Metabolic alkalosis also occurs in patients taking loop or thiazide diuretics. In these patients, the fluid volume decreases and angiotensin II, aldosterone, and adrenergic responses of the kidney increase. Diuretics increase the amount of sodium reaching the distal nephron, resulting in greater acid excretion. Diuretics also increase acid excretion by creating hypokalemia. Increased renal acid excretion results in metabolic alkalosis. This condition has been described as “contraction alkalosis” in those taking diuretics like patients with heart failure [11]. If the compensation level occurring in simple acid-base imbalance is outside the expected compensation range (more or less than the expected value), mixed acid-­ base imbalance may be present. In simple acid-base disturbances, the pH cannot be brought to normal with compensation mechanisms. If there is a normal pH in the presence of pathological PaCO2 and HCO3− levels, the presence of mixed acid-base balance disorder should be considered. Diagnosis can be made by clinical picture and calculation of anion gap. The anion gap represents the difference between measured serum cations (positively charged particles) and anions (negatively charged particles). The cation measured in daily practice is sodium, and the anions are chlorine and bicarbonate [12]. Normally the anion gap is 12 + 2 mEq/L.

10.2.3 Mixed Acid and Base Disorders Mixed acid-base disorder is defined as the coexistence of more than one primary disorder in the same patient. These disorders can occur simultaneously or at different times. Several conditions coexist that can cause mixed acid-base disorder in critically ill patients in intensive care. For example, a patient followed up with sepsis may develop high anion gap metabolic acidosis due to hypotension while initially presenting with respiratory alkalosis. Metabolic alkalosis may develop in COPD, OSAS, and heart failure patients with respiratory acidosis due to a thiazide or loop diuretic given for the treatment of cor pulmonale. Recognition of mixed

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acid-base disorder by the clinician is extremely important for the appropriate treatment of the patient. Failure to recognize metabolic alkalosis in a patient with chronic respiratory acidosis may exacerbate hypoxemia because both disorders are associated with an increase in pCO2. While the NIV therapy is given for the treatment of respiratory acidosis, carbonic anhydrase inhibitors can be used in the treatment of additive metabolic alkalosis.

10.3 Carbonic Anhydrase Inhibitors Following the discovery of carbonic anhydrase (CA) in red cells in the early 1930s, the presence of carbonic anhydrase has been identified in many organs. In the 1950s, enzyme inhibitors began to be applied to treat various diseases with acetazolamide. It has been used orally and intravenously in the treatment of edema in heart failure by the renal effect of acetazolamide on tubular carbonic anhydrase. Since carbonic anhydrase enzyme plays a role in gas exchange, metabolism, membrane ion transport, acid-base regulation, and fluid balance, it has been targeted for the treatment of many diseases. Carbonic anhydrase inhibitors are considered part of the diuretic class of medications. It has been shown to be useful for clinical use in many areas, as well as being FDA-approved uses [13, 14].

10.3.1 FDA-Approved Indications [15–17] • • • • •

Elevated intraocular pressure (angle-closure and open-angle glaucoma). Pseudotumor cerebri. Edema due to congestive heart failure. Centrencephalic epilepsies. Altitude sickness prophylaxis.

10.3.2 Examples of Non-FDA-Approved Indications • • • •

Sleep apnea. Cerebrospinal fluid leak. Reversal of metabolic alkalosis in chronic obstructive pulmonary disease. Prevention of contrast-induced nephropathy.

The carbonic anhydrase enzyme is in the proximal tubule lumen of the kidney. It converts carbonic acid into water and carbon dioxide. The water and carbon dioxide formed to enter the intracellular space by diffusion. The carbonic anhydrase enzyme in the cell converts water and carbon dioxide into carbonic acid, and carbonic acid decomposes into H+ and bicarbonate. Carbonic anhydrase inhibitor drugs inhibit the carbonic anhydrase enzyme and inhibit the absorption of bicarbonate by tubular

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cells. It ultimately leads to the retention of bicarbonate in the tubular lumen. The general effect is that the urine becomes alkaline due to bicarbonate excretion and the blood pH decreases. With its diuretic effect, it causes an increase in water excretion and a decrease in blood pressure. The most often used CA inhibitor is acetazolamide, which plays a crucial role in proximal bicarbonate, sodium, and chloride reabsorption and causes NaCl and NaHCO3 loss. The most common indication for its usage as a diuretic is in edematous individuals with metabolic alkalosis, in whom the elimination of excess bicarbonate in the urine tends to restore acid-base balance. Acetazolamide is also used to correct metabolic alkalosis as a respiratory stimulant to improve oxygenation and reduce oxygen demand in patients and accelerate recovery from mechanical ventilation. As a carbonic anhydrase (CA) inhibitor, it has multiple effects resulting from the functions of carbonic anhydrase enzyme in many tissues, including the kidney, vascular endothelium, red cells, lung, diaphragm, central nervous system, and chemoreceptors. Acetazolamide and other carbonic anhydrase inhibitors play a role in the treatment of many cardiovascular and pulmonary diseases. Acetazolamide has been proven to be safe and effective in correcting metabolic alkalosis by promoting renal excretion of bicarbonate and inducing a decrease in plasmatic bicarbonate concentration [18, 19]. Acetazolamide, by stimulating the central respiratory center, causes a decrease in PaCO2 in patients with COPD and OHS [20, 21]. In metabolic alkalosis, the left-shifting oxygen dissociation curve to its normal position increases PaO2. Studies have suggested that acetazolamide may reduce the duration of mechanical ventilation in patients with metabolic alkalosis by stimulating the respiratory center, increasing minute ventilation and oxygenation [22, 23]. Based on these effects, acetazolamide has been used to stimulate ventilation and improve arterial oxygenation, especially in patients with mild to moderate COPD [24]. Metabolic acidosis caused by acetazolamide increases the minute ventilation by stimulating peripheral and central chemoreceptors. Recently, some studies have reported a potential benefit of acetazolamide in patients with respiratory failure who need mechanical ventilation. Mixed acid-base disturbances are common during noninvasive mechanical ventilation therapy in patients with respiratory failure. Studies have shown that in patients receiving noninvasive ventilation therapy, 500 mg of acetazolamide once a day improves both the clinic and PaCO2, HCO3, serum, and urine pH [25].

10.3.3 Treatment Approach to Metabolic Alkalosis in Patients with Hypercapnic Respiratory Failure and Place of Acetazolamide Metabolic alkalosis should be treated by reversing the etiology of bicarbonate production and the factors preventing the elimination of excess bicarbonate. In patients with metabolic alkalosis, the most prevalent reasons of decreased renal bicarbonate excretion include a reduction in the effective circulation volume, chloride depletion, hypokalemia, and acute and chronic kidney disease. The causes of real volume

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depletion in ICU patients include vomiting, nasogastric suction, diuretic medication, blood loss, and fluid loss into the “third” space. In these individuals, but not in those with heart failure or cirrhosis, metabolic alkalosis should be treated by saline volume expansion. Reduced effective circulation volume and chloride depletion typically occur simultaneously, and therapy with sodium chloride corrects both deficits simultaneously. This often results in an increase in renal bicarbonate excretion in patients with genuine volume depletion. Due to diuretic medication, patients with edematous conditions such as heart failure, cirrhosis, nephrotic syndrome, and cor pulmonale might develop metabolic alkalosis. The treatment of edematous patients with isotonic saline is generally contraindicated since it can exacerbate edema, ascites, and/or effusions and will not correct metabolic alkalosis. These patients may be hypokalemic and deficient of potassium. The metabolic alkalosis of such patients is frequently alleviated by giving potassium chloride. Patients with heart failure or cirrhosis are frequently administered potassium-sparing diuretics such amiloride or mineralocorticoid receptor antagonists (spironolactone). However, their use must be closely controlled to prevent the development of potentially fatal hyperkalemia. If more diuresis is necessary, acetazolamide may be provided (250 to 500 mg, once or twice a day). The carbonic anhydrase inhibitor acetazolamide limits proximal sodium bicarbonate reabsorption, resulting in increased urine bicarbonate excretion. When administered to patients, acetazolamide induces kaliuresis and can cause or aggravate hypokalemia. Potassium chloride substitution may be required. If feasible, potassium salts of organic anions, such as citrate or acetate, should not be administered to this patient, as the metabolism of these anions generates bicarbonate. Recent investigations conducted on individuals with congestive heart failure support the use of acetazolamide to treat congestion more effectively in these patients. In a current multicenter, randomized, placebo-controlled trial involving patients with acute decompensated heart failure and volume overload, the addition of acetazolamide to standardized intravenous loop diuretic therapy was associated with a higher incidence of successful decongestion within 3  days after randomization. Patients who had been treated with acetazolamide had more diuresis and natriuresis, had a shorter hospital stay, and were more likely to be discharged without residual signs of volume overload than those who had received placebo [26].

10.3.4 Treatment of Posthypercapnic Metabolic Alkalosis Chronic respiratory acidosis, which is typically caused by COPD, is initially related with increased renal acid excretion and afterward with increased bicarbonate reabsorption. This leads to an increase in serum bicarbonate concentration that counteracts the decrease in arterial pH. If the partial pressure of carbon dioxide decreases rapidly due to MV and the serum bicarbonate content stays excessive, this indicates posthypercapnic metabolic alkalosis. A combination of chloride depletion, a drop in the circulation volume (e.g., due to diuretic medication or cor pulmonale), and/or a reduction in the glomerular filtration rate prevents such individuals from

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spontaneously excreting excess bicarbonate. Posthypercapnic metabolic alkalosis can impair ventilation, exacerbate respiratory acidosis, delay weaning from mechanical ventilation, and lengthen the patient’s stay in the critical care unit. When volume depletion is the cause of posthypercapnic metabolic alkalosis, it can typically be treated with an isotonic saline infusion. However, if the patient requires further diuresis, acetazolamide can be administered.

10.3.5 Pharmacologic Features of Acetazolamide There is little metabolic change of acetazolamide, and its plasma half-life is 6 to 9 h; renal excretion is the predominant route of disposal. Available dosages include 125 mg, 250 mg, and 500 mg tablets. When treating edema and diuresis in congestive heart failure, it is advised to administer lower doses. The dosage range for these diseases is often between 250 and 375 mg. Carbonic anhydrase inhibitors may have many adverse effects, including changes in taste, fatigue, abdominal pain, diarrhea, nausea, vomiting, blurred vision, tinnitus, paresthesia, headache, rash, anaphylaxis, and, in rare cases, allergic reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Serious adverse effects such as metabolic acidosis, hypokalemia, aplastic anemia, agranulocytosis, nephrolithiasis, and fulminant hepatic necrosis can be seen with the use of systemic carbonic anhydrase inhibitors [27].

10.3.6 Contraindications Because acetazolamide reduces ammonia clearance, it may hasten the onset of hepatic encephalopathy in patients with compromised liver function. Acetazolamide can create electrolyte imbalances and reduce renal function. It should not be administered to patients with hypokalemia, hyponatremia, or decreased renal function. The excretion of salicylates phenytoin, primidone, and quinidine is reduced by acetazolamide. Patients taking these drugs and acetazolamide simultaneously may experience toxicity. Patients on anti-folate medications, such as methotrexate and trimethoprim, should not use acetazolamide.

10.3.7 Conclusion In conclusion, mixed acid-base disturbances are common during noninvasive mechanical ventilation therapy in patients with respiratory failure. Studies have shown that the use of carbonic anhydrase inhibitors in patients receiving noninvasive ventilation therapy improves both clinical findings and PaCO2 and pH.  In patients with respiratory failure, mixed acid-base imbalance that may occur during NIV should be better investigated and treatment should be planned accordingly.

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References 1. Derksen R, Scheffer G, Van Der Hoeven J.  Quantitative acid–base physiology using the Stewart model. Does it improve our understanding of what is really wrong? Eur J Intern Med. 2006;17(5):330–3. 2. De Leeuw P, Dees A.  Fluid homeostasis in chronic obstructive lung disease. Eur Respir J. 2003;22(46 suppl):33s–40s. 3. Terzano C, Di Stefano F, Conti V, Di Nicola M, Paone G, Petroianni A, et al. Mixed acid-base disorders, hydroelectrolyte imbalance and lactate production in hypercapnic respiratory failure: the role of noninvasive ventilation. PLoS One. 2012;7(4):e35245. 4. Navalesi P, Fanfulla F, Frigerio P, Gregoretti C, Nava S. Physiologic evaluation of noninvasive mechanical ventilation delivered with three types of masks in patients with chronic hypercapnic respiratory failure. Crit Care Med. 2000;28(6):1785–90. 5. Prinianakis G, Delmastro M, Carlucci A, Ceriana P, Nava S. Effect of varying the pressurisation rate during noninvasive pressure support ventilation. Eur Respir J. 2004;23(2):314–20. 6. Diaz O, Iglesia R, Ferrer M, Zavala E, Santos C, Wagner PD, et al. Effects of noninvasive ventilation on pulmonary gas exchange and hemodynamics during acute hypercapnic exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997;156(6):1840–5. 7. Dokwal C. Interpretation of arterial blood gases. Pulse. 2009;3(1):15–9. 8. Tanios BY, Omran MO, Noujeim C, Lotfi T, Mallat SS, Bou-Khalil PK, et al. Carbonic anhydrase inhibitors in patients with respiratory failure and metabolic alkalosis: a systematic review and meta-analysis of randomized controlled trials. Crit Care. 2018;22(1):1–12. 9. Khanna A, Kurtzman NA. Metabolic alkalosis. Respir Care. 2001;46(4):354–65. 10. Hodgkin JE, Soeprono FF, Chan DM.  Incidence of metabolic alkalemia in hospitalized patients. Crit Care Med. 1980;8(12):725–8. 11. Kavukçu S. Alkaloz ve Tedavisi. J Curr Pediatr 2007;(5):0–0 12. Grogono AW: Acid-base balance. International Anesthesiology Clinics, Problems and Advances in Respiratory Therapy, Spring 1986, Vol. 24, No. 1, 1986 13. Kassamali R, Sica DA.  Acetazolamide: a forgotten diuretic agent. Cardiol Rev. 2011;19(6):276–8. 14. Farzam K, Abdullah M. Acetazolamide. In: StatPearls; 2021. 15. Van Berkel MA, Elefritz JL.  Evaluating off-label uses of acetazolamide. Am J Health Syst Pharm. 2018;75(8):524–31. 16. Assadi F. Acetazolamide for prevention of contrast-induced nephropathy: a new use for an old drug. Pediatr Cardiol. 2006;27(2):238–42. 17. Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Am J Respir Crit Care Med. 2006;173(2):234–7. 18. Jones P, Greenstone M. Carbonic anhydrase inhibitors for hypercapnic ventilatory failure in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2001;2001:CD002881. 19. Cervera GR, Puigdevall JR, Chorro IM, Delgado MM, la Calle GH, Serra AM, et al. Effects of early administration of acetazolamide on the duration of mechanical ventilation in patients with chronic obstructive pulmonary disease or obesity-hypoventilation syndrome with metabolic alkalosis. A randomized trial. Pulm Pharmacol Ther. 2017;44:30–7. 20. Raurich J-M, Rialp G, Ibáñez J, Llompart-Pou JA, Ayestarán I. Hypercapnic respiratory failure in obesity-hypoventilation syndrome: CO2 response and acetazolamide treatment effects. Respir Care. 2010;55(11):1442–8. 21. Vos P, Folgering H, de Boo TM, Lemmens W, van Herwaarden C. Effects of chlormadinone acetate, acetazolamide and oxygen on awake and asleep gas exchange in patients with chronic obstructive pulmonary disease (COPD). Eur Respir J. 1994;7(5):850–5. 22. Faisy C, Meziani F, Planquette B, Clavel M, Gacouin A, Bornstain C, et al. Effect of acetazolamide vs placebo on duration of invasive mechanical ventilation among patients with chronic obstructive pulmonary disease: a randomized clinical trial. JAMA. 2016;315(5):480–8.

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23. Bahloul M, Chaari A, Tounsi A, Turki O, Chtara K, Hamida CB, et al. Impact of acetazolamide use in severe exacerbation of chronic obstructive pulmonary disease requiring invasive mechanical ventilation. Int J Crit Illn Inj Sci. 2015;5(1):3. 24. Heming N, Faisy C, Urien S. Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients. Crit Care. 2011;15(5):1–9. 25. Fontana V, Santinelli S, Internullo M, Marinelli P, Sardo L, Alessandrini G, et al. Effect of acetazolamide on post-NIV metabolic alkalosis in acute exacerbated COPD patients. Eur Rev Med Pharmacol Sci. 2016;20(1):37–43. 26. Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, et al. Acetazolamide in acute decompensated heart failure with volume overload. N Engl J Med. 2022;387:1185. 27. Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol. 2007;102(4):1313–22.

Role of Analgesics in Noninvasive Ventilation

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Vincent E. DeRienzo and Brenton J LaRiccia

11.1 Introduction Opium poppy, known formally as Papaver somniferum L. (P. somniferum), has been grown and harvested since antiquity for its seeds and latex. The latex of the opium poppy contains many alkaloids of clinical relevance that have led to its use over the centuries in spiritual practice, for recreation, over the counter in tinctures, and finally as a controlled substance (in the United States) since 1970. Cultivation and production of opium is regulated by the United Nations Office on Drugs and Crime through a licensure program. One of the world’s largest legal producers of opium is Tasmania Alkaloids, located in Tasmania. The analgesic properties of opium were first honed in 1806 by Serturner who named the active ingredient morphine after Morpheus, the god of dreams in the Greek pantheon. Morphine would not be commonly used in the surgical world until later in the mid-nineteenth century when the hypodermic syringe and needle were invented. As with many novel medicines, morphine was found to have complications associated with its use including but not limited to the addictive potential of its parent substance, opium. These misgivings lead directly to the development of heroin at the end of the nineteenth century. At the time, it was vaunted as safer than morphine as well as having none of the addictive potential of its predecessor. The

V. E. DeRienzo PA-C, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, Rochester, New York, USA e-mail: [email protected] B. J. LaRiccia (*) Physician Assistant Executive Committee, UR Medicine, Strong Memorial Hospital, Adult Critical Care Services, Rochester, NY, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_11

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later claim would become a hallmark of all novel opioids that has yet to be proven true. Given the public health crisis associated with increased opiate use, the work of colleagues in the fields of medicinal chemistry and neuroscience has become vital in understanding the biochemical pathways that lead not only to the desired analgesic effects of opioids but also in mitigating the deleterious effects. This includes, but is not limited to, paradoxical hyperalgesia, tolerance, opioid-induced constipation, respiratory depression, and associated use disorders. Fundamental to this understanding is the composition of the endogenous opioid system, which comprises four seven-transmembrane G-protein-coupled receptors: mu (𝜇), delta (𝛿), kappa (𝜅), and nociception. Each receptor is encoded by a unique gene, but shares 60% of its amino acid composition. Each of the four receptors has a distinct pattern of expression throughout the nervous system. Separating these opioid receptors from other neuroreceptors is their ubiquity, being present in nearly all neural loci contributing to the perception of pain. Studies conducted with gene knockout therapy for mu receptors in mice confirm that this receptor, specifically, is vital in both the analgesic response to morphine and the deleterious effects discussed above. Included in the aforementioned endogenous opioid system are opioid ligands organized by family: the enkephalins, endorphins, and dynorphins. While more precise understanding of these ligands is an ongoing goal, they have been implicated as neurotransmitters, neurohormones, and neuromodulators [1, 2]. Morphine stands as the prototype and standard against which all other synthetic opioids are compared. Similarly, these morphine-like agonists work primarily as mu-receptor agonists. The inter-group variance relates largely to clinically relevant factors including analgesic potency, pharmacokinetics, and biotransformation. This group includes, but is not limited to, morphine, hydromorphone, methadone, levorphanol, oxymorphone, oxycodone, codeine, and fentanyl. The search for better tolerated analgesia leads to the development of mixed agonist-antagonists (e.g., nalbuphine, butorphanol) and partial agonists (e.g., buprenorphine) [2]. The novel drug program that led to the discovery of remifentanil set out to address a perceived need left by the precursor μ-opioid agonists alfentanil and sufentanil [3], namely, to develop an analgesic for use in surgical procedures that offered quicker onset and offset as well as circumventing the complications of accumulation due to impaired hepatic clearance. This novel drug program coincided with an anticipated increase in the volume in ambulatory surgeries in the United States and internationally, thus the need for a near-instantaneous analgesic with efficacy similar to that of fentanyl and predictable response by virtue of metabolism made for an interesting venture proposition. Interestingly, the chemical basis for this novel analgesic originated from a different class of drug entirely: a beta-blocker. Erhardt et  al. published in 1982 the description of an ultrashort-acting beta-blocker, esmolol [5]. In this publication, Erhardt’s group describes the replacement of an aryl ring on propranolol with a flexible methyl propionate chain. These two structures are hydrophobic and can be envisioned to occupy a lipid-lined, and thus lipophilic, position adjacent to the beta-­ adrenergic receptor. The key difference between the aryl ring of propranolol and the

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methyl propionate chain of esmolol is that the ester group on esmolol is susceptible to enzymatic hydrolysis by naturally occurring esterases in tissues and plasma. This enzymatic activity converts the target ester group into a carboxylic acid cognate. The result is the conversion of a hydrophobic side chain that binds nicely to the beta-adrenergic receptor into a hydrophilic side chain quickly repelled from that same receptor. This chemical equivalent of technologically planned obsolescence is known as the “soft drug” principle [6]. Inspired by this eloquent use of the “soft drug” principle, the novel drug discovery team would apply a similar strategy to what would become remifentanil. The first milestone achieved in this program was the creation of ultrashort-acting μ-opioid agonists by replacing the phenethyl group of the piperidine nitrogen of the fentanyl structure with an ester. Next came the challenge of developing a formulation more potent than the parent compound fentanyl and the successors that were on the market at the time: alfentanil and sufentanil. This achievement came by way of replacing the piperidine ring of fentanyl with that of carfentanil. Thus, a novel μ-opioid agonist that possessed a shorter half-life than its predecessors and did not suffer the sequelae of accumulation due to hepatic or renal impairment was ready to move to market.

11.2 Pharmacokinetics As discussed above, opioid analgesics work primarily on the mu (𝜇), delta (𝛿), kappa (𝜅), and nociception receptors to augment the sensation of pain. Their principal difference among this class of analgesics is their onset, duration of action, and plasma half-life (Table  11.1). These differences are clinically significant in the selection of drugs and dosing, which we will discuss below. Namely, as plasma and context-sensitive half-lives are extended, the risk of accumulation and resultant deleterious effects are increased. As discussed above, the desire of medical chemists to mitigate these effects led directly to the development of remifentanil. A small number of elegant chemical characteristics make remifentanil an important development in fast-on fast-off opioid analgesics with a more tolerable risk profile. The novel ester linkage on remifentanil allows for non-specific circulating and tissue esterases to hydrolyze remifentanil into several metabolites including its prime metabolite remifentanil acid, a carboxylic acid (Fig. 11.1). The most useful quality of this metabolite is that it is 800–2000 less potent than remifentanil itself [3]. The duration of infusion of remifentanil affects neither its functional half-time (3–5 min) nor its blood-brain barrier equilibration time (60–90 s) [7]. This makes for an analgesic infusion that is fast-on and fast-off. This quick onset and offset of action also applies to the side effects associated with the use of remifentanil, namely, respiratory depression, bradycardia, and muscle rigidity. Unfortunately, this benefit is encumbered by a loss of analgesic effect in the time immediately following cessation of the infusion. These side effects appear to have a dose-dependent effect, with bradycardia and hypotension being reported with bolus doses higher than 2  μg/kg−1 as well in

1.5

4

300

3000 300

Name Morphine

Oxycodone

Hydromorphone

Fentanyl

Sufentanil Remifentanil

1–3 (IV) 1–3 (IV)

1–2 (IV)

5–15 (IV)

10–15 (PO)

Onset (min) 6–30 (PO) 5–10 (IV)

5 3–10

30–60

180–360 (IR) > 12 h (XR) 180–220

Duration of actiona (min) 180–300

140–158 –

3.7

2–3

2–3

Plasma half-life (mins) 2–3.5

50 3–5

200 (6-h infusion) 300 (12-h infusion)

N/A

N/A

Contextsensitive half-life (min) N/A

3.5 3–10 min

3

2.5

3.2

Elimination half-life (hours) 3–4

No accumulation in renal and/ or hepatic impairment

Option for those patients with tolerance to fentanyl and/or morphine Accumulates with renal and/or hepatic impairment Less hemodynamically significant than morphine Accumulates easily with hepatic insult Tachyphylaxis with long-term infusions

Notes Accumulation with renal and/ or hepatic impairment Promotes histamine release

IR immediate release, XR extended release a All durations of actions are for IV formulations unless otherwise noted National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 41693. Retrieved May 1, 2022 from https://pubchem.ncbi.nlm. nih.gov/compound/Sufentanil

Morphine equivalency –

Table 11.1  Select opioid analgesics

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b

Fig. 11.1  Remifentanil (a) and remifentanil acid (b), the result of hydrolysis of remifentanil’s methyl ester by numerous, nonspecific esterases makes this far less potent mu-opioid agonist carboxylic acid metabolite [4]

hypovolemic patients receiving concurrent doses of vasodilator sedative medications such as propofol [7]. While clearance of remifentanil is unaffected by hepatic or renal function, increased sensitivity to opioid analgesia in patients with hepatic impairment may warrant dose reduction to avoid undesirable side effects [7]. In patients who receive intraoperative analgesia with μ-opioid agonists like remifentanil, the rapid offset time can precipitate opioid-induced hyperalgesia [8]. While this phenomenon is being explored in the surgical literature, there is a paucity of data to describe the occurrence in nonoperative patients receiving remifentanil infusions for a short period of time. There is some early work, with obvious limitations, that is beginning to explore the use of alpha-2 antagonists, like dexmedetomidine, as a pre-treatment prophylaxis for opioid-induced hyperalgesia.

11.3 Monitoring Clinical assessment of patients on NIPPV includes evaluation of dyspnea, respiratory muscle function, mental alertness, adequacy of ventilation, and comfort. Evaluation of objective variables including pulse oximetry and arterial blood gases are important to evaluate a patient’s response to therapy [9]. Respiratory depression, hypoxia, and somnolence are the most serious side effects of opioids to monitor, especially in patients with respiratory impairment requiring NIPPV [10]. Routine use of continuous telemetry monitoring of heart rate, blood pressure, pulse oximetry, and respiratory rate should be utilized to monitor for bradycardia, hypotension, and muscle rigidity [7].

11.4 Indications for Opiate Use in NIV Most physicians recently surveyed deny use of any analgesia in the management of NIPPV [11]. However, many patients who require NIPPV simultaneously require pain management with analgesics due to acute pain. Postoperative pain management and chest wall trauma or other traumatic injuries are the two most common

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scenarios in which patients who require NIPPV also require opioids [12]. Opioids can be administered to these patients enterally, parenterally, or neuro-axially. Gastric distention is a side effect of NIPPV, and enteral administration is often discouraged.

11.5 Post-Extubation NIV in the ICU In one small retrospective study, patients who received noninvasive ventilation after they were extubated due to interface intolerance were evaluated. In this study, the primary outcome was the rate of failure for noninvasive ventilation defined by reintubation after an extubation trial. Eighty patients placed on NIV after extubation were evaluated who subsequently developed interface intolerance defined by the patients themselves or study criteria. Seventeen of the 80 patients used analgesia (fentanyl or sufentanil), 11 used sedation (propofol or dexmedetomidine), and 13 used both analgesia and a form of sedation at some time during noninvasive ventilation. The study showed a decrease in the failure rate of noninvasive pressure ventilation 15% vs. 38% with a P value of 0.015. There were several limitations to the study including its retrospective nature and small sample size which did not allow for separate analysis of patients in analgesia only, sedation only, or a combination of sedation and analgesia groups. However, it appeared to indicate that in patients who are in a closely monitored environment such as the ICU, careful utilization of sedation and analgesia agents can improve interface intolerance in patients who are receiving noninvasive positive pressure ventilation after they have been extubated [13].

11.6 Use of Remifentanil in NIV In one prospective uncontrolled clinical investigation, 36 patients who developed hypoxic acute respiratory failure, placed on NIV and complained of discomfort requesting interruption of their therapy, were placed on remifentanil. In this study, 22 out of the 36 patients continued their noninvasive ventilation treatment after introduction of the remifentanil infusion. The remifentanil infusion rate used was between 0.025 μg/kg/min and a maximum of 0.12 μg/kg/min for patient comfort. In the success group, the respiratory rate decreased from 34 to 24 breaths/min with a P value of less than 0.0001, and the PaO2/FiO2 ratio increased from an average of 156 to 270 after an hour on remifentanil infusion (P value 40%) [1, 2]. Less than 5% of cases of acute heart failure require hypotension and inotropic therapy [3]. Systemic or pulmonary congestion usually associated with high ventricular diastolic pressure is seen in the clinical picture of most patients hospitalized for AHF. Pulmonary edema is one of the clinical manifestations of acute heart failure and is a medical emergency. The most basic mechanism of AHF pathophysiology is that gradual increases in intravascular volume lead to symptoms of congestion and clinical picture. A significant proportion of heart failure patients have abnormalities in diastolic function. Passive stiffness of the left ventricle, abnormal active relaxation, or both may be associated with disruption of the diastolic phase. Hypertension, tachycardia, and myocardial ischemia may further impair diastolic filling. All these mechanisms contribute to the increase in LV end-diastolic pressure and, accordingly, pulmonary capillary pressure. Diastolic dysfunction alone may be insufficient to cause AHF, but serves as a decompensating substrate in the presence of concomitant factors such as atrial fibrillation, coronary artery disease (CAD), or hypertension. The kidney regulates the loading conditions of the heart by controlling the intravascular volume and is responsible for neurohormonal outputs (renin-angiotensin-­ aldosterone system (RAAS)) and plays an important role in the pathophysiology of HF. Renal function abnormalities are extremely common in patients with AHF [4].

A. Ocal (*) Department of Internal Medicine, Health Sciences University Gulhane Training and Research, Hospital Cardiology Department, Ankara, Turkey © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_12

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Treatment strategies for AHF are largely empirical due to the lack of a thorough understanding of its epidemiology and pathophysiology, as well as the relatively blunt nature of available therapeutic tools. The current general approach is to optimize long-term treatments for successful treatment of clinical and hemodynamic impairment and to reduce undesirable effects on end-organ function. For this approach, the patient should be evaluated for blood pressure, volume status, and kidney function. Blood pressure is one of the most important prognostic indicators in AHF and reflects the interaction between vascular tone and myocardial pump function. Most patients present with high blood pressure and ultimately benefit from vasodilator therapy. Vasodilators can reduce preload by reversing venous vasoconstriction and related central volume redistribution from the peripheral and splanchnic venous systems, as well as reduce afterload by reducing arterial vasoconstriction, resulting in improved cardiac and renal function. Vasodilators are the primary therapy in AHF with pulmonary edema and in non-hypotensive patients with low cardiac output (SBPs above 85 to 100 mmHg). The kidney plays two main roles in the pathophysiology of HF. Renal function abnormalities are extremely common in patients with AHF, and initial chronic kidney disease is a serious risk factor for poor outcomes in AHF. Abnormalities in vascular tone due to disturbances in endothelial function related to nitric oxide-dependent regulation in heart failure are well described [5]. Arterial stiffness associated with blood pressure increases cardiac loading conditions and is associated with poor outcomes in heart failure. Peripheral arterial vasoconstriction increases LV filling pressures, postcapillary pulmonary venous pressures, and afterload, leading to worsening of pulmonary edema and dyspnea. Increased afterload results in cardiac arrhythmias associated with greater ventricular wall stress and increased myocardial ischemia. Abnormal vascular compliance predisposes to significant blood pressure liability with relatively small changes in intravascular volume, resulting in increases in afterload and ultimately LV filling pressures that result in pulmonary congestion. The effects of the vascular abnormality are enhanced by LV diastolic dysfunction. A coordinated and rapid approach to the management of acute heart failure is required, beginning in the outpatient setting, continuing during hospitalization, and extending to the outpatient setting after discharge. The priorities in the management of a patient presenting with AHF are: –– Stabilizing the clinical condition of the patient. –– Identifying the cause and accelerating triggers of the AHF episode. –– Initiation of treatments to provide symptomatic relief. The aim of heart failure treatment is to reduce morbidity and mortality. Treatment includes: • Non-pharmacological treatments: Oxygen and noninvasive positive pressure ventilation, dietary sodium, and fluid restriction.

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• Pharmacological treatments: Diuretics, vasodilators, inotropic agents, anticoagulants, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), digoxin, nitrates, type B natriuretic peptides, I(f) inhibitors, angiotensin receptor-­ neprilysin inhibitors (ARNIs), soluble guanylate cyclase inducers, sodium-­ glucose cotransporter-2 inhibitors (SGLT2Is), and mineralocorticoid receptor antagonists (MRAs). Oxygen administration and noninvasive positive pressure ventilation (NIPPV) provide respiratory support if oxygen saturation is below 90% to prevent intubation of patients. NIPPV has been shown to reduce the intubation rate [6–10]. Reducing the preload results in a reduction in pulmonary capillary hydrostatic pressure. Preload and afterload reduction provide symptomatic relief. Inhibition of the RAAS (renin-angiotensin-aldosterone system) and the sympathetic nervous system causes vasodilation. Vasodilation increases cardiac output and decreases myocardial oxygen demand. Inhibition of RAAS and neurohumoral factors also provides significant reductions in morbidity and mortality [11]. Diuretics are effective in reducing preload by increasing urinary sodium excretion and reducing fluid retention. A combination of three types of drugs (a diuretic, an ACEI or an ARB, and a beta-blocker) is recommended for the routine treatment of most patients with heart failure [12]. ACEIs/ARBs and beta-blockers are often used together.

12.1 Loop Diuretics Agents classified as loop diuretics include furosemide, bumetanide, and torsemide. First, loop diuretics reversibly bind to the Na+-K+-2Cl-cotransporter and reversibly inhibit its action, thereby preventing salt transport in the thick ascending loop of Henle. Loop diuretics also have effects on intracardiac pressure and systemic hemodynamics. Furosemide acts as a venodilator and reduces right atrial and pulmonary capillary wedge pressure in a short time when given intravenously (0.5 to 1.0 mg/kg). Diuretics remain the current standard of care and the mainstay of treatment for acute heart failure. First-line diuretic therapy is a loop diuretic at the lowest effective dose. Furosemide: Initial daily dose 20–40  mg once or twice, maximum daily dose 600 mg. Torsemide: Initial daily dose 10–20 mg once, maximum daily dose 200 mg. Bumetanide: Initial daily dose 0.5–1.0  mg once or twice, maximum daily dose 10 mg.

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12.2 Thiazide Diuretics If patients with heart failure do not respond to treatment with loop diuretics, a thiazide diuretic such as hydrochlorothiazide or metolazone may be added. Combined diuretic therapy should be closely monitored for the development of hypovolemia, hypokalemia, hypomagnesemia, and hyponatremia. Hydrochlorothiazide: Initial daily dose 25 mg once or twice, maximum daily dose 200 mg. Indapamide: Initial daily dose 2.5 mg once, maximum daily dose 5 mg. Chlortalidone: Initial daily dose 25 mg once, maximum daily dose 100 mg. Chlorothiazide: Initial daily dose 250–500 mg once or twice, maximum daily dose 1000 mg.

12.3 Mineralocorticoid Receptor Antagonists Mineralocorticoids (MRAs) such as aldosterone bind to MRA receptors, causing salt and water retention and increasing K+ and H+ excretion.

12.3.1 Spironolactone It competes with aldosterone for receptor sites in the distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. Spironolactone at a target dose of 25 mg has been shown to improve survival in patients with heart failure and reduced ejection fraction.

12.3.2 Eplerenone Eplerenone selectively blocks aldosterone at mineralocorticoid receptors in epithelial (e.g., kidney) and non-epithelial (e.g., heart, blood vessels, and brain) tissues, thereby reducing blood pressure and sodium reabsorption. Although first- and second-generation steroid-based MRAs have been shown to reduce HF mortality rates, the wider use of these agents in HF patients has been limited by significant adverse effects, the most prominent of which is hyperkalemia. Combining the potency and efficacy of spironolactone with the selectivity of eplerenone, a new potent and selective “third-generation” nonsteroidal MRA (finerenone) has entered clinical trials [12].

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12.4 Beta-Blockers Beta-blockers inhibit the sympathomimetic nervous system, resulting in moderate afterload reduction and mild preload reduction. Beta-blockers reduce mortality rates, hospitalizations, and the risk of sudden death and improve LV function and exercise tolerance.

12.4.1 Carvedilol Carvedilol is a nonselective beta- and alpha1-adrenergic blocker. • 3.125 mg PO every 12 h for 2 weeks and then increased to 6.25 mg, 12.5 mg, or 25 mg PO twice daily every 2 weeks as tolerated. • Maximum recommended dose: 25 mg PO twice daily.

12.4.2 Metoprolol Metoprolol is a selective beta1-adrenergic blocker at low doses. In higher doses, it inhibits beta2 receptors. • Initially 25 mg PO daily; increased every 2 weeks; target dose, 200 mg/day. • Customize the dose and monitor closely during the up-titration; biweekly double dose up to the highest tolerated dosage level or 200 mg.

12.4.3 Bisoprolol Bisoprolol is a highly selective beta1-adrenergic receptor blocker. 1.25 mg PO per day; increase gradually, if necessary, not to exceed 10 mg/day.

12.5 ACE Inhibitors Angiotensin-converting enzyme inhibitors (ACEIs) prevent the conversion of angiotensin I to angiotensin II. The use of ACEIs improves symptoms, improves survival, and reduces readmissions.

12.5.1 Enalapril Enalapril prevents the conversion of angiotensin I to the potent vasoconstrictor angiotensin II.  It increases plasma renin levels and causes decreased aldosterone secretion. It helps control blood pressure. It has a positive clinical effect when

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applied over a long period of time. Enalapril has been shown to improve survival at a target dose of 10 mg twice daily. Initial: 2.5 mg PO daily or 12 h. Maintenance: 5–40 mg/day PO divided every 12 h; titrate slowly every 2 weeks.

12.5.2 Captopril Captopril at a target dose of 25 mg three times daily has been shown to improve survival in patients with low ejection fraction after myocardial infarction.

12.5.3 Lisinopril 2.5  mg PO per day initially; 20–40  mg PO per day in increments of ≤10  mg at 2-week intervals.

12.5.4 Ramipril Initial dose: 2.5 mg PO q12hr; 5 mg PO can be titrated to q12hr; Maintenance: After 1  week, increase dose (if tolerated) to target dose of 5 mg q12hr.

12.6 ARBs Angiotensin receptor blockers (ARBs) are appropriate first-line therapy in patients with mild to moderate symptoms of heart failure and left ventricular (LV) dysfunction. ARBs block the renin-angiotensin-aldosterone system (RAAS) by competitive inhibition of the AT1 receptor. It reduces afterload and prevents LV remodeling. The use of ARBs improves survival and reduces hospitalization rates [13].

12.6.1 Valsartan At a target dose of 160 mg twice daily, valsartan has been shown to improve survival in patients with heart failure and reduced ejection fraction. It has been reported to reduce the risk of hospitalization in patients with heart failure (NYHA class II–IV). Initially 40 mg PO BID; may be titrated to 80–160 mg BID as tolerated. The maximum daily dose is 320 mg. Candesartan 4–8 mg PO qDay initially; may increase up to 32 mg/day. Losartan 50 mg PO qDay initially; may increase up to 100 mg/day.

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12.7 Inotropic Agents Inotropic agents such as milrinone, digoxin, dopamine, and dobutamine are used to increase the strength of heart contractions. Intravenous positive inotropic agents should only be used in inpatient settings and in patients presenting with signs and symptoms of low cardiac output syndrome.

12.7.1 Milrinone Milrinone is a type 3 phosphodiesterase inhibitor that increases inotropy, chronotropy, and lucitropy. Milrinone is a potent vasodilator (venous and arterial vasodilator). 50 μg/kg loading dose with IV push in 10  min, followed by 0.375–0.75 μg/ kg/min IV Maintenance: 1.13 mg/kg/day

12.7.2 Digoxin It is a cardiac glycoside with direct inotropic effects in addition to its indirect effects on the cardiovascular system. It increases myocardial systolic contractions by acting directly on the heart muscle. It is used to improve symptoms associated with HF. Although digoxin did not provide benefits in terms of survival, it did reduce the number of hospitalizations that occurred as a result of worsening heart failure. Dosage: 0.125 mg once a day, ≤0.375 mg/day (must be adjusted according to kidney function).

12.7.3 Dopamine Dopamine is a naturally occurring catecholamine that acts as a norepinephrine precursor. It stimulates both adrenergic and dopaminergic receptors. The hemodynamic effect is dose dependent. Low-dose use increases diuresis by causing dilatation of the renal and splanchnic vasculature results in increased diuresis. Moderate doses increase cardiac contractility and heart rate. Higher doses cause increased afterload through peripheral vasoconstriction. Usually used in severe heart failure. 1–5 μg/kg/min IV (low dose): May increase urine output and renal blood flow. 5–15 μg/kg/min IV (medium dose): May increase renal blood flow, cardiac output, heart rate, and cardiac contractility. 20–50 μg/kg/min IV (high dose): May increase blood pressure and stimulate vasoconstriction. Increase the infusion by 1–4 μg/kg/min at 10–30  min intervals until optimal response is achieved.

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12.7.4 Dobutamine Dobutamine, a beta-receptor agonist, increases inotropy and chronotropy and reduces afterload, thereby improving end-organ perfusion. It produces vasodilation and increases the inotropic state. Higher doses can cause an increased heart rate. Careful hemodynamic monitoring is required. Initially 0.5–1 μg/kg/min IV continuous infusion followed by 2–20 μg/kg/min; not to exceed 40 μg/kg/min.

12.8 Vasodilators Vasodilators are recommended for symptom relief in patients with acute heart failure without hypotension. Vasodilators reduce preload and/or afterload as well as reduce systemic vascular resistance (SVR).

12.8.1 Nitroprusside Sodium Nitroprusside sodium is a potent balanced arterial and venous vasodilator and very effectively reduces intracardiac filling pressures. It requires careful hemodynamic monitoring using indwelling catheters and monitoring for cyanide toxicity, especially in the presence of renal dysfunction. Because of the potential for rebound, the drug should be titrated until discontinued rather than abruptly. Initial infusion rate: 0.3 μg/kg/min; evaluate BP for at least 5  min before titration to higher or lower dose. Not to exceed 10 μg/kg/min.

12.8.2 Hydralazine It reduces systemic resistance through direct vasodilation of arterioles. A combination of hydralazine and nitrate reduces preload and afterload. Initial dose: 10–25 mg PO 6–8 h; titrate dose every 2–4 weeks. Maintenance dose: 225–300 mg/day PO divided every 6–8 h.

12.9 Nitrates (Nitroglycerin, Isosorbide Dinitrate, Isosorbide Dinitrate and Hydralazine, Isosorbide Mononitrate) Nitrates contribute to the improvement of hemodynamics by reducing left ventricular filling pressure and systemic vascular resistance, providing a slight improvement in cardiac output in heart failure. Nitroglycerin is a first-line therapy for non-hypotensive patients. Provides excellent and reliable preload reduction. Higher doses provide slight afterload reduction. It produces vasodilation and increases the inotropic activity of the heart. The starting dose of nitroglycerin is usually 20  μg/min, with rapid up-titration every 5 to

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15 min in increments of 20 μg/min or doubling the dose. The nitrate dose may need to be reduced if the SBP is 90 to 100 mmHg and usually needs to be discontinued when the SBP is below 90 mmHg. Isosorbide dinitrate relaxes vascular smooth muscle by stimulating intracellular cyclic GMP.  It reduces left ventricular pressure (preload) and arterial resistance (afterload). It reduces cardiac oxygen demand by lowering left ventricular pressure and widening the arteries. Isosorbide mononitrate arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, mean arterial pressure (afterload), left ventricular end-diastolic pressure, and pulmonary capillary wedge pressure (preload).

12.10 B-Type Natriuretic Peptides (Nesiritide) Human B-type natriuretic peptides (hBNPs), such as nesiritide, reduce PCWP and improve dyspnea in patients with acute decompensated heart failure. 2 μg/kg IV bolus in 1 min, 0.01 μg/kg/min IV infusion.

12.11 I(f) Channel Inhibitors (Ivabradine) The I(f) inhibitor ivabradine is used to lower heart rate and has been shown to reduce the risk of hospitalization. Ivabradine regulates heart rate without any effect on myocardial contractility. It has been shown to reduce the risk of hospitalization due to worsening heart failure in patients with symptomatic chronic heart failure, LVEF ≤35%, in sinus rhythm, and a resting heart rate ≥ 70 bpm despite using beta-blockers [13]. Dosage: 5 mg twice daily, 7.5 mg twice daily.

12.12 Angiotensin Receptor-Neprilysin Inhibitors (ARNi) (Sacubitril/Valsartan) Angiotensin receptor-neprilysin inhibitor (ARNI) combinations have been shown to significantly reduce cardiovascular deaths and hospitalizations in patients with chronic heart failure. It is a molecule that combines valsartan (an AT1 receptor antagonist) and sacubitril (a neprilysin inhibitor) in a mixture. A combination of ARNI slows the degradation of natriuretic peptides, bradykinin and adrenomedullin. Thus, it inhibits renin and aldosterone secretion while increasing diuresis, natriuresis, and myocardial relaxation. By selectively blocking the AT1 receptor, it reduces vasoconstriction, sodium and water retention, and myocardial hypertrophy. Fixed-dose sacubitril/valsartan use, mild to moderate HF (NYHA class II to IV; NYHA class II to IV; NYHA class II) to IV; LVEF ≤35% [14]. Initial dose 24 mg/26 mg twice daily, effective dose 97 mg/103 mg twice daily.

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12.13 SGLT2 Inhibitors (Empagliflozin, Dapagliflozin) Empagliflozin and dapagliflozin are inhibitors of the sodium-glucose co-transporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. It decreases sodium reabsorption and increases sodium delivery to the distal tubule. It can affect physiological functions such as reducing afterload and decreasing sympathetic activity. 10 mg PO per day.

12.14 Soluble Guanylate Cyclase Stimulants (Vericiguat) Impaired nitric oxide (NO) synthesis and decreased soluble guanylate cyclase (sGC) activity in heart failure may contribute to myocardial and vascular dysfunction. Vericiguat increases intracellular cyclic guanosine monophosphate (cGMP) levels, leading to smooth muscle relaxation and vasodilation. Indicated to reduce the risk of hospitalization for heart failure (HF) in patients with symptomatic chronic HF and ejection fraction 1. In comparison, β-lactams, aminoglycosides and glycopeptides have ELF to plasma concentration ratios of ≤1 [35, 36]. This different behaviour in the lung is consistent with their hydrophilic or lipophilic characteristics, since lipophilic compounds achieve higher levels in epithelial lining fluid, compared with hydrophilic agents [1].

16.4 Clinical Results As previously described, antibiotics and NIV are frequently used concomitantly for respiratory infections. There are several guidelines giving recommendations for community- and hospital-acquired pneumonia [37–40] based on the available evidence. In this section, it will be discussed the most common indications for antibiotics during NIV, specifically COPD exacerbation, immunocompromised patients and cystic fibrosis pulmonary exacerbations. Table 16.2 lists the major microorganisms that can potentially be implicated in infection of these patients and provides examples of active antibiotics against them. Table 16.3 summarizes the usual dosage regimens for the most commonly used antibiotics. Conversely, the massive consumption of antibiotics is leading to the emergence of multidrugresistant (MDR) bacteria that are spreading globally, such as extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, MDR Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii, carbapenemase-producing Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus

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Table 16.2 Microorganisms potentially implicated in pulmonary infections during NIV [7, 40–43] Microorganism Gram negative   Haemophilus influenzae   Moraxella catarrhalis

  Klebsiella pneumoniaea   Klebsiella aerogenes   Escherichia coli, Serratia marcescens, Proteus sp., Providencia sp., Citrobacter sp.   Enterobacter sp.a   Pseudomonas aeruginosaab   Acinetobacter baumanniiab   Stenotrophomonas maltophiliab   Burkholderia cepaciab Gram positive   Streptococcus pneumoniae   Staphylococcus aureusa

Atypical bacteria   Chlamydophila pneumoniae   Mycoplasma pneumoniae

Preferred antibiotics (without resistance factors) Amoxicillin-clavulanic acid, cefotaxime, ceftriaxone, azithromycin, levofloxacin, moxifloxacin Amoxicillin-clavulanic acid, cefuroxime, cefotaxime, ceftriaxone, sulfamethoxazole-trimethoprim, azithromycin, clarithromycin, levofloxacin, moxifloxacin Ceftriaxone, cefotaxime, ciprofloxacin Cefepime Ceftriaxone, cefotaxime, ceftazidime, Cefepime, piperacillin/tazobactam, ciprofloxacin, levofloxacin, moxifloxacin, gentamicin, amikacin Piperacillin/tazobactam, meropenem, imipenem, cefepime, ciprofloxacin, levofloxacin Piperacillin/tazobactam, ceftazidime, cefepime, ciprofloxacin, levofloxacin, amikacin Ampicillin-sulbactam, ceftazidime, cefepime, meropenem, imipenem, amikacin Sulfamethoxazole-trimethoprim, levofloxacin Sulfamethoxazole-trimethoprim, levofloxacin, meropenem Amoxicillin-clavulanic acid, cefuroxime, cefotaxime, levofloxacin, moxifloxacin Methicillin-sensitive: flucloxacillin, cefazolin, amoxicillin-clavulanic acid Methicillin-resistant: vancomycin, linezolid, sulfamethoxazole- trimethoprim Doxycycline, azithromycin, levofloxacin, moxifloxacin Doxycycline, azithromycin

 ESKAPE pathogens—group characterized by multidrug resistance and virulence  Non-Fermenting Gram-Negative Bacilli (NFGNB)—group characterized by multidrug-resistant pattern, inherent resistance to many antibiotics and biofilm-forming ability a

b

(MRSA) and vancomycin-resistant Enterococci (VRE) [2]. Identifying risk factors for MDR bacterial infection to guide empirical therapy before the availability of pathogen identification and antimicrobial susceptibility testing (AST) can be a challenge.

16.4.1 COPD Exacerbations The presence of potentially pathogenic microorganisms (PPM) in the lower respiratory tract of patients with COPD is traditionally termed as “bronchial colonization”,

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Table 16.3  Usual dosage regimens for the most common used antibiotics in patients with pulmonary infections during NIV with normal renal function [37, 39] Antibiotic Amoxicillin-clavulanic acid Ampicillin-sulbactam Flucloxacillin Cefuroxime Ceftriaxone Cefotaxime Ceftazidime Cefepime Piperacillin-tazobactam Clarithromycin Azithromycin Ciprofloxacin Levofloxacin Moxifloxacin Doxycycline Imipenem Meropenem Vancomycin Amikacin Gentamicin Tobramycin Linezolid Colistin Sulfamethoxazole- trimethoprim

Usual dosage regimen 1.2 g q8h 1.5 g q6h 1 g q6h 1.5 g q8h 2 g q24h 1 g q8h 2 g q8h 2 g q8h 4.5 g q6h 500 mg q12h 500 mg q24h 400 mg q8h 750 mg q24h 400 mg q24h 100 mg q12h 500 mg q6h 1 g q8h 15 mg/kg q12h 15–20 mg/kg q24h 5–7 mg/kg q24h 5–7 mg/kg/day q24h 600 mg q12h Loading dose 5 mg/kg followed by 2.5 Mg × (1.5 × CrCl +30) q12h 960 mg q12h

CrCl creatinine clearance

but others prefer to use the term “chronic bronchial infection”, although these microorganisms are only present over the mucous layer and do not normally invade the tissues [41]. The group of PPM includes, among others, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae or Pseudomonas aeruginosa. Chronic bronchial infection is a risk factor for more frequent and severe exacerbations and an accelerated progression of the disease. This clinical situation has been associated with the presence of bronchiectasis, but its presence is not necessary [41]. Altered lung microbiological defence mechanisms and frequent exposure of such patients to antibiotics may predispose patients to respiratory tract colonization with MDR bacteria [44]. In patients with exacerbations requiring NIV, cultures from sputum or other materials from the lung should be performed [3]. Mycoplasma pneumoniae and Chlamydia sp. are intracellular bacteria that have also been implicated in exacerbations of COPD [7]. During COPD exacerbations caused by respiratory infection, early adequate antimicrobial therapy is associated with improved outcome and should be based on international guidelines and local bacterial resistance pattern [3]. Usually, initial

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empiric treatment is amoxicillin with clavulanic acid, macrolide or doxycycline. The identification of risk factors for MDR bacteria [37, 40], including recent administration of antibiotics (last 3 months), recent hospitalization, prior respiratory isolation of Pseudomonas aeruginosa/MRSA infection or colonization, severe disease (FEV1  10  mg of prednisolone daily in the last 2 weeks), indicates the use of extended-spectrum antibiotics. During severe COPD exacerbations, which include patients requiring NIV, intravenous antibiotics may be the first choice.

16.4.2 Immunocompromised Patients Immunocompromised patients are susceptible to infection with the same respiratory viruses and bacteria that cause pneumonia in nonimmunocompromised patients, but beyond the core respiratory pathogens, there are many others that differ for different types of immunocompromising conditions [45]. International consensus guidelines, published in 2020 [45], recommend that immunocompromised patients without any additional risk factors for drug-resistant bacteria can receive initial empirical therapy targeting only the core respiratory pathogens (Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Enterobacteriaceae, atypical bacteria). They suggest extending empirical therapy when [1] risk factors for drug-resistant organisms or opportunistic pathogens are present and [2] the delay in empirical antimicrobial therapy will place the patient at increased risk of mortality. This includes covering resistant Gram-positive organisms (e.g. MRSA) and resistant Gram-negative organisms (e.g. Pseudomonas aeruginosa).

16.4.3 Cystic Fibrosis Pulmonary Exacerbations Microorganisms identified in the respiratory tract of patients with cystic fibrosis vary among different age groups [43]. In younger children, Staphylococcus aureus is the most commonly found pathogen. In older children and adults, the most prevalent pathogens are Pseudomonas aeruginosa, Achromobacter spp., Stenotrophomonas maltophilia and species of the Burkholderia cepacia complex (Bcc). Methicillin-­resistant S. aureus (MRSA) infections are more common in young adults than in children [43]. The most common pathogen identified in airway cultures of cystic fibrosis patients is Pseudomonas aeruginosa. For this reason, initial antibiotic choices for treatment of an acute exacerbation should include drugs with antipseudomonal activity [14]. The standard of care has been to use combination antibiotics. Chronic infection with Pseudomonas aeruginosa has been associated with poorer outcomes, such as accelerated lung function decline and earlier mortality [43]. In an attempt to eradicate the organism and avoid these outcomes, initial infections are usually aggressively treated.

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Inhaled and intravenous antibiotics are frequently used concomitantly in treatment of an exacerbation, which could improve drug exposure but also systemic toxicity. Guidelines from the Cystic Fibrosis Foundation suggest that the decision to continue an inhaled antibiotic in conjunction with the same intravenous antibiotic should be determined on a case-by-case basis [14]. Aminoglycosides and β-lactams are commonly used for treating cystic fibrosis pulmonary exacerbations. In severe exacerbations, a combination of an antipseudomonal β-lactam (piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem) with an aminoglycoside (usually tobramycin) or a fluoroquinolone is usually recommended [46]. Colistimethate sodium has also shown efficacy when administered intravenously. New antibiotics, such as ceftazidime-avibactam, ceftolozane-tazobactam and cefiderocol, can be used as alternatives in the case of resistance. There are no recommendations on optimal duration of antibiotic treatment [14], but these are frequently between 10 and 21 days. In a recent RCT, for patients showing early treatment improvement during exacerbation, 10 days of intravenous antimicrobials was not inferior to 14 days. Patients with less improvement after 1 week, 21 days was not superior to 14 days [47].

16.5 Conclusion Antibiotics and NIV are frequently used concomitantly for COPD exacerbations, immunocompromised patients or cystic fibrosis. There are many different classes of antibiotics with different spectrum of activity and PK/PD indices, and this knowledge must be correctly applied for choosing optimal antibiotic therapy for each clinical situation, thus improving clinical outcomes while reducing the emergency of multidrug-resistant bacteria.

References 1. Rello J, Mallol J. Optimal therapy for methicillin-resistant Staphylococcus aureus pneumonia: what is the best dosing regimen? Chest. 2006;130(4):938–40. 2. Timsit JF, Bassetti M, Cremer O, Daikos G, de Waele J, Kallil A, et al. Rationalizing antimicrobial therapy in the ICU: a narrative review. Intensive Care Med. 2019;45(2):172–89. 3. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2022 Report. https:// goldcopd.org/wp-­content/uploads/2021/11/GOLD-­REPORT-­2022-­v1.0-­12Nov2021_WMV. pdf2022. 4. MacLeod M, Papi A, Contoli M, Beghé B, Celli BR, Wedzicha JA, et al. Chronic obstructive pulmonary disease exacerbation fundamentals: diagnosis, treatment, prevention and disease impact. Respirology. 2021;26(6):532–51. 5. Wedzicha JA, Miravitlles M, Hurst JR, Calverley PM, Albert RK, Anzueto A, et al. Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;49(3):1600791.

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6. Ouanes I, Ouanes-Besbes L, Ben Abdallah S, Dachraoui F, Abroug F. Trends in use and impact on outcome of empiric antibiotic therapy and non-invasive ventilation in COPD patients with acute exacerbation. Ann Intensive Care. 2015;5(1):30. 7. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359(22):2355–65. 8. López-Campos JL, Hartl S, Pozo-Rodriguez F, Roberts CM, team ECA.  Antibiotic prescription for COPD exacerbations admitted to hospital: European COPD audit. PLoS One. 2015;10(4):e0124374. 9. Vollenweider DJ, Frei A, Steurer-Stey CA, Garcia-Aymerich J, Puhan MA.  Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2018;10:CD010257. 10. Rochwerg B, Brochard L, Elliott MW, Hess D, Hill NS, Nava S, et  al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J. 2017;50(2):1602426. 11. Wang T, Zhang L, Luo K, He J, Ma Y, Li Z, et al. Noninvasive versus invasive mechanical ventilation for immunocompromised patients with acute respiratory failure: a systematic review and meta-analysis. BMC Pulm Med. 2016;16(1):129. 12. Razlaf P, Pabst D, Mohr M, Kessler T, Wiewrodt R, Stelljes M, et al. Non-invasive ventilation in immunosuppressed patients with pneumonia and extrapulmonary sepsis. Respir Med. 2012;106(11):1509–16. 13. Bello G, De Pascale G, Antonelli M.  Noninvasive ventilation for the immunocompromised patient: always appropriate? Curr Opin Crit Care. 2012;18(1):54–60. 14. Flume PA, Mogayzel PJ, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, et  al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180(9):802–8. 15. Newton TJ.  Respiratory care of the hospitalized patient with cystic fibrosis. Respir Care. 2009;54(6):769–75; discussion 75–6. 16. Spoletini G, Pollard K, Watson R, Darby MJ, Johnstone A, Etherington C, et al. Noninvasive ventilation in cystic fibrosis: clinical indications and outcomes in a large UK adult cystic fibrosis center. Respir Care. 2021;66(3):466–74. 17. Smith S, Rowbotham NJ, Charbek E. Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis. Cochrane Database Syst Rev. 2018;10:CD008319. 18. Cutuli SL, Grieco DL, Menga LS, De Pascale G, Antonelli M. Noninvasive ventilation and high-flow oxygen therapy for severe community-acquired pneumonia. Curr Opin Infect Dis. 2021;34(2):142–50. 19. de Miguel-Díez J, Jiménez-García R, Hernández-Barrera V, Puente-Maestu L, Ji Z, de Miguel-­ Yanes JM, et al. Ventilatory support use in hospitalized patients with community-acquired pneumonia. Fifteen-year trends in Spain (2001-2015). Arch Bronconeumol. 2020;56(12):792–800. 20. Ruzsics I, Matrai P, Hegyi P, Nemeth D, Tenk J, Csenkey A, et  al. Noninvasive ventilation improves the outcome in patients with pneumonia-associated respiratory failure: systematic review and meta-analysis. J Infect Public Health. 2022;15(3):349–59. 21. Zhang Z, Duan J. Nosocomial pneumonia in non-invasive ventilation patients: incidence, characteristics, and outcomes. J Hosp Infect. 2015;91(2):153–7. 22. Kohlenberg A, Schwab F, Behnke M, Geffers C, Gastmeier P. Pneumonia associated with invasive and noninvasive ventilation: an analysis of the German nosocomial infection surveillance system database. Intensive Care Med. 2010;36(6):971–8. 23. Carron M, Freo U, BaHammam AS, Dellweg D, Guarracino F, Cosentini R, et al. Complications of non-invasive ventilation techniques: a comprehensive qualitative review of randomized trials. Br J Anaesth. 2013;110(6):896–914. 24. Gay PC.  Complications of noninvasive ventilation in acute care. Respir Care. 2009;54(2):246–57; discussion 57–8. 25. Park S, Suh ES.  Home mechanical ventilation: back to basics. Acute Crit Care. 2020;35(3):131–41.

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26. Toussaint M, Reychler G. Maintenance protocol for home ventilation circuits. In: Esquinas AM, editor. Noninvasive mechanical ventilation—theory, equipment and clinical applications. Cham: Springer; 2010. p. 51–8. 27. Rehder KJ.  Adjunct therapies for refractory status asthmaticus in children. Respir Care. 2017;62(6):849–65. 28. Althoff MD, Holguin F, Yang F, Grunwald GK, Moss M, Vandivier RW, et al. Noninvasive ventilation use in critically ill patients with acute asthma exacerbations. Am J Respir Crit Care Med. 2020;202(11):1520–30. 29. Gumbo T.  Chapter 52: general principles of antimicrobial therapy. In: Brunton LL, Hilal-­ Dandan R, Knollmann BC, editors. Goodman & Gilman’s: the pharmacological basis of therapeutics. 13th ed. New York, NY: McGraw-Hill Education; 2017. 30. Patel K, Kirkpatrick CM. Chapter 1—basic pharmacokinetic principles. In: Udy AA, Roberts JA, Lipman J, editors. Antibiotic pharmacokinetic/pharmacodynamic considerations in the critically Ill Adis; 2018. p. 1–16. 31. Al-Tawfiq JA, Momattin H, Al-Ali AY, Eljaaly K, Tirupathi R, Haradwala MB, et al. Antibiotics in the pipeline: a literature review (2017-2020). Infection. 2022;50(3):553–64. 32. De Waele JJ, Schouten J, Beovic B, Tabah A, Leone M. Antimicrobial de-escalation as part of antimicrobial stewardship in intensive care: no simple answers to simple questions-a viewpoint of experts. Intensive Care Med. 2020;46(2):236–44. 33. Cotta MO, Roberts JA, Lipman J. Antibiotic dose optimization in critically ill patients. Med Intensiva. 2015;39(9):563–72. 34. Asín-Prieto E, Rodríguez-Gascón A, Isla A. Applications of the pharmacokinetic/pharmacodynamic (PK/PD) analysis of antimicrobial agents. J Infect Chemother. 2015;21(5):319–29. 35. Rodvold KA, George JM, Yoo L. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents. Clin Pharmacokinet. 2011;50(10):637–64. 36. Drwiega EN, Rodvold KA. Penetration of antibacterial agents into pulmonary epithelial lining fluid: an update. Clin Pharmacokinet. 2022;61(1):17–46. 37. Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45–67. 38. Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H, et  al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-­ acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J. 2017;50(3):1700582. 39. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et  al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61–e111. 40. Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M, et al. Guidelines for the management of adult lower respiratory tract infections—summary. Clin Microbiol Infect. 2011;17(Suppl 6):1–24. 41. Lopez-Campos JL, Miravitlles M, de la Rosa CD, Cantón R, Soler-Cataluña JJ, Martinez-­ Garcia MA. Current challenges in chronic bronchial infection in patients with chronic obstructive pulmonary disease. J Clin Med. 2020;9(6):1639. 42. Soler-Cataluña JJ, Piñera P, Trigueros JA, Calle M, Casanova C, Cosío BG, et  al. Spanish COPD guidelines (GesEPOC) 2021 update diagnosis and treatment of COPD exacerbation syndrome. Arch Bronconeumol. 2022;58(2):159–70. 43. Blanchard AC, Waters VJ. Microbiology of cystic fibrosis airway disease. Semin Respir Crit Care Med. 2019;40(6):727–36.

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44. Ling L, Wong WT, Lipman J, Joynt GM. A narrative review on the approach to antimicrobial use in ventilated patients with multidrug resistant organisms in respiratory samples-to treat or not to treat? That is the question. Antibiotics (Basel). 2022;11(4) 45. Ramirez JA, Musher DM, Evans SE, Dela Cruz C, Crothers KA, Hage CA, et al. Treatment of community-acquired pneumonia in immunocompromised adults: a consensus statement regarding initial strategies. Chest. 2020;158(5):1896–911. 46. Girón Moreno RM, García-Clemente M, Diab-Cáceres L, Martínez-Vergara A, Martínez-­ García MÁ, Gómez-Punter RM. Treatment of pulmonary disease of cystic fibrosis: a comprehensive review. Antibiotics. 2021;10:10. 47. Goss CH, Heltshe SL, West NE, Skalland M, Sanders DB, Jain R, et al. A randomized clinical trial of antimicrobial duration for cystic fibrosis pulmonary exacerbation treatment. Am J Respir Crit Care Med. 2021;204(11):1295–305.

Sleep Breathing Disorders: Basic Pharmacology, Classification, and Clinical Trial Drugs

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João Portela and Júlia Silva

17.1 Introduction Diagnostic classification of sleep disorders is important because it improves awareness of the conditions, provides broad differential diagnosis, and facilitates a systematic diagnostic approach. These include seven major categories: insomnia, sleep-related breathing disorders, parasomnias, sleep-related movement disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, and other sleep disorders. Sleep-Related Breathing Disorders are characterized by abnormal respiration during sleep that can occur in both adults and children. They can be divided in four groups: Obstructive Sleep Apneas (OSAs), Central Sleep Apnea (CSA) syndromes, sleep-related hypoventilation disorders, and sleep-related hypoxemia disorder, according to the third edition of the International Classification of Sleep Disorders (ICSD) revised by the American Academy of Sleep Medicine (AASM) [1].

17.2 Obstructive Sleep Apnea (OSAs) Obstructive Sleep Apnea is the most common sleep-related breathing disorder. It predominantly affects middle-aged and elderly males and frequently goes undiagnosed and under-treated [2, 3]. It is characterized by obstructive apneas, hypopneas, and/or respiratory effort-related arousals caused by repetitive collapse of the upper airway during sleep. In the adult, to make an OSA diagnosis we need symptoms (daytime sleepiness, morning headaches, insomnia, nocturia, partner-reported snoring, gasping, choking, J. Portela · J. Silva (*) Pneumology Department, Hospital Garcia de Orta Almada Portugal, Almada, Portugal © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_17

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or interruptions in breathing while sleeping), signs (obesity, large neck/waist circumference, oropharyngeal airway narrowed), or associated medical disorder (cardiovascular risk factors such as diabetes, dyslipidemia or hypertension, or even medical history of heart failure, atrial fibrillation) and a polysomnography (PSG) that documents ≥5 obstructive respiratory events per hour of sleep. Alternatively, a frequency of ≥15 obstructive respiratory events per hour of sleep satisfies the criteria, even in the absence of associated symptoms or disorders [1]. In the pediatric population, to make the diagnosis one of the following signs/ symptoms has to be present: snoring, obstructed breathing, or daytime consequences (hyperactivity, sleepiness) and the PSG criterion requires either one or more obstructive events per hour of sleep or obstructive hypoventilation, manifested by PaCO2 >50 mmHg for >25% of sleep time coupled with snoring, flattening of nasal airway pressure waveform, or paradoxical movements of thoracoabdominal muscles [1].

17.2.1 Treatment Options for OSA Although it seems harmless, if untreated the OSA can increase the risk of stroke, hypertension, atrial fibrillation, myocardial infarction, and even pulmonary hypertension. This is due to multifactorial factors such as endothelial dysfunction, hyperactive sympathetic dysfunction, or systemic inflammation [4]. Therefore, the goals of OSA therapy are to resolve signs and symptoms, improve sleep quality, and normalize the apnea-hypopnea index, resulting in reduced healthcare utilization and costs, decreased cardiovascular morbidity and mortality, and improved overall quality of life [5]. The first step in the treatment is to educate the patient and review the results and severity of the OSA. The patient should know the risk factors, natural history, consequences of OSA, and the risk of motor vehicle crashes associated with untreated OSA. Then, a good sleep hygiene should be promoted (sleep in a quiet, dark bedroom with comfortable temperature, and without electronic devices such as smart phones, TVs, or tablets), avoiding caffeine and alcohol before bedtime [6]. Weight loss and exercise should be recommended to all patients who are overweight or obese, because it can reduce the apnea-hypopnea index (AHI) and improve overall health and metabolic parameters (i.e., reduce blood pressure) [7].

17.2.2 Positional Therapy Some patients will have OSA that develops or worsens during sleep in supine position, which can be corrected or improved if the patient sleeps in a non-supine position. There are several commercial devices that use vibratory feedback around the chest or neck to restrict supine sleep, or even sewing a tennis ball into a patch on the back of a t-shirt can help prevent the supine position (Fig. 17.1). However, these should not be used as a primary therapy unless normalization of the AHI has been confirmed by a PSG and adherence can be verified [8].

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Fig. 17.1  Use of tennis ball as a positional therapy. (Source: Bignold et al. [35])

The use of concomitant medications that inhibit the central nervous system should be avoided in untreated patients (i.e., benzodiazepines, barbituric, antihistamines, and opiates), since they can exacerbate OSA and theoretically worsen daytime sleepiness.

17.2.3 Positive Airway Pressure Therapy The use of Positive Airway Pressure (PAP) therapy is the gold standard in adults with OSA, since it stabilizes the upper airway through increased end-expiratory lung volume preventing respiratory events due to upper airway collapse, and maintains a positive pharyngeal transmural pressure so that the intraluminal pressure exceeds the surrounding pressure [9]. There are multiple randomized trials and meta-analysis showing that PAP therapy reduces the AHI, decreases the risk of crashes and daytime sleepiness, and improves systemic blood pressure and quality of life [10]. The most common modes of PAP include Continuous Positive Airway Pressure (CPAP), Auto-titrating CPAP (APAP), and Bilevel PAP (BiPAP). Even though many clinicians prefer CPAP as initial therapy, APAP is being used more in suitable candidates. Some patients who decline or fail to adhere to PAP therapy can choose oral appliances (such as mandibular advancement devices) since they hold the soft tissues of the oropharynx away from the posterior pharyngeal wall, thereby maintaining upper airway patency. If the oral appliance is ineffective, patients can undergo upper airway surgery such as tonsillectomy or adenoidectomy [11].

17.2.4 Alternative Pharmacological Therapy There are alternative pharmacological therapies that can help reduce the severity of OSA, which are divided in four groups, according to their underlying mechanism: upper airway anatomic occlusion or impaired anatomy; high loop gain; improving pharyngeal dilator function; low respiratory arousal threshold [12, 13].

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17.2.4.1 Upper Airway Anatomic Occlusion or Impaired Anatomy The use of weight loss drugs, such as liraglutide (1.5–3.0  mg/day), orlistat (60–120 mg tid), and phentermine (15 mg/daily)/topiramate ER (92 mg/daily), has been studied evaluating weight loss in those with OSA [14–16]. However, even though they seem to be beneficial, further studies are needed to corroborate this hypothesis. The use of nasal decongestions may improve symptoms of OSA because another mechanism many have hypothesized in OSA is nasal obstruction. Therefore, a randomized clinical trial correlates the use of Oxymetazoline 0.05% applied as 0.4 mL in each nostril (sympathomimetic vasoconstrictor), with a reduction in OSA severity and improvement in oxygen saturation in patients with chronic nasal obstruction [17]. There is another study that shows that the use of phenylephrine (5% nasal spray, 0.5 mL in each nostril) can reduce the nasal resistance, even though it had no significant effect on the severity of OSA [18]. 17.2.4.2 High Loop Gain The loop gain is the input-output function of the feedback loop controlling ventilation, which determines the magnitude and time course of the ventilatory response that follows a ventilatory disturbance. A high loop gain signifies the unbalanced response to minor changes in PaCO2, leading to hyperventilation mixed with hypoventilation. Therefore, patients with high loop gain and collapsible upper airway experience negative inspiratory pressures that force the airway closed [19]. The use of carbonic anhydrase inhibitors can decrease the PaCO2 since it works by preventing the breakdown of carbonic acid, making the carbonic acid accumulate in the body reducing the blood pH and resulting in a brief metabolic acidosis and possible hyperventilation. There is a clinical trial that studies the use of Acetazolamide (250 mg QID) in patients with moderate-to-severe OSA, resulting in a metabolic acidosis with reduction of PaCO2 and 52% reduction in AHI compared to placebo. Even though the results seem promising, the sleep arousals per hour and the previous symptoms mentioned have not been changed [20]. 17.2.4.3 Improving Pharyngeal Dilator Function During REM sleep, the excitatory effect of serotonin on 5-HT receptor of the upper airway motor neurons and respiratory neurons is reduced, causing upper airway collapse in patients with OSA. Therefore, several studies were conducted to assess the possibility of serotonin reuptake inhibitors (SRIs) being an alternative therapy in OSA [21]. The use of SRIs such as Paroxetine and Fluoxetine did not show a change in AHI, despite an increase in genioglossus activity and muscle responsiveness. The trial using buspirone in patients with OSA showed a 36% reduction in AHI and improvement in sleep quality and total sleep time; however it only had a sample size of five patients [12]. 17.2.4.4 Low Respiratory Arousal Threshold Patients with OSA often experience sudden awakenings from sleep, because they have a low respiratory arousal threshold leading to sleep fragmentation and daily

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fatigue. There are studies trying to correlate the use of sedatives with the intent of increasing arousal threshold, while maintaining appropriate upper airway muscle activity, to reduce OSA severity. In conclusion, the use of most benzodiazepines can worsen symptoms even though there are studies that show some efficacy of Temazepam, Triazolam, and Nitrazepam. The use of Z-drugs is a good option (such as Zolpidem 10 mg) since they do not produce myorelaxant effects and are associated with fewer adverse side effects, increasing the arousal threshold without inhibiting upper airway muscle response, even though it did not reduce AHI or change OSA severity. The same applies to Trazodone 100 mg, a tricyclic antidepressant that has sedative effects by blocking muscarinic α-adrenoreceptors [12]. Future Studies  At the moment, there are ongoing several clinical trials that are trying to expand the pharmacological options for OSA and can contribute as a noninvasive option for patients, such as the use of a combination of Acetazolamide, Eszopiclone, and Venlafaxine or even the metabolic effects of Metformin in patients with OSA.

17.3 Central Sleep Apnea (CSA) Syndrome Central Sleep Apnea is a disorder characterized by a lack of drive to breathe during sleep, resulting in repetitive cessation or decrease of both airflow and ventilatory effort. It is less common than OSA and usually associated with other medical conditions (i.e., heart failure, stroke, and the use of opioid medications). In the ICSD-3, the CSA can be divided into eight different disorders: (1) Central sleep apnea with Cheyne-Stokes breathing; (2) Central sleep apnea due to a medical disorder without Cheyne-Stokes breathing; (3) Central sleep apnea due to high-­altitude periodic breathing; (4) Central sleep apnea due to a medication or substance; (5) Primary central sleep apnea; (6) Primary central sleep apnea of infancy; (7) Primary central sleep apnea of prematurity; (8) Treatment-emergent central sleep apnea [1]. The criteria for diagnosis of a Central Sleep Apnea syndrome vary according to the pathology and all cannot be better explained by another current sleep disorder: –– Central sleep apnea with Cheyne-Stokes breathing—PSG reveals ≥5 central apneas/hypopneas per hour of sleep; there are at least three consecutive central apneas or separated by crescendo-decrescendo breathing with a cycle length of at least 40 s (Cheyne-Stokes pattern); and the number of central apneas/hypopneas is >50% to the total AHI. Also, the patient has to report symptoms (daytime sleepiness, gasping, snoring, insomnia, etc.), and the pattern has to be associated with heart failure/neurological disorder/atrial fibrillation. –– Central sleep apnea due to high-altitude periodic breathing—Patient has to have a history of a recent ascent to a high altitude (at least 2500  m) plus report ­symptoms that are clinically attributable to high-altitude periodic breathing. Polysomnography reveals central AHI ≥5/h during NREM sleep.

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–– Central sleep apnea due to a medication or substance—Patient reports symptoms plus use of respiratory depressant substance (i.e., opioid) and PSG reveals ≥5 central apneas/hypopneas per hour of sleep; no Cheyne-Stokes breathing pattern and the number of central apneas/hypopneas is >50% to the total AHI. –– Primary central sleep apnea—PSG reveals ≥5 central apneas/hypopneas per hour of sleep; no Cheyne-Stokes breathing pattern and the number of central apneas/hypopneas is >50% to the total AHI; patient reports symptoms and there is no evidence of daytime or nocturnal hypoventilation. –– This last edition added the treatment-emergent central sleep apnea, which is diagnosed by the demonstration of predominately OSA followed by significant resolution of the obstructive apnea and emergence or persistence of CSA (not caused by another identifiable comorbidity such as CSB or substance) during PSG with positive airway pressure (PAP) without backup rate [1].

17.3.1 Treatment Options for CSA The goals of therapy in patients with CSA syndrome are to normalize sleep breathing patterns, normalizing AHI, and avoid oxygen desaturations, improving the quality of life by decreasing daytime symptoms and improving quality of sleep [22]. The Graphic 17.1 summarizes the treatment options. The first step is to treat the underlying cause (i.e., heart failure, neurological disorder, avoid opioid usage), as it can result in improvement in CSA.

17.3.2 Positive Airway Pressure Therapy In patients with Primary CSA, CSA associated with Cheyne-Stokes breathing, CSA due to high-altitude periodic breathing, and CSA due to medical condition, the first-­ line therapy is the use of CPAP, since it has been demonstrated to decrease the frequency of central apneas in several trials. There are no guidelines that give, at the moment, the best initial CPAP pressure; however the titration is useful to determine

- CSA due to neurological disorder - CSA due to use of respiratory depressant drugs

Central Sleep Apnea

Treat Underlying Cause (I.E., Heart Failure, Neurological Disorder, Respiratory Depressant Drugs)

BiPAP with or without back-up rate

- Primary CSA - CSA associated with Cheyne-Stokes breathing

CPAP Therapy

If not tolerated or fail to use

CPAP Therapy

If not tolerated or fail to use

- CSA due to high altitude periodic breathing - CSA due to medical condition (Heart Failure)

CPAP with adjuvant oxygen or oxygen alone

Ejection Fraction 45%, then they can use ASV or BiPAP with backup rate [22, 23]. In patients with CSA due to neurological disorder or use of respiratory depressant drugs, the first-line therapy is BiPAP.

17.3.3 Alternative Pharmacological Therapy By the same reason as in OSA, the use of Acetazolamide (carbonic anhydrase inhibitor) can reduce the central respiratory events, as shown in a clinical trial [24]. Future Studies  At the moment, there are a few clinical trials ongoing to show, for example, the efficacy of Fluoxetine against seizure-induced central apneas or the effects of Naltrexone on nocturnal breathing patterns at altitude.

17.4 Sleep-Related Hypoventilation Disorders The ICSD-3 defines these disorders as having all hypoventilation present. This is defined by AASM as patients that present one of the following criteria during sleep: There is an increase in the arterial PaCO2 to a value >55 mmHg for ≥10 min; there is ≥10 mmHg increase in PaCO2 during sleep (in comparison to an awake supine value) to a value >50 mmHg for ≥10 min [25]. The vast group of sleep-related hypoventilation disorders can be divided into the following pathologies: (1) Obesity hypoventilation syndrome (OHS); (2) Congenital central alveolar hypoventilation syndrome; (3) Late-onset central hypoventilation with hypothalamic dysfunction; (4) Idiopathic central alveolar hypoventilation; (5) Sleep-related hypoventilation due to a medication or substance; (6) Sleep-related hypoventilation due to a medical disorder [1]. The daytime hypoventilation is not required to diagnose sleep-related hypoventilation disorders with the exception of obesity hypoventilation syndrome: Criteria require a daytime elevation of PaCO2 (>45 mmHg) in a patient with a body mass index >30  kg/m2, as well as no other underlying cause for hypoventilation (i.e., medications, neuromuscular disease, lung disease, deformities of chest wall) [1].

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17.4.1 Treatment Options In patients with obesity hypoventilation syndrome the first-line therapy is to change lifestyle and weight loss, since it can improve alveolar ventilation, improve nocturnal oxyhemoglobin saturation, improve pulmonary function, and decrease the frequency of respiratory events during sleep (if concomitant OSA). In some patients, the referral to a bariatric expert is appropriate [26, 27]. All patients with OHS have some form of sleep-disordered breathing, making them candidates to PAP therapy which should not be delayed while the patient tries to change lifestyle. If the patient presents OHS with OSA then CPAP is the first-line therapy while BiPAP S/T is reserved for those who fail CPAP. If the patient presents OHS with hypoventilation, then the first-line therapy is BiPAP [28].

17.4.2 Alternative Pharmacological Therapy The use of respiratory stimulants such as Acetazolamide is reserved as a last resort and should be used as an adjuvant therapy along with PAP therapy and lifestyle modifications [29]. Patients should be warned to avoid alcohol and sedatives since they can mitigate the benefit of PAP therapy.

17.5 Sleep-Related Hypoxemia Disorder Pulmonary disorders that can cause or exacerbate abnormal breathing (hypoventilation or hypoxemia) make the diagnosis of sleep-related hypoxemia. The most common pathologies are chronic obstructive pulmonary disease (COPD) and asthma, but also interstitial lung diseases [1]. COPD is frequently associated with OSA, CSA, respiratory effort-related arousals, sleep-related hypoventilation, and hypoxemia in up to 40% of the patients. The prevalence of nocturnal hypoxemia increases along with the severity of COPD, and it is defined by a fall in PaO2 >10 mmHg or a SpO2 under 88% for more than 5 min. Therefore, the study with an overnight pulse oximetry (in asymptomatic patients) or the use of a PSG is important to diagnose this sleep-related hypoxemia [30].

17.5.1 Treatment Options After excluding other sleep-related breathing disorders, the treatment of sleep-­ related hypoxemia is guided by the severity and duration of hypoxemia and associated clinical features. The criteria for nocturnal oxygen supplementation vary from country to country, but according to Medicare they are: (1) PaO2 ≤55 mmHg or SpO2 ≤88%; (2) associated symptoms or signs reasonably attributed to hypoxemia (morning headaches,

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erythrocytosis, pulmonary hypertension, impaired cognition); (3) a decrease in SpO2 >5% for at least 5 min during sleep; (4) absence of another cause of sleep-­ related hypoxemia. The supplemental oxygen is supplied by nasal cannula at a flow rate sufficient to maintain the SpO2 >90% [31, 32]. According to BTS guidelines, patients with COPD who have nocturnal hypoxemia and fail to meet the criteria for long-term oxygen therapy should not be given nocturnal oxygen supplementation. Patients with heart failure disease and evidence of sleep breathing disorder (daytime symptoms) can be prescribed with nocturnal oxygen supplementation, after exclusion of other causes of nocturnal desaturation and treatment for heart failure has been optimized [33]. Even though its efficacy is highly proven, the risk of hypoventilation with supplemental oxygen is not negligible, since 20% of patients can worsen hypoventilation during sleep, even though the rise in CO2 rarely worsens hypercapnia and acidosis in the morning. Nevertheless, in some patients the institution of BiPAP therapy can mitigate the worsening of hypoventilation [34].

References 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders third edition. Darien IL: American Academy of Sleep Medicine; 2014. 2. Young T, Palta M, et  al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328:1230. 3. Young T, Evans L, et al. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep. 1997;20:705–6. 4. Tietjens JR, Claman D, et al. Obstructive sleep apnea in cardiovascular disease: a review of the literature and proposed multidisciplinary clinical management strategy. J Am Heart Assoc. 2019;8:e010440. 5. Qaseem A, Holty JE, Owens DK, et  al. Management of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013;159:471. 6. Stepanski EJ, Wyatt JK. Use of sleep hygiene in the treatment of insomnia. Sleep Med Rev. 2003;7:215. 7. Tuomilehto HP, Seppä JM, Partinen MM, et al. Lifestyle intervention with weight reduction: first-line treatment in mild obstructive sleep apnea. Am J Respir Crit Care Med. 2009;179:320. 8. Eijsvogel MM, Ubbink R, Dekker J, et al. Sleep position trainer versus tennis ball technique in positional obstructive sleep apnea syndrome. J Clin Sleep Med. 2015;11:139. 9. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet. 2014;383:736. 10. Giles TL, Lasserson TJ, Smith BJ, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev. 2006;(1):CD001106. 11. Kent D, Stanley J, Aurora RN, et al. Referral of adults with obstructive sleep apnea for surgical consultation: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17:2499. 12. Arredondo E, DeLeon M, Masozera I, Panahi L, Udeani G, Tran N, Nguyen CK, Atphaisit C, de la Sota B, Gonzalez G Jr, Liou E, Mayo Z, Nwosu J, Shiver TL. Overview of the role of pharmacological management of obstructive sleep apnea. Medicina (Kaunas). 2022;58(2):225. 13. Malhotra A, Mesarwi O, Pepin J-L, Owens RL. Endotypes and phenotypes in obstructive sleep apnea. Curr Opin Pulm Med. 2020;26:609–14.

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14. Blackman A, Foster GD, Zammit G, Rosenberg R, Aronne L, Wadden T, Claudius B, Jensen CB, Mignot E.  Effect of liraglutide 3.0  mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes. 2016;40:1310–9. 15. Rössner S, Sjöström L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res. 2000;8(1):49–61. 16. Winslow DH, Bowden CH, DiDonato KP, McCullough PA.  A randomized, double-blind, placebo-­controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults. Sleep. 2012;35:1529–39. 17. An Y, Li Y, Kang D, Sharama-Adhikari SK, Xu W, Li Y, Han D. The effects of nasal decongestion on obstructive sleep apnoea. Am J Otolaryngol. 2019;40:52–6. 18. Wijesuriya NS, Eckert DJ, Jordan AS, Schembri R, Lewis C, Meaklim H, Booker L, Brown D, Graco M, Berlowitz DJ. A randomised controlled trial of nasal decongestant to treat obstructive sleep apnoea in people with cervical spinal cord injury. Spinal Cord. 2019;57:579–85. 19. Terrill PI, Edwards BA, et al. Quantifying the ventilatory control contribution to sleep apnoea using polysomnography. Eur Respir J. 2015;45(2):408–18. 20. Whyte KF, Gould GA, Airlie MAA, Shapiro CM, Douglas NJ. Role of protriptyline and acetazolamide in the sleep apnea/hypopnea syndrome. Sleep. 1988;11:463–72. 21. Taranto-Montemurro L, Messineo L, Wellman A. Targeting endotypic traits with medications for the pharmacological treatment of obstructive sleep apnea. A review of the current literature. J Clin Med. 2019;1846:8. 22. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353:2025. 23. Naughton MT, Benard DC, Liu PP, et al. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med. 1995;152:473. 24. Ni YN, Yang H, Thomas RJ. The role of acetazolamide in sleep apnea at sea level: a systematic review and meta-analysis. J Clin Sleep Med. 2021;17:1295. 25. Berry RB, et  al. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications, version 2.0.3. American Academy of Sleep Medicine; 2014. 26. Martí-Valeri C, Sabaté A, Masdevall C, Dalmau A.  Improvement of associated respiratory problems in morbidly obese patients after open Roux-en-Y gastric bypass. Obes Surg. 2007;17:1102. 27. Lumachi F, Marzano B, Fanti G, et  al. Relationship between body mass index, age and hypoxemia in patients with extremely severe obesity undergoing bariatric surgery. In Vivo. 2010;24:775. 28. Berry RB, Chediak A, Brown LK, et al. Best clinical practices for the sleep center adjustment of noninvasive positive pressure ventilation (NPPV) in stable chronic alveolar hypoventilation syndromes. J Clin Sleep Med. 2010;6:491. 29. Powers MA.  Obesity hypoventilation syndrome: bicarbonate concentration and acetazolamide. Respir Care. 2010;55:1504. 30. Sanders MH, Newman AB, Haggerty CL, et al. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med. 2003;167:7. 31. Jacobs SS, Lederer DJ, Garvey CM, et  al. Optimizing home oxygen therapy. An official American Thoracic Society Workshop Report. Ann Am Thorac Soc. 2018;15(12):1369–81. 32. Centers for Medicare and Medicaid Services. Home oxygen therapy. Department of Health and Human Services; 2015. 33. Hardinge M, et al. British Thoracic Society guidelines for home oxygen use in adults. Thorax. 2015;70:i1–i43. 34. Dunn WF, Nelson SB, Hubmayr RD. Oxygen-induced hypercarbia in obstructive pulmonary disease. Am Rev Respir Dis. 1991;144:526. 35. Bignold J, et al. Poor long-term patient compliance with the tennis ball technique for treating positional obstructive sleep apnea. J Clin Sleep Med. 2009;5:428–30.

Psychiatric Pharmacology and Acute Respiratory Failure

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Omar Soubani, Ashika Bains, and Ayman O. Soubani

18.1 Psychiatric and Respiratory Illness Psychiatric and respiratory illnesses have an intricate bidirectional association made more complex with the added consideration of iatrogenic effects. Psychiatric illness can predispose a patient to poor self-care including less healthy habits and nonadherence to medications for chronic illnesses such as asthma, chronic obstructive pulmonary disorder (COPD), obstructive sleep apnea (OSA), and others, leading to exacerbations of underlying pulmonary conditions. Additionally, it can be difficult to discern if somatic symptoms such as fatigue, palpitations, hyperventilation, or chest tightness originate from psychiatric or respiratory illnesses as there can be significant symptomatic overlap in diagnosis. Chronic neurovegetative symptoms from undertreated underlying medical conditions can present as psychiatric illness. Certain treatments for depression or anxiety disorder can worsen pulmonary

O. Soubani (*) Department of Psychiatry, Detroit Medical Center, Detroit, MI, USA Wayne State University School of Medicine, Detroit, MI, USA e-mail: [email protected] A. Bains Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA e-mail: [email protected] A. O. Soubani Wayne State University School of Medicine, Detroit, MI, USA Division of Pulmonary, Critical Care and Sleep Medicine, Detroit Medical Center, Detroit, MI, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_18

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function, and, vice versa, there are important neuropsychiatric sequelae to consider when choosing medication for respiratory illnesses.

18.1.1 Asthma and Depression Patients suffering from asthma have a higher prevalence of depressive disorders which are characterized by chronic depressed mood and loss of pleasure in daily activities. Furthermore, neurovegetative symptoms of depression such as fatigue, anergia, and sleep distortion can resemble chronic untreated asthma. There is a link between psychological features of denial, fear, and inappropriate coping skills and suboptimal asthma control leading to exacerbations and increased use of healthcare services like the emergency department. There is also an increased risk of sudden death which may be due to poor compliance for treatment of asthma among patients with depressive disorders. It has been speculated that depressed patients have an impaired voluntary respiratory drive when compared with nondepressed patients. A cross-sectional study also demonstrated that depression was independently associated with reduced bronchodilator response among participants with asthma [1]. Symptomatic depression is associated with higher incident asthma, service utilization, and poor outcomes, making screening for depression an aspect of comprehensive care of patients with asthma. Clinicians may consider screening tools such as Patient Health Questionnaire-9 (PHQ-9) or Beck’s Depression Inventory to track symptoms and response. Treatment of depression in these patients with first-line treatments such as SSRIs or SNRIs may improve pulmonary function, and a study using citalopram showed reduction in need for oral corticosteroid and improvement in asthma symptoms and asthma-related quality of life (QOL) [2]. A small study of trial of escitalopram for patients with asthma and depressive symptoms demonstrated an improvement in asthma control (via a questionnaire) and reduction in oral corticosteroid use in patients with severe asthma with use of escitalopram [3]. SSRIs mostly lack the cholinergic and adrenergic effects that would alter respiratory function. Citalopram and escitalopram may increase the risk of QTc prolongation when combined with albuterol. Second-line treatments such as tricyclic antidepressants have shown moderate effect which may be related to anticholinergic effects of tricyclics causing bronchodilation [2].

18.1.2 Asthma and Anxiety Anxiety disorders are more common in patients with asthma than in the general population [2]. Symptoms of dyspnea, chest tightness, and choking sensations are common in both anxiety disorders and asthma. The presence of asthma is also a risk factor for the development of a panic disorder [4]. Patients with comorbid asthma and anxiety disorders often report perceptions of dyspnea despite absence of physiologic changes in airways. Some have theorized that there is a cyclical link between dyspnea and fear, where hyperventilatory panic attacks arise from an emotional

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response to severe breathlessness. This can lead to overuse of medications and unnecessary steroid treatment which increases risk of neuropsychiatric medication side effects. The most common psychiatric side effects of steroid treatment include agitation, anxiety, distractibility, fear, insomnia, irritability, rapid speech, restlessness, and tearfulness. Relaxation therapies, including hypnotherapy, biofeedback techniques, and mental and muscle relaxation therapies, have shown modest benefits in patients with comorbid anxiety and asthma [5].

18.1.3 Chronic Obstructive Pulmonary Disease and Psychiatric Illness Smokers are more likely to meet criteria for mood, anxiety, and psychotic disorder when compared to nonsmokers [6]. Conversely, individuals with psychiatric disorders are far more likely to smoke cigarettes. The most commonly held view is that patients with mental health conditions smoke in an effort to regulate the symptoms associated with their disorder [6]. Long-term smokers have a higher risk of developing COPD. Some studies have estimated that up to 40% of COPD patients experience depressive episodes, 15.8% meet criteria for generalized anxiety disorder, and 37% report symptoms of panic disorder [7]. Patients with COPD and these comorbid mental illnesses have greater disability, decreased functional capacity and lung function, and higher morbidity [8]. As mentioned above, treatment of these mental illnesses with antidepressants, specifically nortriptyline, for its anticholinergic effects, has shown some benefits in the functional status of these patients [2]. Psychotic illnesses such as schizophrenia, schizoaffective disorder, and bipolar disorder have an even higher association with smoking cigarettes, with 71.6% of individuals suffering from schizophrenia smoking cigarettes [9]. Some have suggested that cigarette smoking briefly dulls auditory hallucinations, improves negative symptoms of schizophrenia, increases metabolism of antipsychotic medications, and reduces medication-induced Parkinsonism [10]. Chronic smoking is a major risk factor for developing COPD and individuals suffering from schizophrenia and bipolar disorder having a higher prevalence of COPD as compared to the general population [11]. These patients are less likely to follow up with outpatient care or take long-acting bronchodilators and have a higher mortality rate following a COPD exacerbation [12].

18.1.4 Obstructive Sleep Apnea and Psychiatric Illness Symptomatic overlap with obstructive sleep apnea (OSA), depression, and anxiety may complicate diagnosis and treatment of each individual disorder. Studies have shown that patients with OSA are at higher risk for depression and anxiety and more likely to present with these symptoms rather than those typical of OSA [13, 14]. There have even been case reports of recurrent delirium and psychosis in patients with OSA that resolved with CPAP [15]. Effective screening and treatment of

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mental disorders in the setting of OSA may improve patient outcomes and prevent further illness. Conversely, psychiatric patients, specifically those taking CNS depressants, CNS stimulants, and mood stabilizers, are at high risk for developing OSA and should be screened appropriately [16].

18.2 Medication Side Effects 18.2.1 Psychiatric Side Effects of Pulmonary Medications Psychiatric side effects may develop with the use of medications in the management of pulmonary diseases and critical illnesses. Side effects can resemble primary psychiatric disorders and can appear at any time during course of treatment. Clinicians should consider iatrogenic effects in the differential if a patient presents with new-­ onset psychiatric symptoms, particularly if the symptoms are acute in onset and the patient does not have a prior psychiatric history. The psychiatric side effects of medications can occur with regular doses, with high doses, or even after discontinuation of the medication (withdrawal). The factors that increase the risk of psychiatric side effects from pulmonary medications include age (extremes of age), organ dysfunction (such as renal or hepatic), past or present psychiatric disorder, critical illness and stressful situations, polypharmacy, and higher doses or narrow therapeutic index of the medication [17]. The criteria that suggest that the psychiatric symptom is related to a medication include: • Temporal relation between the start of the medication and the development of symptoms • The medication that is known to cause psychiatric side effects • Other conditions that may lead to the symptoms have been ruled out • Improvement or resolution of the symptoms with the discontinuation of the medication • Reappearance of the symptoms by rechallenging the patient with the same medication It is worth noting that not all of these criteria must be met to attribute side effects to a particular medication. Commonly, high index of suspicion associated with sound clinical judgment is the basis of attributing the side effect to a medication. Medications used in the management of pulmonary conditions can cause a wide range of psychiatric side effects that include anxiety, depression, mania, psychosis, hallucinations, delusions, and suicidal ideations. Patients may also present with disordered sleep, confusion, and agitation. Table 18.1 provides a description of medications commonly used in the management of respiratory diseases that have been associated with psychiatric side effects (Drug Information Portal).

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18  Psychiatric Pharmacology and Acute Respiratory Failure Table 18.1  Psychiatric side effects of medications commonly used in respiratory diseases Class of medication Clinical use Antibiotics Pneumonia and other respiratory infections

Psychiatric side effects  – Penicillins and cephalosporins: irritability, anxiety, and hallucinations  – Quinolones: sleep and mood disturbances, psychosis  – Antimycobacterial medications (isoniazid, rifampicin, and ethionamide): irritability, depression, psychosis, and suicidal ideations Aggression, agitation, anxiety, depersonalization, depression, delirium, psychosis. Short-term use of steroids typically causes anxiety, while chronic use will lead to depressive states

Corticosteroids

Management of acute exacerbation of COPD or asthma and interstitial lung disease

Leukotriene modifiers

Long-term management of asthma

Bupropion

Smoking cessation

Varenicline

Smoking cessation

Agitation, aggression, depression, sleep disturbances, suicidal ideations Increased energy, insomnia, agitation, and nervousness. Can worsen preexisting anxiety and panic disorders. Can precipitate manic episode in bipolar patients. Rare cases of psychosis and suicidal ideations have been reported Depression, suicidal ideation, night terrors

Bronchodilators-­ aminophylline and salbutamol

Treatment of airway diseases

Agitation, euphoria, and delirium

Comments

Risk of psychiatric side effects increases with higher doses, duration of treatment, older age, and underlying psychiatric or personality disorders. Withdrawal of corticosteroids may induce insomnia, mood changes, and cognitive impairment Rare

Inhibits norepinephrine and dopamine reuptake. It also inhibits nicotinic acetylcholine receptors. Can lower seizure threshold

Blocks the ability of nicotine to activate α4β2 receptors and thus stimulates the central nervous mesolimbic dopamine system leading to decreased cravings

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These psychiatric side effects can affect compliance of medications or may force clinicians to discontinue treatment which may in turn lead to deterioration of the underlying lung disease. When the psychiatric side effects are severe, but the patient is in need of treatment to maintain respiratory function, simultaneous treatment of psychiatric symptoms may be required (antipsychotics, mood stabilizer, benzodiazepines). Failure to control these symptoms (agitation, depression, psychosis) may in turn lead to worsening of respiratory status such as acute respiratory failure. However, careful consideration is required with the use of psychotropic medications as they may also cause respiratory depression as previously mentioned.

18.2.2 Pulmonary Side Effects of Psychiatric Medications Benzodiazepines are primarily utilized in the treatment of anxiety disorders, acute treatment for seizures, and management of GABAergic withdrawal, given the mechanism of action of gamma-aminobutyric acid (GABA) receptor agonists. Benzodiazepines, given alone or in combination with opiates, cause produce respiratory depression, aspiration, confusion, falls, and death in patients with respiratory compromise [18, 19]. Long-term antidepressant use can result in other side effects, for instance, some antidepressants have been associated with hypertension or some has been associated with weight gain, and this can produce downstream pulmonary consequences. Pulmonary complications have been reported in TCA overdose. Antipsychotic use and respiratory complications are further discussed in detail in the chapter.

18.3 Critically Ill Patients and Psychiatric Illness As outlined above, psychiatric comorbidities can contribute to less healthy lifestyle, poor medication compliance for chronic pulmonary disease, and adverse pulmonary side effects of certain psychotropic medications. Taken together, this may increase the risk for multiple exacerbations of pulmonary illnesses and acute respiratory failure requiring admission to the intensive care unit (ICU), noninvasive mechanical ventilation, and invasive mechanical ventilation, which are associated with higher rates of mortality. Traumatic experiences in the ICU can lead to the development of psychiatric complications including depression, anxiety, and trauma responses. Post-traumatic stress disorder (PTSD) after ICU admission is commonly missed, with reported incidence between 4% and 25% [2]. Length of ICU hospitalization and mechanical ventilation, level of sedation, and recollection of traumatic memories are among the risk factors for development of post-ICU PTSD [20]. There has been some debate regarding the use of sedation of mechanically ventilated patients and the future development of PTSD. Some studies have found that the fewer memories recalled from ICU admission correlated with less PTSD symptoms, suggesting total amnesia using sedation to prevent development of PTSD [21]. Others have

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found that interruption of daily sedation in mechanically ventilated patients led to fewer subsequent symptoms of PTSD [22].

18.3.1 Delirium Diagnosis and Epidemiology The use of noninvasive positive pressure ventilation (NIPPV) in the treatment of ARF has become common with several advantages over invasive ventilation. Delirium has been postulated to be an important factor contributing to NIPPV failure. Delirium is a syndrome characterized by fluctuating impairments in consciousness, sensorium, attention, and perception. The pathophysiology of delirium can be multifactorial, and common etiologies include pneumonia, anemia, pulmonary embolism, acute respiratory failure, and others. Hypoxia is considered one of the life-threatening causes of delirium. Rates of delirium for patients in intensive care units are estimated to be approximately 30%, and rates for patients who require intubation or mechanical ventilation are estimated to be higher than 80% [23, 24]. Studies have found that delirium is associated with increased length of hospital stay, longer duration of mechanical ventilation, and increased risk of mortality [23, 25]. Additional studies have established an association between delirium and cognitive impairment, increased mortality, and worse activities of daily living (ADL) scores after discharge [24, 26, 27]. An observational study evaluating delirium and outcomes in noninvasive ventilation has found that delirium is associated with increases in poor outcomes such as NIV failure, ICU mortality, and hospital mortality [28]. Another observational study followed patients for a year and reported the presence of delirium as a strong predictor of mortality [29]. Given the acute and chronic impact of delirium, identification, prevention, and treatment of delirium is an important aspect of care for critically ill patients. Screening tools such as the Intensive Care Delirium Screening Checklist (ICDSC) or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) are validated bedside tools that enable clinicians to screen critically ill patients for delirium. However, the heterogeneity of presentation can result in diagnostic challenges. The Diagnostic and Statistical Manual of Mental Disorders (DSM) denotes a diagnosis of delirium as an acute onset (hours to days) of disturbance in attention and orientation which represents a change from baseline mentation, tends to fluctuate in severity during the day, and has evidence that the disturbance is a direct physiological consequence. Of the motor subtypes, hyperactive delirium characterized by psychomotor agitation is more frequently identified than hypoactive which presents as lethargy and carries a worse prognosis. Many risk factors, such as age, baseline major neurocognitive disorder, and severity of illness, contribute to risk of development of delirium.

18.3.2 Delirium Management Nonpharmacologic interventions are thought to be effective in the prevention and treatment of delirium. Strategies include minimizing polypharmacy, conducting

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spontaneous awakening and breathing trials, daily interruption of sedation, encouraging early mobility, family participation, and regulating sleep-wake cycle. A recent systematic review and meta-analysis reviewed 35 studies for effects of nonpharmacological interventions for prevention of ICU delirium and concluded that overall nonpharmacological interventions were more effective in shortening the duration of delirium than lowering delirium occurrence [30]. The interventions were classified into one of nine categories: multicomponent, physical environment, daily interruption of sedation, exercise, or patient education, automatic warning system, cerebral hemodynamics improvement, family participation, and sedation reducing protocol. Physical environment referred to providing appropriate stimulation while reducing unnecessary stimulation at night, and multicomponent referred to a combination of some of the nine interventions. The review reported that multicomponent interventions significantly reduced the occurrence of delirium and did not significantly shorten the duration of delirium. Physical environment interventions did not have significant effects on either the occurrence or the duration of delirium, though multicomponent interventions included environmental interventions. No adverse effects were reported due to nonpharmacological interventions. Pharmacological interventions are aimed at reducing harm such as management of agitation and promotion of sleep at nighttime. Special attention should be paid to medications that have been associated with the development of delirium such as benzodiazepines, anticholinergic agents, and certain opiates such as meperidine. Pharmacological approaches are varied, and clinicians need to consider risk-benefit ratios and multiple available therapeutic interventions without having evidence from direct comparisons or head-to-head trials. A systematic review and meta-analysis of interventions for delirium in ICU patients reported that alpha2 agonists such as dexmedetomidine may reduce duration of mechanical ventilation as compared to benzodiazepines, may reduce length of ICU stay as compared with placebo and antipsychotics, and may reduce the odds of delirium occurrence relative to placebo. The evidence was less certain for opioids, sedation interruption, or protocolized sedation in this review [31]. The properties of dexmedetomidine, including minimal impact on respiratory effort, make it a more favorable medication as compared to benzodiazepines which can increase delirium prevalence, worsen sleep architecture, and suppress respiratory drive. A Cochrane review of interventions for preventing delirium in ICU patients reviewed randomized controlled trials (RCTs) of adult medical or surgical ICU patients [32]. Two studies reviewed utilized early treatment with haloperidol during the ICU admission and found no difference between groups in outcomes of in-­ hospital mortality within 28  days, number of delirium- and coma-free days, ventilator-­free days, or length of stay in the ICU.  The studies did report adverse effects of prolonged QT intervals and extrapyramidal effects, unrelated to medication in one study. The results together indicated a limited role for haloperidol in prophylaxis treatment of delirium. A study examining the effect of dexmedetomidine versus lorazepam, both administered as infusions in ICU participants until extubation or for a maximum of 120 h, reported no effect on the event rate of ICU delirium, in-hospital mortality, ventilator-free days, or length of stay in the ICU. The

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dexmedetomidine group had more delirium- and coma-free days within 12 days. The quality of the evidence was considered low for these outcomes due to a single study. That being said, further investigations of alpha2 agonist are required to assess for utility in delirium. A study of 90 ICU participants with less severe disease receiving noninvasive mechanical ventilation assessed trial of either dexmedetomidine, haloperidol, or saline infusions and reported a reduced event rate of ICU delirium in the dexmedetomidine group compared to the haloperidol group with a number needed to treat for an additional benefit of three. In-hospital mortality was similar in all three groups. The dexmedetomidine group had a shorter length of ICU stay compared to the haloperidol group and the placebo group. Adverse events reported were bradycardia, arrhythmia, and QTc interval.

18.3.3 Agitation Management and Antipsychotic Medications Antipsychotic medications are commonly utilized in agitation management for patients with hyperactive delirium. Atypical antipsychotics have lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. Antipsychotic use, however, is not without risk of adverse events. Clinicians must weigh the benefits with the risk of use. Due to histamine receptor antagonism, antipsychotics can be sedating, and antipsychotics with high muscarinic receptor antagonism could precipitate delirium as well as dysregulate circadian rhythm. Antipsychotics may also decrease the seizure threshold, may cause metabolic derangements such as hyperglycemia, and can cause neuroleptic malignant syndrome (NMS), and some are associated with QTc prolongation,. Though this is rare, NMS is a serious and potentially fatal adverse effect that typically occurs within 2  weeks of exposure to a neuroleptic medication, and symptoms include muscle rigidity, hyperthermia, autonomic instability, and altered mental status. Respiratory distress occurs in about a third of patients with NMS and is a predictor of mortality. Risk of developing NMS is related to higher doses, rapid dose escalation, intravenous and intramuscular administration, and antipsychotics with greater D2 blockade. Higher rates of QTc prolongation were associated with first-generation antipsychotics, and second-generation antipsychotics are associated with an increased risk of death, particularly in the elderly, which may be dose dependent.

18.3.4 Antipsychotic Medication and Respiratory Complications Respiratory complications from antipsychotic use are less common or may be underreported in the literature. Antipsychotic adverse effect of ARF is controversial. Case reports have documented difficulty breathing and ARF in patients within hours to days of starting antipsychotic medications [33]. One study showed a strong association between antipsychotic agents and the risk of developing acute respiratory failure in patients with COPD: in a large case-crossover study in Taiwan, 61,620 patients with COPD were evaluated to identify if a relationship existed

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between antipsychotic use and ARF. The population-based study used the Taiwan National Health Insurance Research Database to study patients with COPD who were newly diagnosed with ARF in hospital or emergency care settings necessitating intubation or mechanical ventilation. Results showed an increased risk of ARF if the patient was given antipsychotic medications, regardless of class and administration route. The study reported a 66% increased risk of ARF regardless of baseline COPD severity within 2 weeks of antipsychotic initiation. The risk of ARF was dose dependent, with a number needed to harm of 87 for high-dose antipsychotics. Typical and atypical antipsychotics were found to have a similar risk of ARF [34, 35]. A large case-control study revealed a twofold increased risk of ARF with current use of antipsychotics compared with nonuse. These findings persisted with case crossover analysis and comparison with carbamazepine. Researchers also noted decreased risks of developing ARF within 15–90  days of discontinuing antipsychotic therapy [36]. Deep vein thrombosis and fatal pulmonary embolism are also rarely reported in patients using antipsychotic medications. Studies have suggested a higher risk of fatal PE in patients using antipsychotics, specifically first-generation agents and clozapine [37]. Special consideration should be taken with use of antipsychotics in the demented elderly. Currently, there are no FDA-approved antipsychotic medications for management of agitation in these patients. Based on the current evidence, it seems that risperidone, aripiprazole, and olanzapine are the most efficacious for reduction of aggressive and agitated behavior in these patients. This should be weighed against the increased risk of cardiac-related complications such as sudden cardiac death [38]. These patients are also at risk of aspiration pneumonia, likely due to anticholinergic and H1 receptor blocking actions, causing sedation, dry mouth, and subsequent impairment of bolus transport [39, 40]. Another possible and important mechanism to consider is extrapyramidal symptoms from antipsychotics in the form of laryngeal dystonia, which presents as dyspnea, stridor, and extreme distress. The classic case of acute laryngeal dystonia presents in young males during the first days of high-potency antipsychotic therapy, often seen grabbing their throats. The use of antipsychotics to control agitation in the ICU in medication-naive patients who present with difficulty breathing or swallowing should raise a high index of suspicion for acute laryngeal dystonia. Acute laryngeal dystonia is considered an emergency: the patient’s airway should be maintained, the antipsychotic stopped, and anticholinergics, such as benztropine, should be given intramuscularly or intravenously [41].

18.3.5 Delirium and Acute Respiratory Distress Syndrome A multicenter prospective cohort study of ICU patients revealed that acute respiratory distress syndrome (ARDS) was independently associated with higher odds for delirium compared with mechanical ventilation without ARD, suggesting

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respiratory disease has its own pathophysiological connection toward delirium [42]. A hypothesis outlining the potential mechanism for pathogenesis of delirium in acute respiratory failure is neuroinflammation and cerebral hypoperfusion. Inflammation regulatory proteins known as cytokines are known to modulate the permeability of the blood-brain barrier by altering the resistance of tight gap junctions of endothelial cells, thereby providing a connection between peripheral and central inflammation. Microglia, specialized cell types associated with cerebral inflammation, activate in response to cytokines or other signaling molecules of acute inflammation. Inflammation can also lead to disruption in cerebral blood flow. It is theorized that patients with ARDS develop hypoxemia which subsequently contributes to neuroinflammation and altercations in cerebral perfusion precipitating delirium. Although many neurotransmitter systems have been implicated, commonly neurotransmitter disruptions associated with the development of delirium include reduced acetylcholine and elevated levels of dopamine, norepinephrine, and/or glutamate [43]. The connection between respiratory illness and delirium becomes more involved as studies of delirium in SARS-CoV-2 cases have been becoming more prevalent. Recently published articles relay that an acute confusion/delirium can be a primary manifestation of COVID-19 and should be recognized as a potential feature of infection [44, 45]. There have been reports of altered mental status without respiratory symptoms or respiratory failure which raise the concern of central nervous system (CNS) injury; the pathophysiology by which SARS-CoV-2 causes encephalopathy is unknown. Investigators have proposed potential mechanisms such as infectious spread to the CNS, neuroinflammation as described above, autoimmune reactions, and hypoxemic/thrombotic neuronal injury. Baller et  al. proposed an algorithm for management of delirium in patients with SARS-CoV-2 infection beginning with maximizing behavioral management approaches as discussed above and reserving pharmacologic treatment for cases where behavior strategies are insufficient. Pharmacologic treatment algorithm, extrapolated from previous delirium literature and clinical experience from the Massachusetts General Hospital Consultation-Liaison Psychiatry COVID-19 Workgroup, suggested using melatonin at first for circadian rhythm regulation, then alpha2 agonists as needed for agitation, and then low-potency antipsychotic agents if needed for continued agitation [46].

18.3.6 Acute Respiratory Failure Associated with Psychiatric Conditions or Antipsychotic Medications The management of acute respiratory failure that may be associated with psychiatric conditions, or with the use of antipsychotic medications or the psychiatric side effects of medications used in the management of pulmonary diseases as detailed above, is usually complex and needs to be individualized. As a general rule, the management should follow that of acute respiratory failure in other conditions and takes into consideration the severity and acuity of the situation; the patient’s hemodynamic status, mental status, and ability to cooperate with treatment; and the type

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of respiratory failure (primarily hypoxemic vs. hypercapnic). In patients who are relatively are hemodynamically stable, primarily hypercapnic, and can cooperate with treatment, an approach that utilizes noninvasive ventilation should be considered. Such patients should be closely monitored in an intensive care setting whenever is possible as their condition may deteriorate and they may require intubation and invasive mechanical ventilation [47]. It is also worth noting in this context that noninvasive ventilation may lead to or worsen delirium in critically ill patients. Delirium was estimated to have a pooled prevalence of 37% in a meta-analysis with a pooled risk ratio at 2.12 (95% CI 1.41–3.18) [48]. These patients should be routinely assessed for delirium using a standardized scale such as confusion assessment method (CAM) or CAM for intensive care unit (CAM-ICU).

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15. Lombardi C, Rocchi R, Montagna P, Silani V, Parati G. Obstructive sleep apnea syndrome: a cause of acute delirium. J Clin Sleep Med. 2009;05(06):569–70. 16. Tanielian M, Doghramji K, Certa K. Obstructive sleep apnea in psychiatric inpatients. J Nerv Ment Dis. 2020;208(3):190–3. 17. Gupta A, Chadda RK. Adverse psychiatric effects of non-psychotropic medications. BJPsych Adv. 2016;22(5):325–34. 18. Ekstrom MP, Bornefalk-Hermansson A, Abernethy AP, Currow DC. Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study. BMJ. 2014;348:445. 19. Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system–mediated effects. Ochsner J. 2013;13(2):214–23. 20. Schelling G, Stoll C, Haller M, Briegel J, Manert W, Hummel T, et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med. 1998;26(4):651–9. 21. Jackson JC, Hart RP, Gordon SM, Hopkins RO, Girard TD, Ely EW.  Post-traumatic stress disorder and post-traumatic stress symptoms following critical illness in medical intensive care unit patients: assessing the magnitude of the problem. Crit Care. 2007;11(1):27. 22. Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003;168(12):1457–61. 23. Caplan JP.  Delirious Patients. In: Stern TA, Freudenreich O, Smith FA, Fricchione GL, Rosenbaum JF, editors. Handbook of general hospital psychiatry. 7th ed. Elsevier; 2018. p. 83–93. 24. Brummel NE, Jackson JC, Pandharipande PP, Thompson JL, Shintani AK, Dittus RS, Gill TM, Bernard GR, Ely EW, Girard TD. Delirium in the intensive care unit and subsequent long-term disability among survivors of mechanical ventilation. Crit Care Med. 2014;42(2):369. 25. Lin SM, Liu CY, Wang CH, Lin HC, Huang CD, Huang PY, Fang YF, Shieh MH, Kuo HP. The impact of delirium on the survival of mechanically ventilated patients. Crit Care Med. 2004;32(11):2254–9. 26. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753–62. 27. Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, Serafim RB, Stevens RD.  Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015;350:h2538. 28. Zhang R, Bai L, Han X, Huang S, Zhou L, Duan J. Incidence, characteristics, and outcomes of delirium in patients with noninvasive ventilation: a prospective observational study. BMC Pulm Med. 2021;21(1):1–8. 29. Chan KY, Cheng LS, Mak IW, Ng SW, Yiu MG, Chu CM.  Delirium is a strong predictor of mortality in patients receiving non-invasive positive pressure ventilation. Lung. 2017;195(1):115–25. 30. Kang J, Lee M, Ko H, Kim S, Yun S, Jeong Y, Cho Y. Effect of nonpharmacological interventions for the prevention of delirium in the intensive care unit: a systematic review and meta-­ analysis. J Crit Care. 2018;48:372–84. 31. Burry LD, Cheng W, Williamson DR, Adhikari NK, Egerod I, Kanji S, Martin CM, Hutton B, Rose L.  Pharmacological and non-pharmacological interventions to prevent delirium in critically ill patients: a systematic review and network meta-analysis. Intensive Care Med. 2021;47(9):943–60. 32. Herling SF, Greve IE, Vasilevskis EE, Egerod I, Mortensen CB, Møller AM, Svenningsen H, Thomsen T. Interventions for preventing intensive care unit delirium in adults. Cochrane Database Syst Rev. 2018;11:CD009783. 33. Jabeen S, Polli SI, Gerber DR. Acute respiratory failure with a single dose of quetiapine fumarate. Ann Pharmacother. 2006;40(3):559–62.

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Carrillo Andres, Guia Miguel, and Bayoumy Pablo

19.1 Introduction Noninvasive ventilation (NIV) is effective in the treatment of acute respiratory failure (ARF) of different aetiologies and is frequently used as the first line of treatment in patients with ARF, even if without strong evidence for its use [1]. Cooperation is essential to achieve the necessary comfort that leads to adequate patient interface/ ventilator interaction, avoiding NIV failure [2]. Among the factors related to NIV failure, poor tolerance to NIV is one of the most important, especially in immediate or early failure [1]. Intolerance may be caused by the interface, the ventilation mode used or inadequate setting of the ventilator parameters. The incidence of intolerance is highly variable depending on the definition used. In a single-center study, intolerance, defined as total rejection of NIV, occurred in 5.2% of patients [3]. In another study, intolerance to the interface, claimed by patients themselves, was present in 25.9% of patients with NIV after extubation [4]. The relationship between the development of intolerance and prognosis was shown by Antonelli et al. in a multicenter observational study. Analysis of risk factors for NIV failure in patients with hypoxemic ARF showed that 9% of patients were intubated due to intolerance to NIV [5].

C. Andres (*) Intensive Care Unit, Hospital Morales Meseguer, Murcia, Spain e-mail: [email protected] G. Miguel · B. Pablo Sleep and Non-Invasive Ventilation Unit, Thorax Department, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_19

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19.2 Neuropsychological Complications in the Critically Ill Patient Alterations in neuropsychological status are common in patients admitted to the intensive care unit (ICU). The incidence of anxiety in critically ill patients is between 30 and 80% [6], that of agitation is between 12 and 70% [7] and that of delirium is around 60–80% in patients on mechanical ventilation and between 20 and 50% in less severe critical patients [8]. Any of these processes hinders the use or success of NIV. Anxiety, agitation and delirium are often interrelated since many of the risk factors for the development of these complications are similar [6–8]. The presence of agitation/delirium is related to deleterious consequences for the patient, including unplanned removal of organ support devices or catheters, falls, inability to apply treatments that require patient participation such as physiotherapy or respiratory treatments, higher rate of nosocomial infection and surgical reinterventions, increased ICU and hospital stay, and increased hospital mortality [7, 8]. On the other hand, harmful events can also be produced by the use of sedative treatments and physical measures used against agitation, including immobility, changes in the level of consciousness, loss of protective airway reflexes or involvement of the upper airway, favouring obstructive events. All of these predispose the patient to a longer time on mechanical ventilation, ventilator-associated pneumonia, lung injury, malnutrition, muscle weakness acquired in the ICU and long-term negative psychiatric effects (post-traumatic stress disorders) [9] (Table 19.1).

19.3 Delirium and NIV The presence of agitation and/or delirium has been analysed in patients on NIV. A systematic review showed a prevalence of delirium of 37%, with a relative risk for NIV failure of 2.12 (95% CI: 1.41 to 3.18) [10]. Subsequently, different observational studies have shown that the incidence of delirium in patients with NIV is high, between 18.1% and 37% [11–15]. Furthermore, some of the characteristics and strategies of NIV are related to the development of delirium. In an observational study, helmet use and a poor interface tolerance score were related to the development of delirium [15]. The importance of delirium during NIV is determined not

Table 19.1  Main antipsychotic drugs used in the ICU Drug Haloperidol Olanzapine Quetiapine Risperidone Loxapine Tiapride

Starting dose 0.25–1 mg q4h 0.25–1 mg q4–1 h 25-50 mg q12 h 0. 25–1 mg q4–12h 150 mg/d 100–300 mg/d

Route PO/IM/(IV) PO/IM PO PO PO/IM/(IV)/inhaled PO/IM/IV

Onset time (iv) 15 min 15–45 min (IM) 1. 5–6 h 4 h (PO) 30 min 15 min

h hours, IM intramuscular, IV intravenous, mg milligrams, min minutes, PO oral

Half life 21 h 21–54 h 6–7 h 24 h 8 h 3 h

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only by its high frequency but also because most studies show a relationship between the presence of delirium, NIV failure and a worse prognosis [12–15]. The presence of delirium makes the use of NIV difficult or impossible. In an international internet survey on the use of NIV during delirium, 16.3% of the respondents stated that they would never use NIV in a patient with delirium, and 44.5% only occasionally [16]. In this study, 63.3% of the responding physicians reported using medication when delirium occurs during NIV, with haloperidol being the most used drug, followed by atypical antipsychotics, dexmedetomidine and benzodiazepines [16].

19.4 Antipsychotic Drugs in the ICU Neuroleptics or antipsychotics are a group of medications with a chemically heterogeneous nature but with a common main mechanism of action: the blockade of brain dopaminergic D2 receptors [7]. Although these drugs interact with multiple transmitters, their therapeutic effects are the result of competitive blockade of dopamine and serotonin receptors, while side effects are attributed to blockade of a wide variety of receptors. Antipsychotics are classified as typical (or first generation), with greater or equal affinity for D2 receptors than for serotonin; and atypical (or second generation), with greater affinity for serotonin receptors than for D2, although some have increased affinity for D3 or D4 receptors. The most used antipsychotic drugs in the ICU are [7]:

19.4.1 Haloperidol Butyrophenone with sedative action. It is the most studied drug for the prevention and treatment of agitation and delirium in the ICU. Its main action is through the blockade of dopaminergic D2 receptors in the central nervous system. For years it has been the first-line treatment in the agitated patient in the ICU. However, in 2018 two large multicentre randomized controlled trials that evaluated the use of haloperidol as prevention or treatment of delirium in the ICU, and that were subsequently included in two systematic reviews [8], did not show any benefit with the use of antipsychotic drugs. The 2018 Pain, Agitation, Delirium, Immobility, and Sleep Guidelines from the Society of Critical Care Medicine advocate against the routine use of haloperidol to treat delirium [17].

19.4.2 Loxapine Typical antipsychotic is used in the treatment of the agitated patient in the context of schizophrenia or bipolar disorder. It can be used in inhaled form. It has a rapid action, short half-life and the possibility of being used intravenously. A multicentre randomized controlled trial to assess the drug in agitated patients during weaning had to be stopped prematurely due to insufficient inclusion rate. Although time to

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extubation did not differ between patients assigned to loxapine or placebo, those treated with loxapine required less reuse of sedation. Due to this and its pharmacokinetic properties, it can be considered for the treatment of agitated patients in the ICU [7].

19.4.3 Tiapride Selective dopamine antagonist is used primarily in alcohol withdrawal syndrome, negative symptoms of psychosis and agitation in the elderly patient. It has few extrapyramidal side effects. Its intravenous use can be useful in patients with moderate agitation with a delusional or anxious component, due to its good tolerability and the relative lack of interactions with other drugs.

19.4.4 Atypical Antipsychotics They were developed to avoid extrapyramidal side effects. Almost all atypical antipsychotics antagonize dopamine D2 and D3 receptors, as well as adrenergic receptors, and act as partial agonists at serotonin receptors. Many of them, particularly olanzapine and quetiapine, have anticholinergic and antihistamine effects. They have also calming effects and have been used, above all, in agitated delirium. The most used have been olanzapine, quetiapine, risperidone and ziprasidone. The slow onset of action and the need for oral administration make its use in the ICU difficult. Although they have fewer extrapyramidal effects than typical antipsychotics, they cause greater sedation, orthostatic hypotension and anticholinergic effects, and have been associated with pro-arrhythmic states and an increased risk of polymorphic ventricular tachycardia. Few controlled studies have evaluated the use of these drugs in the treatment of patients with delirium. Ziprasidone was evaluated in a trial comparing it with haloperidol and placebo, without showing any benefit [18]. A small randomized controlled trial compared quetiapine and placebo in critically ill patients who remain delirious after haloperidol, suggesting that quetiapine may be beneficial by shortening the duration of delirium [19]. The main indication for the use of neuroleptic drugs in critically ill patients is the development of agitation and/or delirium [7, 8]. In a retrospective study conducted between 2014 and 2016 in patients admitted to the ICU [20], almost half of patients with delirium received antipsychotic medication. The most used drugs were: haloperidol (61.4% of cases), olanzapine (in 47.8%) and quetiapine in (47.8%); 30.6% of treated patients received two drugs and 17.1% received three or more drugs. Despite the fact that the latest published guidelines [17] recommend against the use of antipsychotic drugs, a multinational electronic survey directed to physicians working in adult ICUs carried out between September 2019 and January 2020 showed that 68.8% of the respondents continue to use haloperidol and 69.4% atypical antipsychotics [21].

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The use of antipsychotic drugs and its relationship with prognosis has shown contradictory results. In an observational study, the use of haloperidol and olanzapine were independently associated with non-resolution of delirium and increased mortality, while quetiapine was associated with decreased mortality [20]. Smit et al. showed that the use of haloperidol and clonidine was associated with a lower probability of delirium resolution compared to untreated patients [22]. In an international cohort study conducted in 1260 patients in 99 ICUs in 13 countries, the drug most used in the management of delirium was haloperidol; the use of this drug in the first 72 hours after admission was related to an increase in need for circulatory support but not with mortality [23]. However, in a post hoc analysis of the REDUCE trial conducted in patients at high risk of developing delirium in the ICU, it was shown that the use of haloperidol to treat incidental delirium, not present at the time of admission to the ICU, was associated with a lower mortality at 28 days, in a doseand time-dependent manner [24]. The pharmacological management of the agitated patient is based on the use of one drug or the combination of several of them. There is no clear consensus or guidelines for the use of one drug over another or which drugs can be combined. When antipsychotic drugs are prescribed in delirium or agitation, clinicians should discuss the risks, benefits and alternatives. The choice is based on the profile of side effects, risks and desired effects. The use of antipsychotic drugs must take into account the clinical circumstances of the patient, the interaction between the different drugs received, the severity of the respiratory affectation and the prolongation of the QT interval in the electrocardiographic recording. There is currently no evidence that the use of antipsychotic drugs shortens the course of delirium in hospitalized patients. Neither do they reduce the severity of delirium, nor the duration of symptoms, nor do they reduce the risk of death [8]. The studies carried out show that the adverse effects reported are infrequent [8]. The lack of benefit in the different studies carried out may be related to the heterogeneity of patients with delirium (presence of hypo or hyperactivity), different pathophysiological pathways and mediators involved. It should also be borne in mind that most of the studies conducted analysing the use of antipsychotic drugs in the treatment of delirium include a very high proportion of patients with hypoactive delirium, so the results cannot be extrapolated to hyperactive or agitated patients.

19.5 Use of Antipsychotics During NIV The deleterious effects of NIV on the patient are multiple: pain, anxiety, dysphoria, altered sleep quality, asynchrony and intolerance to the interface or the ventilator. Pharmacological treatment aims to facilitate mechanical ventilation and sleep, relieve anxiety, eliminate pain and delirium, while alleviating the physiological response to stress, including tachycardia, dyspnoea and arterial hypertension, without depressing ventilation, hypoxic respiratory drive and cough reflex. But if the agitation is related to the presence of hypoxemia or hypercapnia, the use of sedation or neuroleptic medication can deteriorate an already unstable condition [2]. Because

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of this, it is important to quantify pain, anxiety or delirium, and tolerance to NIV. When faced with a patient with poor tolerance to NIV, the first thing is to identify the causes of discomfort: anxiety, agitation, delirium, pain, dyspnoea, sleep disturbance, and explore the patient’s expectations. Initially, non-pharmacological management is recommended: explanation of how NIV works and what the patient will feel when connected to this device, special attention to the interface and harness, and elimination of intense light and noise. An approach to the non-­ pharmacological management of ICU patients to prevent anxiety, agitation or delirium is the use of the ABCDEF bundle [17]. If agitation persists after that, the use of drugs for the treatment and control of the symptoms can be tried, parenteral and short-acting medication being the first choice. The drugs used are mainly sedatives and neuroleptics or antipsychotics. Treatment of agitated patients with antipsychotic drugs can be started when the symptoms are very distressing (hallucinations, delusions or severe anxiety) or dangerous (removal of devices, falls, aggressive behaviour towards health personnel), starting at low doses and for a short period of time (generally less than a week), stopping when the patient has been free of delirium for at least 2 days. If treatment with antipsychotics is decided, interactions with other medications, adverse events and the dose to be administered should be assessed daily.

19.6 Antipsychotic Drugs in the ICU During the COVID-19 Pandemic A population especially predisposed to the development of neuropsychiatric disorders has been COVID-19 patients with ARF.  These patients frequently present severe delirium or psychomotor agitation, especially those admitted to the ICU, where it can affect 65–80% of critically ill patients [25]. For some authors, the delirium developed during COVID-19 is more frequent, more severe and with a greater need for drugs and higher doses than those developed in non-COVID-19 patients [25]. The COVID-19 pandemic has conditioned a reduction in the monitoring of delirium, in the establishment of preventive measures and patient care, a greater use of deep sedation with benzodiazepines and neuromuscular blockade in intubated patients, greater immobility, lack of personnel specialist, decreased communication with health personnel and reduced access to rehabilitation and family visits. All of these limitations have increased the incidence of delirium. In this situation, detection of delirium has been a very low-priority measure. The management of delirium or agitation in the COVID-19 patient does not differ from the treatment performed in other aetiologies. The use of sedative and/or neuroleptic medication continues to be the most widely used therapeutic option in these patients. In the experience of the authors of this review, in a series of 321 patients with ARF due to COVID-19 treated with NIV, 19.6% developed hyperactive delirium with great agitation. All patients received treatment with antipsychotic drugs, the most frequent being olanzapine (96.8%), haloperidol (77.8%) and tiapride (50.8%). The most used sedative drugs were dexmedetomidine (71.4%), intravenous benzodiazepines

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(14.3%) and propofol (3.1%). Ninety percent of the patients required a combination of antipsychotic drugs and sedatives.

19.7 Conclusion The presence of agitation or hyperactive delirium is common in critically ill patients. Patients with ARF and NIV are especially vulnerable. The persistence of symptoms or the presence of severe agitation often requires the use of sedative medication and antipsychotics. Although there is no evidence for the use of one drug over others, the use of medication with a short onset of action and for short periods of time is preferred. Key Messages  ARF patients treated with NIV frequently present poor tolerance, agitation or delirium. • NIV failure is related to the presence of intolerance or agitation. • The prevention of delirium in the ICU must be carried out fundamentally with non-pharmacological measures. • Current evidence on the treatment of the patient with delirium does not support the use of antipsychotic drugs. • Patients with distressing symptoms or severe agitation may be treated with antipsychotic drugs and/or sedatives.

References 1. Bourke SC, Piraino T, Pisani L, Brochard L, Elliott MW.  Beyond the guidelines for non-­ invasive ventilation in acute respiratory failure: implications for practice. Lancet Respir Med. 2018;6(12):935–47. https://doi.org/10.1016/S2213-­2600(18)30388-­6. 2. Nava S, Ceriana P. Patient-ventilator interaction during noninvasive positive pressure ventilation. Respir Care Clin N Am. 2005;11(2):281–93. https://doi.org/10.1016/j.rcc.2005.02.003. 3. Liu J, Duan J, Bai L, Zhou L. Noninvasive ventilation intolerance: characteristics, predictors, and outcomes. Respir Care. 2016;61(3):277–84. https://doi.org/10.4187/respcare.04220. 4. Ni YN, Wang T, Yu H, Liang BM, Liang ZA. The effect of sedation and/or analgesia as rescue treatment during noninvasive positive pressure ventilation in the patients with interface intolerance after extubation. BMC Pulm Med. 2017;17(1):125. https://doi.org/10.1186/ s12890-­017-­0469-­4. 5. Antonelli M, Conti G, Moro ML, Esquinas A, Gonzalez-Diaz G, Confalonieri M, et  al. Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study. Intensive Care Med. 2001;27(11):1718–28. https://doi.org/10.1007/s00134-­001-­1114-­4. 6. Tate JA, Devito Dabbs A, Hoffman LA, Milbrandt E, Happ MB.  Anxiety and agitation in mechanically ventilated patients. Qual Health Res. 2012;22(2):157–73. https://doi. org/10.1177/1049732311421616.

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23. Collet MO, Caballero J, Sonneville R, Bozza FA, Nydahl P, Schandl A, et al. Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study. Intensive Care Med. 2018;44(7):1081–9. https://doi. org/10.1007/s00134-­018-­5204-­y. 24. Duprey MS, Devlin JW, van der Hoeven JG, Pickkers P, Briesacher BA, Saczynski JS, et al. Association between incident delirium treatment with haloperidol and mortality in critically ill adults. Crit Care Med. 2021;49(8):1303–11. https://doi.org/10.1097/CCM.0000000000004976. 25. Ragheb J, McKinney A, Zierau M, Brooks J, Hill-Caruthers M, Iskander M, et al. Delirium and neuropsychological outcomes in critically ill patients with COVID-19: a cohort study. BMJ Open. 2021;11(9):e050045. https://doi.org/10.1136/bmjopen-­2021-­050045.

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Omar Soubani, Ashika Bains, and Ayman O. Soubani

20.1 Psychiatric and Respiratory Illness Psychiatric and respiratory illnesses have an intricate bidirectional association made more complex with the added consideration of iatrogenic effects. Psychiatric illness can predispose a patient to poor self-care including less healthy habits and non-­ adherence to medications for chronic illnesses such as asthma, chronic obstructive pulmonary disorder (COPD), obstructive sleep apnea (OSA), and others, leading to exacerbations of underlying pulmonary conditions. Additionally, it can be difficult to discern if somatic symptoms such as fatigue, palpitations, hyperventilation, or chest tightness originate from psychiatric or respiratory illnesses as there can be significant symptomatic overlap in diagnosis. Chronic neurovegetative symptoms from undertreated underlying medical conditions can present as psychiatric illness. Certain treatments for depression or anxiety disorder can worsen pulmonary function and, vice versa, there are important neuropsychiatric sequelae to consider when choosing medication for respiratory illnesses.

O. Soubani Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA e-mail: [email protected] A. Bains Department of Psychiatry, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA, USA e-mail: [email protected] A. O. Soubani (*) Division of Pulmonary, Critical Care, and Sleep Medicine, Wayne State University School of Medicine, Detroit, MI, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_20

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20.1.1 Asthma and Depression Patients suffering from asthma have a higher prevalence of depressive disorders, which are characterized by chronic depressed mood and loss of pleasure in daily activities. Furthermore, neurovegetative symptoms of depression such as fatigue, anergia, and sleep distortion can resemble chronic untreated asthma. There is a link between psychological features of denial, fear, and inappropriate coping skills and suboptimal asthma control, leading to exacerbations and increased use of health care services like the emergency department. There is also an increased risk of sudden death, which may be due to poor compliance for treatment of asthma among patients with depressive disorders. It has been speculated that depressed patients have an impaired voluntary respiratory drive when compared with non-depressed patients. A cross-sectional study also demonstrated that depression was independently associated with reduced bronchodilator response among participants with asthma [1]. Symptomatic depression is associated with higher incident asthma, service utilization, and poor outcomes, making screening for depression an aspect of comprehensive care of patients with asthma. Clinicians may consider screening tools such as Patient Health Questionnaire-9 (PHQ-9) or Beck’s Depression Inventory to track symptoms and response. Treatment of depression in these patients with first-line treatments such as SSRIs or SNRIs may improve pulmonary function. A study using citalopram showed reduction in the need for oral corticosteroid and improvement in asthma symptoms and asthma-related quality of life (QOL) [2]. A small study of trial of escitalopram for patients with asthma and depressive symptoms demonstrated an improvement in asthma control (via a questionnaire) and reduction in oral corticosteroid use in patients with severe asthma with use of escitalopram [3]. SSRIs mostly lack the cholinergic and adrenergic effects that would alter respiratory function. Citalopram and escitalopram may increase the risk of QTc prolongation when combined with albuterol. Second-line treatments such as tricyclic antidepressants have shown moderate effect, which may be related to anticholinergic effects of tricyclics causing bronchodilation [2].

20.1.2 Asthma and Anxiety Anxiety disorders are more common in patients with asthma than in the general population [2]. Symptoms of dyspnea, chest tightness, and choking sensations are common in both anxiety disorders and asthma. The presence of asthma is also a risk factor for the development of a panic disorder [4]. Patients with co-morbid asthma and anxiety disorders often report perceptions of dyspnea despite the absence of physiologic changes in airways. Some have theorized that there is a cyclical link between dyspnea and fear, where hyper ventilatory panic attacks arise from an emotional response to severe breathlessness. This can lead to overuse of medications and unnecessary steroid treatment which increases risk of neuropsychiatric

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medication side effects. The most common psychiatric side effects of steroid treatment include agitation, anxiety, distractibility, fear, insomnia, irritability, rapid speech, restlessness, and tearfulness. Relaxation therapies, including hypnotherapy, biofeedback techniques, and mental and muscle relaxation therapies have shown modest benefits in patients with co-morbid anxiety and asthma [5].

20.1.3 Chronic Obstructive Pulmonary Disease and Psychiatric Illness Smokers are more likely to meet criteria for mood, anxiety, and psychotic disorder when compared to non-smokers [6]. Conversely, individuals with psychiatric disorders are far more likely to smoke cigarettes. The most commonly held view is that patients with mental health conditions smoke in an effort to regulate the symptoms associated with their disorder [6]. Long-term smokers have a higher risk of developing COPD. Some studies have estimated that up to 40% of COPD patients experience depressive episodes, 15.8% meet criteria for generalized anxiety disorder, and 37% report symptoms of panic disorder [7]. Patients with COPD and these comorbid mental illnesses have greater disability, decreased functional capacity and lung function, and higher morbidity [8]. As mentioned above, treatment of these mental illnesses with antidepressants, specifically nortriptyline, for its anticholinergic effects, has shown some benefits in the functional status of these patients [2]. Psychotic illnesses such as schizophrenia, schizoaffective disorder, and bipolar disorder have an even higher association with smoking cigarettes, with 71.6% of individuals suffering from schizophrenia smoking cigarettes [9]. Some have suggested that cigarette smoking briefly dulls auditory hallucinations, improves negative symptoms of schizophrenia, increases metabolism of antipsychotic medications, and reduces medication-induced Parkinsonism [10]. Chronic smoking is a major risk factor for developing COPD and individuals suffering from schizophrenia and bipolar disorder having a higher prevalence of COPD as compared to the general population [11]. These patients are less likely to follow up with outpatient care or take long-acting bronchodilators and have a higher mortality rate following a COPD exacerbation [12].

20.1.4 Obstructive Sleep Apnea and Psychiatric Illness Symptomatic overlap with obstructive sleep apnea (OSA), depression, and anxiety may complicate diagnosis and treatment of each individual disorder. Studies have shown that patients with OSA are at higher risk for depression and anxiety and more likely to present with these symptoms rather than those typical of OSA [13, 14]. There have even been case reports of recurrent delirium and psychosis in patients with OSA that resolved with CPAP [15]. Effective screening and treatment of mental disorders in the setting of OSA may improve patient outcomes and prevent

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further illness. Conversely, psychiatric patients, specifically those taking CNS depressants, CNS stimulants, and mood stabilizers are at high risk for developing OSA and should be screened appropriately [16].

20.2 Medication Side Effects 20.2.1 Psychiatric Side Effects of Pulmonary Medications Psychiatric side effects may develop with the use of medications used in the management of pulmonary diseases and critical illnesses. Side effects can resemble primary psychiatric disorders and can appear at any time during the course of treatment. Clinicians should consider iatrogenic effects in the differential if a patient presents with new-onset psychiatric symptoms, particularly if the symptoms are acute in the onset and the patient does not have a prior psychiatric history. The psychiatric side effects of medications can occur with regular doses, with high doses, or even after discontinuation of the medication (withdrawal). The factors that increase the risk of psychiatric side effects from pulmonary medications include age (extremes of age), organ dysfunction (such as renal or hepatic), past or present psychiatric disorder, critical illness and stressful situations, polypharmacy, and higher doses or narrow therapeutic index of the medication [17]. The criteria that suggest that the psychiatric symptom is related to a medication include: • Temporal relation between the start of the medication and the development of symptoms. • The medication is known to cause psychiatric side effects. • Other conditions that may lead to the symptoms have been ruled out. • Improvement or resolution of the symptoms with the discontinuation of the medication. • Re-appearance of the symptoms by re-challenging the patient with the same medication. It is worth noting that not all of these criteria must be met to attribute side effects to a particular medication. Commonly, high index of suspicion associated with sound clinical judgment are the basis of attributing the side effect to a medication. Medications used in the management of pulmonary conditions can cause a wide range of psychiatric side effects that include anxiety, depression, mania, psychosis, hallucinations, delusions, and suicidal ideations. Patients may also present with disordered sleep, confusion, and agitation. Table 20.1 provides a description of medications commonly used in the management of respiratory diseases that have been associated psychiatric side effects (Drug Information Portal).

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Table 20.1  Psychiatric side effects of medications commonly used in respiratory diseases Class of medication Clinical use Antibiotics Pneumonia and other respiratory infections

Psychiatric side effects −  Penicillins and Cephalosporins: Irritability, anxiety, and hallucinations −  Quinolones: Sleep and mood disturbances, psychosis − Antimycobacterial medications (isoniazid, rifampicin, and ethionamide): Irritability, depression, psychosis, and suicidal ideations Aggression, agitation, anxiety, depersonalization, depression, delirium, psychosis. Short-term use of steroids typically causes anxiety, while chronic use will lead to depressive states

Corticosteroids

Management of acute exacerbation of COPD or asthma and interstitial lung disease

Leukotriene modifiers

Long-term management of asthma

Bupropion

Smoking cessation

Varenicline

Smoking cessation

Agitation, aggression, depression, sleep disturbances, suicidal ideations Increased energy, insomnia, agitation, and nervousness. Can worsen preexisting anxiety and panic disorders. Can precipitate manic episode in bipolar patients. Rare cases of psychosis and suicidal ideations have been reported Depression, suicidal ideation, night terrors

Bronchodilators-­ aminophylline and salbutamol

Treatment of airway diseases

Agitation, euphoria, and delirium

Comments

Risk of psychiatric side effects increases with higher doses, duration of treatment, older age, and underlying psychiatric or personality disorders. Withdrawal of corticosteroids may induce insomnia, mood changes, and cognitive impairment Rare

Inhibits norepinephrine and dopamine re-uptake. It also inhibits nicotinic acetylcholine receptors. Can lower seizure threshold Blocks the ability of nicotine to activate α4β2 receptors and thus stimulates the central nervous mesolimbic dopamine system, leading to decreased cravings

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These psychiatric side effects can affect compliance of medications or may force clinicians to discontinue treatment, which may in turn lead to deterioration of the underlying lung disease. When the psychiatric side effects are severe, but the patient is in the need of treatment to maintain respiratory function, simultaneous treatment of psychiatric symptoms may be required (antipsychotics, mood stabilizer, and benzodiazepines). Failure to control these symptoms (agitation, depression, and psychosis) may in turn lead to worsening of respiratory status such as acute respiratory failure. However, careful consideration is required with the use of psychotropic medications as they may also cause respiratory depression as previously mentioned.

20.2.2 Pulmonary Side Effects of Psychiatric Medications Benzodiazepines are primarily utilized in the treatment of anxiety disorders, acute treatment for seizures, and management of GABAergic withdrawal given the mechanism of action of gamma-amino butyric acid (GABA) receptor agonists. Benzodiazepines, given alone or in combination with opiates, cause produce respiratory depression, aspiration, confusion, falls, and death in patients with respiratory compromise [18, 19]. Long-term antidepressant use can result in other side effects; for instance, some antidepressants have been associated with hypertension or some has been associated with weight gain. This can produce downstream pulmonary consequences. Pulmonary complications have been reported in TCA overdose. Antipsychotic use and respiratory complications are discussed in detail further in the chapter.

20.3 Critically Ill Patients and Psychiatric Illness As outlined above, psychiatric comorbidities can contribute to less healthy lifestyle, poor medication compliance for chronic pulmonary disease, and adverse pulmonary side effects of certain psychotropic medications. Taken together, this may increase the risk for multiple exacerbations of pulmonary illnesses and acute respiratory failure requiring admission to the intensive care unit (ICU), noninvasive mechanical ventilation, and invasive mechanical ventilation, which are associated with higher rates of mortality. Traumatic experiences in the ICU can lead to the development of psychiatric complications, including depression, anxiety, and trauma responses. Post-traumatic stress disorder (PTSD) after ICU admission is commonly missed, with reported incidence between 4% and 25% [2]. Length of ICU hospitalization and mechanical ventilation, level of sedation, and recollection of traumatic memories are among the risk factors for the development of post ICU PTSD [20]. There has been some debate regarding the use of sedation of mechanically ventilated patients and the future development of PTSD.  Some studies have found that the fewer memories recalled from ICU admission correlated with less PTSD symptoms, suggesting total amnesia using sedation to prevent the development of PTSD [21].

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Others have found that interruption of daily sedation in mechanically ventilated patients led to fewer subsequent symptoms of PTSD [22].

20.3.1 Delirium Diagnosis and Epidemiology The use of noninvasive positive pressure ventilation (NIPPV) in the treatment of ARF has become common with several advantages over invasive ventilation. Delirium has been postulated to be an important factor contributing to NIPPV failure. Delirium is a syndrome characterized by fluctuating impairments in consciousness, sensorium, attention, and perception. The pathophysiology of delirium can be multifactorial; common etiologies include pneumonia, anemia, pulmonary embolism, acute respiratory failure, and others. Hypoxia is considered one of the life-­ threatening causes of delirium. Rates of delirium for patients in intensive care units are estimated to be approximately 30%, and rates for patients who require intubation or mechanical ventilation are estimated to be upwards of 80% [23, 24]. Studies have found that delirium is associated with increased length of hospital stay, longer duration of mechanical ventilation, and increased risk of mortality [23, 25]. Additional studies have established an association between delirium and cognitive impairment, increased mortality, and worse activities of daily living (ADL) scores after discharge [24, 26, 27]. An observational study evaluating delirium and outcomes in noninvasive ventilation has found that delirium is associated with increases in poor outcomes such as NIV failure, ICU mortality, and hospital mortality [28]. Another observational study followed patients for a year and reported the presence of delirium as a strong predictor of mortality [29]. Given the acute and chronic impact of delirium, identification, prevention, and treatment of delirium are important aspects for care for critically ill patients. Screening tools such as the Intensive Care Delirium Screening Checklist (ICDSC) or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) are validated bedside tools that enable clinicians to screen critically ill patients for delirium. However, the heterogeneity of presentation can result in diagnostic challenges. The Diagnostic and Statistical Manual of Mental Disorders (DSM) denotes a diagnosis of delirium as an acute onset (hours to days) of disturbance in attention and orientation, which represents a change from baseline mentation, tends to fluctuate in severity during the day and has evidence that the disturbance is a direct physiological consequence. Of the motor subtypes, hyperactive delirium characterized by psychomotor agitation is more frequently identified than hypoactive, which presents as lethargy and carries a worse prognosis. Many risk factors such as age, baseline major neurocognitive disorder, and severity of illness contribute to risk of development of delirium.

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20.3.2 Delirium Management Nonpharmacologic interventions are thought to be effective in the prevention and treatment delirium. Strategies include minimizing polypharmacy, conducting spontaneous awakening and breathing trials, daily interruption of sedation, encouraging early mobility, family participation, and regulating sleep-wake cycle. A recent systematic review and meta-analysis reviewed 35 studies for the effects of nonpharmacological interventions for the prevention of ICU delirium and concluded that overall nonpharmacological interventions were more effective in shortening the duration of delirium than lowering delirium occurrence [30]. The interventions were classified into one of nine categories: multicomponent, physical environment, daily interruption of sedation, exercise, patient education, automatic warning system, cerebral hemodynamics improvement, family participation, and sedationreducing protocol. Physical environment referred to providing appropriate stimulation while reducing unnecessary stimulation at night, and multicomponent referred to a combination of some of the nine interventions. The review reported multicomponent interventions significantly reduced the occurrence of delirium and did not significantly shorten the duration of delirium. Physical environment interventions did not have significant effects on either the occurrence or the duration of delirium, though multicomponent interventions included environmental interventions. No adverse effects were reported due to nonpharmacological interventions. Pharmacological interventions are aimed at reducing harms such as management of agitation and promotion of sleep at nighttime. Special attention should be paid to medications that have been associated with the development of delirium such as benzodiazepines, anticholinergic agents, and certain opiates such as meperidine. Pharmacological approaches are varied, and clinicians need to consider risk-benefit ratios and multiple available therapeutic interventions without having evidence from direct comparisons or head-to-head trials. A systematic review and meta-analysis of interventions for delirium in ICU patients reported alpha2 agonists such as dexmedetomidine may reduce duration of mechanical ventilation as compared to benzodiazepines, may reduce length of ICU stay as compared with placebo and antipsychotics, and may reduce the odds of delirium occurrence relative to placebo. The evidence was less certain for opioids, sedation interruption, or protocolized sedation in this review [31]. The properties of dexmedetomidine, including minimal impact on respiratory effort, make it a more favorable medication as compared to benzodiazepines, which can increase delirium prevalence, worsen sleep architecture, and suppress respiratory drive. A Cochrane review of interventions for preventing delirium in ICU patients reviewed randomized controlled trials (RCTs) of adult medical or surgical ICU patients [32]. Two studies reviewed utilized early treatment with haloperidol during the ICU admission and found no difference between groups in the outcomes of in-­ hospital mortality within 28  days, the number of delirium- and coma-free days, ventilator-free days, or length of stay in the ICU.  The studies did report adverse effects of prolonged QT intervals and extrapyramidal effects, unrelated to medication in one study. The results together indicated a limited role for haloperidol in

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prophylaxis treatment of delirium. A study examining the effect of dexmedetomidine versus lorazepam, both administered as infusions in ICU participants until extubation or for a maximum of 120 h, reported no effect on the event rate of ICU delirium, in-hospital mortality, ventilator-free days, or length of stay in the ICU. The dexmedetomidine group had more delirium- and coma-free days within 12 days. The quality of the evidence was considered low for these outcomes due to a single study. That being said, further investigations of alpha2 agonist are required to assess for utility in delirium. A study of 90 ICU participants with less severe disease receiving noninvasive mechanical ventilation assessed trial of either dexmedetomidine, haloperidol, or saline infusions and reported a reduced event rate of ICU delirium in the dexmedetomidine group compared to the haloperidol group with a number needed to treat for an additional benefit of three. In-hospital mortality was similar in all three groups. The dexmedetomidine group compared to haloperidol group and placebo group had a shorter length of ICU stay. Adverse events reported were bradycardia, arrhythmia, and QTc interval.

20.3.3 Agitation Management and Antipsychotic Medications Antipsychotic medications are commonly utilized in agitation management for patients with hyperactive delirium. Atypical antipsychotics have lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. Antipsychotic use, however, is not without risk of adverse events. Clinicians must weigh the benefits with the risk of use. Due to histamine receptor antagonism, antipsychotics can be sedating, and antipsychotics with high muscarinic receptor antagonism could precipitate delirium as well as dysregulate circadian rhythm. Antipsychotics may also decrease the seizure threshold, cause metabolic derangements such as hyperglycemia, some associated with QTc prolongation, and can cause neuroleptic malignant syndrome (NMS). Though this is rare, NMS is a serious and potentially fatal adverse effect that typically occurs within 2 weeks of exposure to a neuroleptic medication. Symptoms include muscle rigidity, hyperthermia, autonomic instability, and altered mental status. Respiratory distress occurs in about a third of patients with NMS and is a predictor of mortality. Risk of developing NMS is related to higher doses, rapid dose escalation, intravenous and intramuscular administration, and antipsychotics with greater D2 blockade. Higher rates of QTc prolongation were associated with first-generation antipsychotics, and second-­ generation antipsychotics are associated with an increased risk of death, particularly in the elderly, which may be dose dependent.

20.3.4 Antipsychotic Medication and Respiratory Complications Respiratory complications from antipsychotic use are less common or may be underreported in the literature. The antipsychotic adverse effect of ARF is controversial. Case reports have documented difficulty breathing and ARF in patients

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within hours to days of starting antipsychotic medications [33]. One study showed a strong association between antipsychotic agents and the risk of developing acute respiratory failure in patients with COPD: in a large case-crossover study in Taiwan, 61,620 patients with COPD were evaluated to identify if a relationship existed between antipsychotic use and ARF. The population-based study used the Taiwan National Health Insurance Research Database to study patients with COPD who were newly diagnosed with ARF in hospital or emergency care settings necessitating intubation or mechanical ventilation. Results showed an increased risk of ARF if the patient was given antipsychotic medications, regardless of class and administration route. The study reported a 66% increased risk of ARF regardless of baseline COPD severity within 2 weeks of antipsychotic initiation. The risk of ARF was dose dependent, with a number needed to harm of 87 for high-dose antipsychotics. Typical and atypical antipsychotics were found to have a similar risk of ARF [34, 35]. A large case control study revealed a twofold increased risk of ARF with current use of antipsychotics compared with nonuse. These findings persisted with case-­ crossover analysis and comparison with carbamazepine. Researchers also noted decreased risks of developing ARF within 15–90  days of discontinuing antipsychotic therapy [36]. Deep vein thrombosis and fatal pulmonary embolism is also rarely reported in patients using antipsychotic medications. Studies have suggested a higher risk of fatal PE in patients using antipsychotics, specifically first-generation agents and clozapine [37]. Special consideration should be taken with the use of antipsychotics in the demented elderly. Currently, there are no FDA-approved antipsychotic medications for the management of agitation in these patients. Based on the current evidence, it seems that risperidone, aripiprazole, and olanzapine are the most efficacious for the reduction of aggressive and agitated behavior in these patients. This should be weighed against the increased risk of cardiac-related complications such as sudden cardiac death [38]. These patients are also at risk of aspiration pneumonia, likely due to anticholinergic and H1 receptor blocking actions, causing sedation, dry mouth, and subsequent impairment of bolus transport [39, 40]. Another possible and important mechanism to consider is extrapyramidal symptoms from antipsychotics in the form of laryngeal dystonia, which presents as dyspnea, stridor, and extreme distress. The classic case of acute laryngeal dystonia presents in young males during the first days of high-potency antipsychotic therapy, often seen grabbing their throats. The use of antipsychotics to control agitation in the ICU in medication-­naive patients who present with difficulty breathing or swallowing should raise a high index of suspicion for acute laryngeal dystonia. Acute laryngeal dystonia is considered an emergency: the patient’s airway should be maintained, the antipsychotic stopped, and anticholinergics, such as benztropine, given intramuscularly or intravenously [41].

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20.3.5 Delirium and Acute Respiratory Distress Syndrome A multi-center prospective cohort study of ICU patients revealed that acute respiratory distress syndrome (ARDS) was independently associated with higher odds for delirium compared with mechanical ventilation without ARD suggesting respiratory disease has its own pathophysiological connection toward delirium [42]. A hypothesis outlining the potential mechanism for pathogenesis of delirium in acute respiratory failure is neuroinflammation and cerebral hypoperfusion. Inflammation regulatory proteins known as cytokines are known to modulate the permeability of the blood-brain barrier by altering the resistance of tight gap junctions of endothelial cells, thereby providing a connection between peripheral and central inflammation. Microglia, specialized cell types associated with cerebral inflammation, activate in response to cytokines or other signaling molecules of acute inflammation. Inflammation can also lead to disruption in cerebral blood flow. It is theorized that patients with ARDS develop hypoxemia, which subsequently contributes to neuroinflammation and altercations in cerebral perfusion precipitating delirium. Although many neurotransmitter systems have been implicated, commonly neurotransmitter disruption associated with the development of delirium includes reduced acetylcholine, elevated levels of dopamine, norepinephrine, and/or glutamate [43]. The connection between respiratory illness and delirium becomes more involved as studies of delirium in SARS-COV-2 cases have been becoming more prevalent. Recently published articles relay that an acute confusion/delirium can be a primary manifestation of COVID-19 and should be recognized as a potential feature of infection [44, 45]. There have been reports of altered mental status without respiratory symptoms or respiratory failure, which raise the concern of central nervous system (CNS) injury, the pathophysiology by which SARS-CoV-2 causes encephalopathy is unknown. Investigators have proposed potential mechanisms such as infectious spread to the CNS, neuroinflammation as described above, autoimmune reactions, and hypoxemic/thrombotic neuronal injury. Baller et  al. proposed an algorithm for the management of delirium in patients with SARS-COV-2 infection beginning with maximizing behavioral management approaches as discussed above and reserving pharmacologic treatment for cases where behavior strategies are insufficient. Pharmacologic treatment algorithm, extrapolated from previous delirium literature and clinical experience from the Massachusetts General Hospital Consultation-Liaison Psychiatry COVID-19 Workgroup, suggested using melatonin at first for circadian rhythm regulation, then alpha2 agonists as needed for agitation, then low potency antipsychotic agents if needed for continued agitation [46].

20.3.6 Acute Respiratory Failure Associated with Psychiatric Conditions or Anti-psychotic Medications The management of acute respiratory failure that may be associated with psychiatric conditions, or with the use of antipsychotic medications or the psychiatric side

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effects of medications used in the management of pulmonary diseases as detailed above, is usually complex and needs to be individualized. As a general rule, the management should follow the that of acute respiratory failure in other conditions and takes into consideration the severity and acuity of the situation, the patient’s hemodynamic status, mental status and ability to cooperate with treatment, and the type of respiratory failure (primarily hypoxemic vs hypercapnic). In patients who are relatively hemodynamically stable, primarily hypercapnic, and can cooperate with treatment, an approach that utilizes noninvasive ventilation should be considered. Such patients should be closely monitored in an intensive care setting whenever is possible as their condition may deteriorate and they may require intubation and invasive mechanical ventilation [47]. It is also worth noting in this context that noninvasive ventilation may lead to or worsen delirium in critically ill patients. Delirium was estimated to have a pooled prevalence of 37% in a meta-­analysis with a pooled risk ratio at 2.12 (95% CI 1.41–3.18) [48]. These patients should be routinely assessed for delirium using a standardized scale such as confusion assessment method (CAM) or CAM for intensive care unit (CAM-ICU).

References 1. Gerald JK, Moreno FA.  Asthma and depression: It's complicated. J Allergy Clin Immunol. 2016;4(1):74–5. 2. Shanmugam G, Bhutani S, Khan DA, Brown ES.  Psychiatric considerations in pulmonary disease. Psychiatr Clin N Am. 2007;30(4):761–80. 3. Brown ES, Sayed N, Van Enkevort E, Kulikova A, Nakamura A, Khan DA, Ivleva EI, Sunderajan P, Bender BG, Holmes T. A randomized, double-blind, placebo-controlled trial of escitalopram in patients with asthma and major depressive disorder. J Allergy Clin Immunol. 2018;6(5):1604–12. 4. Carr RE. Panic disorder and asthma. J Asthma. 1999;36(2):143–52. 5. Meuret AE, Ritz T.  Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies. Int J Psychophysiol. 2010;78(1):68–79. 6. Minichino A, Bersani F, Calò W, Spagnoli F, Francesconi M, Vicinanza R, et  al. Smoking behaviour and mental health disorders—mutual influences and implications for therapy. Int J Environ Res Public Health. 2013;10(10):4790–811. 7. Chaudhary SC, Nanda S, Tripathi A, Sawlani KK, Gupta KK, Himanshu D, Verma AK. Prevalence of psychiatric comorbidities in chronic obstructive pulmonary disease patients. Lung India. 2016;33(2):174. 8. Abrams TE, Vaughan-Sarrazin M, Vander Weg MW. Acute exacerbations of chronic obstructive pulmonary disease and the effect of existing psychiatric comorbidity on subsequent mortality. Psychosomatics. 2011;52(5):441–9. 9. Kheradmand A, Ziaaddini H, Vahabi M.  Prevalence of cigarette smoking in schizophrenic patients compared to other hospital admitted psychiatric patients. Eur Psychiatry. 2011;26(S2):1417. 10. Dervaux A, Laqueille X.  Tobacco and schizophrenia: therapeutic aspects. L’Encephale. 2007;33(4):629–32. 11. Zareifopoulos N, Bellou A, Spiropoulou A, Spiropoulos K. Prevalence of comorbid chronic obstructive pulmonary disease in individuals suffering from schizophrenia and bipolar disorder: a systematic review. COPD: J Chron Obstruct Pulmon Dis. 2018;15(6):612–20.

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12. Jørgensen M, Mainz J, Lange P, Paaske JS. Quality of care and clinical outcomes of chronic obstructive pulmonary disease in patients with schizophrenia. A Danish nationwide study. Int J Qual Health Care. 2018;30(5):351–7. 13. Ejaz SM, Khawaja IS, Bhatia S, Hurwitz TD. Obstructive sleep apnea and depression. Innov Clin Neurosci. 2011;8(8):17–25. 14. Rezaeitalab F, Moharrari F, Saberi S, Asadpour H, Rezaeetalab F. The correlation of anxiety and depression with obstructive sleep apnea syndrome. J Res Med Sci. 2014;19(3):205–10. 15. Lombardi C, Rocchi R, Montagna P, Silani V, Parati G. Obstructive sleep apnea syndrome: a cause of acute delirium. J Clin Sleep Med. 2009 Dec;05(06):569–70. 16. Tanielian M, Doghramji K, Certa K. Obstructive sleep apnea in psychiatric inpatients. J Nerv Ment Dis. 2020;208(3):190–3. 17. Gupta A, Chadda RK. Adverse psychiatric effects of non-psychotropic medications. BJPsych Adv. 2016;22(5):325–34. 18. Ekstrom MP, Bornefalk-Hermansson A, Abernethy AP, Currow DC. Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study. BMJ. 2014;348:445. 19. Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system–mediated effects. Ochsner J. 2013;13(2):214–23. 20. Schelling G, Stoll C, Haller M, Briegel J, Manert W, Hummel T, et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med. 1998;26(4):651–9. 21. Jackson JC, Hart RP, Gordon SM, Hopkins RO, Girard TD, Ely EW.  Post-traumatic stress disorder and post-traumatic stress symptoms following critical illness in medical intensive care unit patients: assessing the magnitude of the problem. Crit Care. 2007;11(1):27. 22. Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003;168(12):1457–61. 23. Caplan JP.  Delirious patients. In: Stern TA, Freudenreich O, Smith FA, Fricchione GL, Rosenbaum JF, editors. Handbook of general hospital psychiatry. 7th ed. Amsterdam: Elsevier; 2018. p. 83–93. 24. Brummel NE, Jackson JC, Pandharipande PP, Thompson JL, Shintani AK, Dittus RS, Gill TM, Bernard GR, Ely EW, Girard TD. Delirium in the intensive care unit and subsequent long-term disability among survivors of mechanical ventilation. Crit Care Med. 2014;42(2):369. 25. Lin SM, Liu CY, Wang CH, Lin HC, Huang CD, Huang PY, Fang YF, Shieh MH, Kuo HP. The impact of delirium on the survival of mechanically ventilated patients. Crit Care Med. 2004;32(11):2254–9. 26. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753–62. 27. Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, Serafim RB, Stevens RD.  Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015;350:h2538. 28. Zhang R, Bai L, Han X, Huang S, Zhou L, Duan J. Incidence, characteristics, and outcomes of delirium in patients with noninvasive ventilation: a prospective observational study. BMC Pulm Med. 2021;21(1):1–8. 29. Chan KY, Cheng LS, Mak IW, Ng SW, Yiu MG, Chu CM.  Delirium is a strong predictor of mortality in patients receiving non-invasive positive pressure ventilation. Lung. 2017;195(1):115–25. 30. Kang J, Lee M, Ko H, Kim S, Yun S, Jeong Y, Cho Y. Effect of nonpharmacological interventions for the prevention of delirium in the intensive care unit: a systematic review and meta-­ analysis. J Crit Care. 2018;48:372–84. 31. Burry LD, Cheng W, Williamson DR, Adhikari NK, Egerod I, Kanji S, Martin CM, Hutton B, Rose L.  Pharmacological and non-pharmacological interventions to prevent delirium in critically ill patients: a systematic review and network meta-analysis. Intensive Care Med. 2021;47(9):943–60.

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32. Herling SF, Greve IE, Vasilevskis EE, Egerod I, Mortensen CB, Møller AM, Svenningsen H, Thomsen T. Interventions for preventing intensive care unit delirium in adults. Cochrane Database Syst Rev. 2018;11:CD009783. 33. Jabeen S, Polli SI, Gerber DR. Acute respiratory failure with a single dose of quetiapine fumarate. Ann Pharmacother. 2006;40(3):559–62. 34. Wang M-T, Tsai C-L, Lin CW, Yeh C-B, Wang Y-H, Lin H-L. Association between antipsychotic agents and risk of acute respiratory failure in patients with chronic obstructive pulmonary disease. JAMA Psychiatry. 2017;74(3):252–60. 35. Torbic H, Duggal A. Antipsychotics, delirium, and acute respiratory distress syndrome: what is the link? Pharmacotherapy. 2018 Apr;38(4):462–9. 36. Wang M, Lin CW, Tsai C, Wang Y, Lai J, Yeh C, et al. Use of antipsychotics and the risk of acute respiratory failure among adults: a disease risk score-matched nested case–control study. Br J Clin Pharmacol. 2020;86(11):2204. 37. Manoubi SA, Boussaid M, Brahim O, Ouanes S, Mahjoub Y, Zarrouk L, et al. Fatal pulmonary embolism in patients on antipsychotics: case series, systematic review and meta-analysis. Asian J Psychiatr. 2022;73(1):103–5. 38. Marvanova M. Antipsychotic use in elderly patients with dementia: efficacy and safety concerns. Ment Health Clin. 2014;4(4):170–6. 39. Steinberg M, Lyketsos CG. Atypical antipsychotic use in patients with dementia: managing safety concerns. Am J Psychiatr. 2012;169(9):900–6. 40. Gareri P, Manfredi V, De Fazio P, Bruni A, Ciambrone P, Cerminara G, et al. Use of atypical antipsychotics in the elderly: a clinical review. Clin Interv Aging. 2014;9:1363–73. 41. Christodoulou C, Kalaitzi C. Antipsychotic drug-induced acute laryngeal dystonia: two case reports and a mini review. J Psychopharmacol. 2005;19(3):307–11. 42. Hsieh SJ, Soto GJ, Hope AA, Ponea A, Gong MN. The association between acute respiratory distress syndrome, delirium, and in-hospital mortality in intensive care unit patients. Am J Respir Crit Care Med. 2015;191(1):71–8. 43. Maldonado JR. Acute brain failure: pathophysiology, diagnosis, management, and sequelae of delirium. Crit Care Clin. 2017;33(3):461–519. 44. Beach SR, Praschan NC, Hogan C, Dotson S, Merideth F, Kontos N, Fricchione GL, Smith FA. Delirium in COVID-19: a case series and exploration of potential mechanisms for central nervous system involvement. Gen Hosp Psychiatry. 2020;65:47–53. 45. Harapan BN, Yoo HJ. Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J Neurol. 2021;268(9):3059–71. 46. Baller EB, Hogan CS, Fusunyan MA, Ivkovic A, Luccarelli JW, Madva E, Nisavic M, Praschan N, Quijije NV, Beach SR, Smith FA.  Neurocovid: pharmacological recommendations for delirium associated with COVID-19. Psychosomatics. 2020;61(6):585–96. 47. Stefan MS, Priya A, Pekow PS, Steingrub JS, Hill NS, Lagu T, et al. A scoring system derived from electronic health records to identify patients at high risk for noninvasive ventilation failure. BMC Pulm Med. 2021;21(1):52. 48. Charlesworth M, Elliott MW, Holmes JD. Noninvasive positive pressure ventilation for acute respiratory failure in delirious patients: understudied, underreported, or underappreciated? A systematic review and meta-analysis. Lung. 2012;190(6):597–603.

Nutrition Drugs: Noninvasive Ventilation

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Hulya Yigit Ozay

21.1 Introduction Nutrition is an integral component of treatment in the intensive care unit (ICU). However, adequate daily calories cannot be given to critically ill patients for various reasons. Although the optimal nutritional route is not reported in the current literature on the nutritional management of critically ill adult patients requiring noninvasive ventilation (NIV), “Nil nutrition” or oral nutrition is reported more frequently than enteral nutrition (EN) or parenteral nutrition (PN). When considering optimal nutrition, adequate intake should not be planned according to a single factor but should be planned by considering both clinical risk and patient outcome [1]. NIV refers to mechanical ventilation delivered through a noninvasive interface, such as a face mask, nasal mask, orofacial mask, or nasal prongs (nasal pillows) [2]. The application of NIV has been accepted as a basic treatment step in the treatment of patients with acute and chronic respiratory failure for 20 years [1]. NIV provides greater comfort and less need for sedation than conventional mechanical ventilation administered through an endotracheal tube. In addition, it can prevent further deterioration of respiratory status and reduces the work of breathing [3]. The prevalence of malnutrition is likely to be high in patients with respiratory failure requiring NIV [4]. While respiratory failure can affect the nutritional status of patients and cause malnutrition, malnutrition can also affect pulmonary structure and respiratory functions and cause respiratory failure. Malnutrition causes atrophy in respiratory muscles, decreased ventilation capacity, parenchymal changes, depressed pulmonary immune function, blunted hypoxic ventilatory response, decreased oxidation and exercise capacity of the muscles, and increased morbidity H. Y. Ozay (*) Department of Anesthesiology and Reanimation, Ankara City Hospital, University of Health Sciences, Ankara, Turkey © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_21

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and mortality [5, 6]. It is known that NIV reduces mortality, especially in patients experiencing acute exacerbations of chronic obstructive pulmonary disease (COPD) or acute cardiogenic pulmonary edema. Both acute respiratory failure and COPD may cause malnutrition that may adversely affect patient outcomes. A large observational study, regarding nutritional support in patients receiving NIV, showed that approximately 60% of patients fasted during the first 2 days of treatment, 32.7% received oral feeding, and 2.6% received enteral nutrition [7]. In the European Society of Parenteral and Enteral Nutrition (ESPEN) guideline, the initiation of medical nutrition therapy for all patients expected to stay in the intensive care unit for more than 48 hours is presented as a strong recommendation (100% agreement). Medical nutrition therapy is a term that includes oral nutritional supplements, EN, and PN [8]. Providing oral or enteral nutritional support during NIV may be perceived as unsafe due to the potential risk of aspiration, so these patients are often deprived of adequate caloric and protein intake [8]. The widespread use of high-flow nasal cannula (HFNC) oxygen therapy in the treatment of respiratory failure in the Covid pandemic has allowed patients to be fed orally without leaving positive pressure ventilation support. However, HFNC has been found to cause a significant increase in the number of minor and massive gastroesophageal refluxes, which impair calorie and protein intake [9]. Critically ill patients often require enteral tubes to provide nutritional support or administer medication. These tubes may increase the risk of air leakage when NIV is delivered via oro-nasal interfaces. Although air leaks can be clinically challenging, they can sometimes be reduced in size by adjusting the patient interface but may increase patient discomfort and cause skin lesions. A closure adapter attached to the ventilator during swallowing in NIV support has proven effective in allowing patients to eat enough [10]. In addition, a new tube adaptor for NIV designed to minimize air leaks has been shown to improve patient comfort and significantly reduce the volume of air leaks in patients with one or two naso-enteral tubes and patients with administered NIV via an oro-nasal mask [11]. The use of NIV poses several barriers to nutrition delivery. Patients may be fasted if intubation is anticipated. For oral intake, removal of the NIV interface may be required and the location of an enteral feeding tube may cause an air leak, which may affect respiratory function [1]. However, enteral feeding via the nasogastric tube is associated with decreased NIV efficiency and tracheobronchial aspiration of stomach contents [12]. Patients must tolerate short periods of withdrawal from NIV to maintain their nutrient intake to meet the increased physiological requirements associated with increased respiratory effort. Increasing ventilatory support should be considered in patients who cannot tolerate these NIV periods [1, 13]. Although enteral nutrition has been associated with a lower infection rate than parenteral nutrition in patients with adequate bowel function in the literature [14, 15], peripheral or central parenteral nutrition should be considered if the patient cannot receive oral or enteral nutrition. The nutritional needs of patients should be reevaluated for the changing clinical conditions and appropriate nutritional support treatments should be established.

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21.2 Medical Nutrition Therapy According to the last updated guideline of ESPEN, if the critically ill patient in the ICU can eat enough to meet 70% of their needs without the risk of vomiting or aspiration, they should be fed orally, and if they cannot be fed orally, they should take EN within the first 48 h. If oral and EN are contraindicated, PN should be initiated within 3–7 days. Gastric access should be used as the standard approach for patients having a functional gastrointestinal tract. Measurement of gastric residual volume (GRV) is common for the assessment of gastrointestinal dysfunction and can help identify EN intolerance during the onset and progression of EN. However, it may not be necessary to monitor EN with continuous GRV measurements. It is suggested that enteral feeding should be delayed when GRV is >500 mL/6 h. In that case, if the abdominal examination does not show acute abdomen complications, the application of prokinetics should be considered. Intravenous erythromycin (usually at dosages of 100–250 mg 3 times a day) should be used in first-line prokinetic therapy. Alternatively, iv metoclopramide (at usual doses of 10  mg two to three times a day) or a combination of metoclopramide and erythromycin may be preferred. Postpyloric nutrition should be used in patients with gastric feeding intolerance that cannot be resolved with prokinetic agents. Jejunal feeding can be performed in patients who are thought to be at high risk of aspiration. Continuous EN should be given instead of bolus EN [8]. Standard enteral products are at a level to meet the daily energy needs of patients.

21.3 Energy Energy expenditure (EE) is variable, depending on age, gender, body mass, type, and severity of the disease. Total energy expenditure in critically ill patients can be measured by indirect calorimetry or estimated using various existing equations and then multiplied by the “stress factor” in the range of 1.0–2.0. Energy can also be calculated as 20–25  kcal/kg/day. In the early stage of acute disease, hypocaloric nutrition (not exceeding 70% of EE) should be applied, and after the third day, it can be increased to 80–100% of EE [8].

21.4 Carbohydrates Carbohydrates are a good non-protein energy source. When carbohydrates, proteins, and fats are used to create energy, the most CO2 formation (RQ = 1) is seen in carbohydrates, while the nutrient that creates the least CO2 (RQ = 0.7) is fats. Depending on the increase in carbohydrates in the diet, the amount of CO2 increases. Since CO2 removal is limited in pulmonary diseases, additional PaCO2 increases minute ventilation and oxygen consumption. Since patients cannot increase alveolar ventilation very much, existing respiratory distress may increase. It is recommended that the ratio of daily energy coming from carbohydrates should be between 40 and

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55% in patients with COPD. It should not be forgotten that insufficient calories will cause rhabdomyolysis, and excess calories will cause an increase in CO2 production [16]. In lung diseases, it is emphasized that the excess of total energy intake rather than the content of the diet will increase the respiratory coefficient. A balanced diet should be applied in terms of calories, in which the amount of carbohydrates does not exceed 5 mg per kilogram per minute [8].

21.5 Proteins While protein-energy malnutrition (PEM) in patients with COPD is accompanied by weight loss, weight loss and a decrease in fat-free mass negatively affect pulmonary functions and cause an increase in morbidity and mortality. In patients, a positive nitrogen balance should be maintained. In general, guidelines recommend that critically ill patients should receive some protein between 1.5 and 2.0 g/kg daily [17]. Proteins do not cause an excessive increase in respiratory functions due to their low respiratory coefficients. For protein not to be used in energy production, carbohydrates and fat, which are non-protein energy sources, should be taken in sufficient quantities. The non-protein calorie/nitrogen ratio should be 150 kcal/L g nitrogen. Protein, up to 20% of total calories, is recommended for maintaining and replacing fat-free mass [16].

21.6 Glutamine Glutamine is the most abundant amino acid in the human body and has important roles as a metabolic and immune substrate. In critically ill patients, muscle-released glutamine circulates, liver and immune cells take up more glutamine from the blood, and thus its uptake from the intestinal mucosa remains unchanged or relatively reduced. Glutamine becomes an essential amino acid during such illness, as the consumption of glutamine in critically ill patients is higher than in glutamine stores. In randomized studies in critically ill patients, it has been reported that parenteral glutamine supplementation can reduce infection, length of stay, and mortality [18]. Oxidative stress creates an increased need for glutathione in COPD patients. Whey protein sources contribute more to increasing glutathione content than casein. Branched-chain amino acids reduce azotemia, increase nitrogen retention, and inhibit rhabdomyolysis [19]. Although the best route for glutamine administration is not yet known, randomized controlled studies show that the intravenous route has more positive effects on mortality and morbidity [20]. Enteral glutamine provides beneficial effects in ICU patients, especially in burns and trauma patients, by reducing infectious complications and length of stay [21]. On the other hand, clinical studies have shown that high levels of glutamine may lead to an increase in mortality [22]. Heyland et al. find that given early-term glutamine both enterally and parenterally in critically ill patients increases 28-day mortality [23].

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The ESPEN guidelines recommend the use of 0.2–0.3 g/kg/day glutamine for an average of 5–7 days to treat low plasma glutamine levels in burn and trauma patients. They report that there is not enough data to support the administration of additional enteral glutamine to critically ill patients in the ICU [24].

21.7 Lipids Lipids provide a significant part of the non-protein energy requirement in respiratory failure diseases due to the low RQ (respiratory quotient) values compared to carbohydrates [16]. In addition, lipids have many functions such as contributing to the structural and physical properties of the cell membrane, acting as the precursor of bioactive lipid metabolites such as prostaglandins, and regulating cell responses such as gene expression. The use of lipids as an energy source is important to meet the need for essential fatty acids. Linoleic acid (18-carbon omega-6) and alpha-­ linolenic acid (18-carbon omega-3 fatty acid) are essential for the human body and must be taken externally. Intensive care patients should take 9–12 g linoleic acid (omega-6) and 1–3 g alpha-linolenic acid (omega-3) per day. These essential fatty acids are synthesized by plants and are found in high amounts in vegetable oils (corn, sunflower, soybean, etc.). They can be metabolized into long-chain polyunsaturated fatty acids such as arachidonic acid (omega-6), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (omega-3). Fish oil also contains EPA and DHA. Olive oil contains oleic acid, an omega-9 monounsaturated fatty acid [25]. To prevent respiratory difficulties in COPD patients, it is recommended that the daily energy from fats should be between 30–45% to close the energy deficit instead of the reduced carbohydrate sources in the diet [16]. In a study conducted with COPD patients given high, medium, and low-fat diets, a high-fat diet was found to be more advantageous in terms of gas output and energy use [26]. Administration of intravenous lipid emulsions is often part of PN. Lipid formulations used in parenteral nutrition include phospholipids and triglycerides. Different formulations are available [21]: • • • •

Soy-based; often described as long-chain triglycerides (LCT). Mixture of long- (LCT) and medium-chain triglycerides (MCT) (usually 50/50). LCT and olive oil blend (20/80). Structural lipids (triglyceride mixtures whose chain lengths are converted into a predetermined structure by enzymatic manipulation of LCT and MCT). • Omega-3 fish oil used as a support is mixed with soybean oil. • Lipid mixtures containing varying amounts of fish oil (LCT, MCT, olive oil and fish oil mixture 30/30/25/15; LCT, MCT, and fish oil mixture 40/50/10). Intravenous lipid should not exceed 1.5 g lipid/kg/day and should be adapted to individual tolerance [8]. While slow infusion of lipids may cause pulmonary vasodilation, rapid infusion may cause pulmonary vasoconstriction. Therefore, the infusion rate should be considered [19].

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Pulmonary enteral formulas containing omega-3, omega-6, and antioxidants are beneficial in patients with acute lung injury and acute respiratory distress syndrome (ARDS) [27]. Omega-3 fatty acids have an anti-inflammatory effect and also reduce lung fibrosis. A daily intake of 500 mg eicosapentaenoic acid (EPA)-docosahexaenoic acid (DHA) is recommended for healthy people, and this rate may increase 3–7 times in intensive care patients [8]. The combination of eicosapentaenoic acid, docosahexaenoic acid, and gamma-linolenic acid (GLA) can positively reduce the pulmonary inflammatory response as well as support vasodilation and oxygenation. Studies have shown that the use of omega-3 fatty acids in patients with acute lung injury or ARDS can prevent oxidative cellular injury, alter the metabolic response caused by stress, and have been associated with a reduction in intensive care unit length of stay, morbidity, and mortality [28]. Over the years, technical developments have enabled the blending of LCT, MCT, fish oil and olive oil; and these blends show a better antioxidant effect in stressed patients in ICUs. In a meta-analysis of randomized controlled trials, it is shown that these four fatty acid emulsions are safe, cause fewer changes in liver function, and reduce the inflammatory response [29]. In addition, many studies are reporting that intravenous lipid emulsions cause pulmonary dysfunction. Lipids reduce the respiratory burden of the patient by reducing CO2 production, but they can also negatively affect gas exchange in the lungs [8]. According to ESPEN guidelines, high doses of omega-3 enriched enteral formulas should not be given routinely (level of evidence B). EPA + DHA 0.1–0.2 g/kg/day parenteral lipid emulsions can be used in patients receiving parenteral nutrition [8].

21.8 Micronutrients Micronutrients, i.e., trace elements and vitamins, are essential for the metabolism of carbohydrates, proteins and lipids, immune and antioxidant defense, endocrine function, gene repair, cell signaling, and DNA synthesis. In the case of oxidative stress, antioxidant deficiencies such as copper, selenium, zinc, and vitamins E and C occur. Vitamin D deficiency has also been associated with poor outcomes such as excessive mortality, longer mechanical ventilation length of stay, and higher incidence of sepsis [30]. In critically ill patients, it is shown that there is an increase in the production of free radicals as a result of the increase in the inflammatory response. The oxidative stress is proportional to the severity of the condition [31]. Industrial parenteral formulas do not contain micronutrients to avoid chemical interactions and stability issues. Trace elements and vitamins should be added daily to parenteral nutrition. In a study, positive results were reported that the infection rates and length of stay of the patients who were administered micronutrients decreased, and wound healing increased [32]. In a prospective cohort, micronutrient levels in critically ill patients were not associated with disease severity, inflammation, or micronutrient intake at admission [33]. The ESPEN guidelines do not recommend the administration of antioxidants as high-dose monotherapy without proven deficiency. In critically ill patients with low plasma levels of vitamin D

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(25-hydroxy-vitamin D 1 min) desaturation under 90% or a fall over 4% on pulse oximeter values to reduce the risk of complications [1]. FOB under NIV support has been demonstrated as safe and effective, allowing patients with respiratory hypoxemic and/or hypercapnic failure to undergo this diagnostic or therapeutic procedure [6–10]. Siccar M et al. (2019) described a series of 28 acute hypoxemic patients successfully submitted to FOB with NIV support. Of these patients, 17 were previously on NIV due to respiratory failure. All the patients demonstrated good procedure tolerance with lidocaine topical anaesthesia, even though sedation with propofol 1% and midazolam was performed only in 15 of the cases. In this study, all the 10 patients with atelectasis had a complete resolution. The rentability of BAL microbiology sample was 75% (n = 24). Regarding complications, in patients submitted to biopsies, 1 patient had a pneumothorax and 3 patients had significant bleeding. Mechanical ventilation was required in 2 patients after 6 h due to subsequent deterioration, 1 patient died 2 days after FOB due to myocardial infarction [6]. Conceiçao et al. (2000) also demonstrate the success of this approach in a population of 10 patients with global respiratory failure due to COPD exacerbation requiring diagnostic FOB and BAL. All of the enrolled patients tolerated the procedure without needing intubation [9]. Antonelli et al. (2002), in a randomized study comparing FOB during conventional oxygen therapy and NIV in patients with acute hypoxemic failure, reported the superiority of NIV support in maintaining oxygen saturation (SpO2) during and after the procedure, showing a better haemodynamic stability [8]. FOB under NIV is often performed in intensive or intermediate care units when approaching acute critical patients, or in bronchoscopy rooms if adequate equipment and safety conditions are guaranteed [11]. Common monitoring during FOB includes noninvasive blood pressure, pulse oximetry, and electrocardiogram. The capacity for monitorization after the procedure, before discharge or ward transfer, is

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a determinant of the room where it is performed. The type and depth of sedation are also important determinants of the type and period of monitorization needed.

22.3 Contraindications Contraindications for FOB under NIV are the same as described for each technique alone. NIV should be avoided in the case of facial deformity, severe gastrointestinal bleeding, upper airway obstruction, inability to guarantee airway protection or high risk of aspiration, significant change in the state of consciousness, severe hemodynamic instability, and respiratory or cardiac arrest. On other hand, common contraindications such as airway obstruction or mucous plugging are potential indications for bronchoscopy with the need for NIV support. In turn, FOB is contraindicated in cases of unstable angina and recent acute myocardial infarction (under 40 days), severe arrhythmias, and low platelet count (less than 60,000/mL) or other coagulation disorders. If oxygen saturation above 85% is not achievable despite high fractional inspired oxygen (FiO2) support, intubation and invasive ventilation are recommended if FOB is considered. Also, BAL should be avoided in patients with refractory hypoxemia, as PaO2  10 yrs. 2.5–5 μg/kg/day 18 yrs. or > 40 kg: 2.5–15 mg/day 50 kg 49/51–97/103 PO BID

Most of the recommendations for chronic pediatric HF therapy were extrapolated from adult heart failure trials [9, 10]. Treatment includes beta-blockers and blockade of the renin-angiotensin converting enzyme-aldosterone system, as a cornerstone of therapy. Drugs include angiotensin converting enzyme inhibitors (ACEi), or angiotensin receptor blockers (ARBs), combined with a mineralocorticoid receptor antagonists (MRA), either spironolactone or eplerenone, as the current standard of care (Table 32.1).

32.2.1 Angiotensin Converting Enzyme Inhibitors ACEi therapy introduction should occur after the stabilization of HF symptoms with diuretic and simultaneous to inotropic support withdrawal. Maintenance diuretic therapy is reserved for patients with intractable volume overload related symptoms, secondary to heart failure. Captopril is the typical first choice for most infants, while enalapril is an appropriate choice for those older than the age of 2 years. In older children with stable hemodynamic status, longer-acting ACEi therapy, such as ramipril and perindopril, might be considered for use to enhance adherence. Caution is advised when these agents are used in the first 4 months of life, because renal dysfunction is more common, and up-titration must be carefully monitored. A small drop in systolic blood pressure is typically noted in patients who take an ACEi. This might occasionally exceed the expected 5%–10% drop in baseline values, necessitating observation for up to 2 hours after the first dose. A creatinine rise of greater than 50% over baseline value in any patient requires a reassessment of fluid balance, and

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consideration for a dosage reduction of ACEi. This class of drugs showed a survival benefit in adult population affected by chronic heart failure (SOLVD trial) while so strong evidence is lacking in children with left ventricular dysfunction. In Duchenne population, the use of perindopril allowed preventing ventricular dysfunction after 10 years of age and improving cardiovascular mortality in this subgroup of patients, so this class of drugs is currently prescribed for preventive strategy [11]. In single ventricle circulation after 1 stage of palliation, ACE inhibitors failed to improve survival [12].

32.2.2 Mineralocorticoid Receptor Antagonists Spironolactone is typically initiated for patients in whom therapy with an ACEi and b-blocker has not resulted in improved ventricular function or reversal of ventricular remodeling. Hyperkalemia might result in patients who receive spironolactone and an ACEi, especially if renal function is already compromised. Therefore, potassium levels and renal function indices should be checked before starting and periodically thereafter. Male gynecomastia is a complication and must be closely monitored. Eplerenone has also shown to be effective to reverse ventricular remodeling, also in Duchenne population [13].

32.2.3 Beta Adrenergic Receptor Antagonists The addition of a b-adrenergic receptor antagonist (b-blocker), both asymptomatic and symptomatic patients with moderate or severe ventricular dysfunction is indicated. Carvedilol (a nonselective b-adrenoreceptor antagonist with a-adrenergic blocking activity) is commonly used in pediatric patients with HF. A multicenter, randomized, double-blind, placebo controlled study of children and adolescents with symptomatic systolic HF did not show an improvement in their composite clinical status after 8 months of treatment with carvedilol, although improvements in EF were noted [14]. The study, however, was underpowered and included children with different physiology, and this diversity might have compromised the ability to determine a real benefit. On the other hand the study of Adorisio et  al. demonstrated that a high dose of carvedilol is effective in improving EF and survival in children with HF [15]. The evidence to support the use of alternative b-adrenergic blockers such as metoprolol or bisoprolol is well established in adults but can only be extrapolated to children with HF.

32.2.4 Digoxin Digoxin is not routinely recommended but can be useful for patients who remain symptomatic after treatment with other drugs is maximized. In children, the addition of digoxin to diuretic therapy has traditionally occurred in

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infants with a large ventricular septal defect and pulmonary congestion because of overcirculation. However, digoxin is not reported to result in improved contractility, or improvement in clinical symptoms in this setting. There are no pediatric data supporting the use of digoxin in children with structurally normal hearts and systolic dysfunction. If it is used in conjunction with carvedilol in children (for arrhythmic control for example), digoxin dosing might require reduction [9].

32.2.5 New Drugs in Pediatric Heart Failure Today new drugs are emerging in pediatric heart failure and in cardiomyopathies. Ivabradine was actually investigated in pediatric trials [16, 17] and new and promising one is emerging with a new trial: Sacubitril-Valsartan. Recently, the use of SGLTs showed improvement in survival in adult chronic heart failure but no data are currently available in children.

32.2.5.1 Ivabradine Additional treatments such as Ivabradine will be indicated in patients who have not reached a satisfactory reduction in heart rate with b-blockers. Ivabradine targets the voltage-regulated inward funny current (If) in sinoatrial tissue and slows the rate of phase-4 depolarization, reducing heart rate. The safety of ivabradine in children has been validated in a pediatric phase II/III dose finding clinical trial of children with stable HF [17]. Ivabradine resulted in a reduction in heart rate, an increase in EF, and a trend toward improved quality of life [16, 17]. A retrospective analysis of children with dilated cardiomyopathy from the Pediatric Cardiomyopathy Registry found that elevated heart rate was independently associated with death or transplantation, after correcting for age, ventricular function, and cardiac medication use [18]. 32.2.5.2 Sacubitril Valsartan Sacubitril-Valsartan is a first in class drug, which combines a neprilysin inhibitor, and an angiotensin II receptor antagonist results in significant benefit in the treatment of HF. In adult PARADIGM-HF Trial, and pediatric PANORAMA-HF study, the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan was demonstrated to be superior to enalapril in reducing the sudden cardiac death or hospitalization for heart failure It has also been shown to improve quality of life, reduce pulmonary artery pressure, and reduce the biomarker N-terminal proBNP [19, 20]. FDA approved the use of sacubritil/valsartan for pediatric patients with symptomatic heart failure with systemic left ventricular systolic dysfunction, older than 1 year of age. Sacubitril/valsartan was however associated with a higher incidence of hypotension, although there was a lower incidence of elevated creatinine or serum potassium when compared with enalapril.

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References 1. Cleland JG, Yassin AS, Khadjooi K.  Acute heart failure: focusing on acute cardiogenic pulmonary oedema. Clin Med (Lond). 2010;10(1):59–64. https://doi.org/10.7861/ clinmedicine.10-­1-­59. 2. Witharana TN, Baral R, Vassiliou VS. Impact of morphine use in acute cardiogenic pulmonary oedema on mortality outcomes: a systematic review and meta-analysis. Ther Adv Cardiovasc Dis. 2022;16:17539447221087587. https://doi.org/10.1177/17539447221087587. PMID: 35343809; PMCID: PMC8966112. 3. Cekmen B, Bildik B, Bozan O, Atis SE, Dogan S, Kocak AO. Utility of non-invasive synchronized intermittent mandatory ventilation in acute cardiogenic pulmonary edema. Am J Emerg Med. 2022;56:71–6. https://doi.org/10.1016/j.ajem.2022.03.044. Epub ahead of print. PMID: 35367682. 4. Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359:142. 5. Bello G, De Pascale G, Antonelli M.  Noninvasive ventilation. Clin Chest Med. 2016;37(4):711–21. 6. British Thoracic Society Standards of Care Committee. Non-invasive ventilation in acute respiratory failure. Thorax. 2002;57(3):192–211. https://doi.org/10.1136/thorax.57.3.192. PMID: 11867822; PMCID: PMC1746282. 7. Rochwerg B, Brochard L, Elliott MW, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J Aug. 2017;50(2):1602426. 8. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American college of cardiology/American heart association task force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure). J Am Coll Cardiol. 2001;38:2101–13. https://doi.org/10.1016/ s0735-­1097(01)01683-­7. 9. Kantor PF, Lougheed J, Dancea A, McGillion M, Barbosa N, Chan C, et al. Presentation, diagnosis, and medical management of heart failure in children: Canadian cardiovascular society guidelines. Can J Cardiol. 2013;29:1535–52. https://doi.org/10.1016/j.cjca.2013.08.008. 10. Kirk R, Dipchand AI, Rosenthal DN, Addonizio L, Burch M, Chrisant M, et  al. The International Society for Heart and Lung Transplantation guidelines for the management of pediatric heart failure: executive summary. J Heart Lung Transplant. 2014;33:888–909. https://doi.org/10.1016/j.healun.2014.06.002. 11. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Bécane HM.  Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol. 2005;45(6):855–7. https://doi.org/10.1016/j.jacc.2004.09.078. PMID: 15766818. 12. Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, Barker PC, Ravishankar C, McCrindle BW, Williams RV, et  al. Enalapril in infants with single ventricle: results of a multicenter randomized trial. Circulation. 2010;122:333–40. 13. Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, McCarthy B, Taylor MD, Jefferies JL, Rafael-Fortney JA, Lowe J, Roble SL, Cripe LH.  Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14(2):153–61. https://doi.org/10.1016/ S1474-­4422(14)70318-­7. Epub 2014 Dec 30. Erratumin: Lancet Neurol. 2015 Feb;14(2):135. PMID: 25554404; PMCID: PMC4361281. 14. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007;298:1171–9. 15. Adorisio R, Cantarutti N, Ciabattini M, Amodeo A, Drago F. Real-world use of carvedilol in children with dilated cardiomyopathy: long-term effect on survival and ventricular function. Front Pediatr. 2022;10:845406. https://doi.org/10.3389/fped.2022.845406. PMID: 35433536; PMCID: PMC9010785.

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16. Adorisio R, Calvieri C, Cantarutti N, D’Amico A, Catteruccia M, Bertini E, et al. Heart rate reduction strategy using ivabradine in end-stage Duchenne cardiomyopathy. Int J Cardiol. 2019;280:99–103. https://doi.org/10.1016/j.ijcard.2019.01.052. 17. Bonnet D, Berger F, Jokinen E, Kantor PF, Daubeney PEF. Ivabradine in children with dilated cardiomyopathy and symptomatic chronic heart failure. J Am Coll Cardiol. 2017;70:1262–72. https://doi.org/10.1016/j.jacc.2017.07.725. 18. Rossano J, Kantor P, Shaddy R, Shi L, Wilkinson J, Jefferies J, et al. Increased heart rate is independently associated with worse survival in pediatric patients with dilated cardiomyopathy: a multicentre study from the pediatric cardiomyopathy registry. Eur Heart J. 2017;38:210. https://doi.org/10.1093/eurheartj/ehx502.965. 19. Packer M, McMurray JJ, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131:54–61. https://doi.org/10.1161/ CIRCULATIONAHA.114.013748. 20. Shaddy R, Canter C, Halnon N, Kochilas L, Rossano J, Bonnet D, et al. Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). Am Heart J. 2017;193:23–34. https://doi.org/10.1016/j.ahj.2017.07.006.

Adaptation-Intolerance, Delirium in Agitated Patients. Neuromuscular Disorders: Breathing and Swallowing

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Marcella Aversa and Susanna Staccioli

33.1 Adaptation-Intolerance, Delirium in Agitated Patients 33.1.1 Introduction During hospitalization in pediatric age, especially in an intensive setting, the development of intolerance and maladjustment to existing therapies is frequent, even in neurologically healthy subjects. Psychomotor agitation is frequent, an extreme form of excitement with an increase in verbal and motor activity that is not aimed at the development of forms of delirium. Delirium is a syndrome characterized by an acute and fluctuating alteration of cognition and awareness [1], not to be confused with the withdrawal crisis. Routine bedside screening using validated tools can allow for early diagnosis [2]. The incidence of delirium in children in intensive care is around 25% overall, with reports of rates ranging from 12% to 65% depending on the specific population under study. Among those diagnosed, the onset is early, so much so that it is already present after 3 days of hospitalization in TIP in 78%. Delirium is jointly responsible for unfavorable outcomes such as increased hospitalization days, increased mortality, cognitive dysfunction, altered memories, and/ or hallucinations (present in 33%).

M. Aversa (*) Pediatric Intensive Care, Bambino Gesù Children’s Hospital - Palidoro (Fiumicino), Rome, Italy e-mail: [email protected] S. Staccioli (*) Department of Neurorehabilitation, Bambino Gesù Children’s Hospital - Palidoro (Fiumicino), Rome, Italy e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_33

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It is often not diagnosed and treated adequately, especially in the hypoactive forms, as it is not sought after and, therefore, not included in the global treatment plan, which is mainly aimed at diagnostic-therapeutic interventions relating to the disease that led to hospitalization. In this way, the effects on the psyche of the acute pathology and the treatments implemented for its resolution are underestimated, reducing the possibility of a complete recovery without sequelae or with minimal neuro-psychiatric outcomes [3].

33.1.2 Pathogenesis and Classification of Delirium The pathogenesis of delirium is incompletely understood; however, several hypotheses have been proposed [4]. The most relevant in pediatrics is the neuroinflammatory one according to which the underlying medical condition induces systemic inflammation. Activation of the inflammatory system in the brain causes increased permeability of the blood-brain barrier dysfunction of neurons and synapses with consequent excitotoxicity and apoptosis. Another hypothesis is the neuroendocrine one according to which delirium is a reaction to acute stress, with an increase in endogenous glucocorticoids affecting the CNS from increased neuroinflammation. Another developmental phenomenon is the diurnal dysregulation of the circadian cycle with sleep deprivation, which contributes to the dysfunction of the immune system. In any case, delirium is the result of three separate but synergistic causes, namely, the disease underlying iatrogenic factors and the hospital environment. Delirium can be classified into: Hyperactive delirium (8%): Increased psychomotor activity and prevailing agitation. State of anxiety, hyperactivity or aggression, disorientation in space and time, and visual and auditory hallucinations. Hyporeactive delirium (46%): Reduction in psychomotor activity, lethargy, hypoactivity, ideomotor slowdown, absence or delay in communication, and response to stimuli of various kinds prevail. Mixed delirium (45%): Hyper- or hypo-reactivity with the alternation of these two conditions.

33.1.3 Screening and Monitoring Tests Diagnosis and recognition of delirium is often very difficult as it is purely clinical, based on the observation and information of the nurse who assists the patient and who, therefore, must be properly trained. The most commonly used screening tests [5] in children are further discussed.

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33.1.3.1 Comfort B Scale Evaluate the level of agitation/sedation, or the correct management of analgo-­ sedation, in patients from 1 month onwards [6]. Composed of six variables (score for each item from 0 to 2), it measures alertness, calm/agitation, respiratory response, body movements, muscle tone, facial tension, heart rate, and blood pressure. It is performed from the first day of hospitalization 4 times/day. A score between 17 and 26 is indicative of an excellent analgo-sedation (absence of stress) in patients with an infusion of analgesics and/or sedatives, and neurological patients even without an infusion of analgesics and/or sedatives. If the score is 12, delirium monitoring with CAP-D is activated every 12 h. 33.1.3.2 CAP-D (Cornell Assessment of Pediatric Delirium) [7] (Fig. 33.1) Observational screening that can be applied from 6 months of life. Composed of seven items, with a score from 0 to 4 (score from 0 to 32 points). A score >9 is significant for delirium (sensitivity 94%, specificity 79%).

Fig. 33.1  Cornell assessment of pediatric delirium (CAP-D) revised. Score  >  10  =  delirium present

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Fig. 33.2  Assessment and management of delirium in pediatric intensive care (PIC)

Since 2016, the European Society of Pediatric and Neonatal Intensive Care has attributed evidence “A” to the recommendation for intensivists on the use of CAP-D in the diagnosis and monitoring of delirium [8]. If CAP-D 9: suggestive for Delirium. –– –– –– ––

I’M A PERSON is evaluated, Non-pharmacological interventions are activated. Identification of the type of delirium. Evaluation of pharmacological therapy in relation to the type of diagnosed delirium which, in principle, provides for:

CAP-D  >23: HYPERACTIVE DELIRIUM (agitated, restless, with hallucinations, distressed): Haloperidol and/or benzodiazepines. CAP-D  9 With altered state of consciousness: MIXED/ALTERNATING DELIRIUM (alternation between agitation, restlessness and confusion, hallucinations and reduced reactivity): Seroquel and/or Haloperidol.

33.1.3.3 I’m a Person Research to identify a precipitating cause of delirium, investigating: –– The presence of infections (fever, leukocytosis) confirmed by blood culture. –– The use of aids for immobilization. –– Endocrine-metabolic disorders: uremia, hepatic encephalopathy, hypoglycemia, hyperthyroidism, adrenal insufficiency), which can induce an alteration of the mental state. “Targeted” laboratory investigations. –– Loss of the sleep-wake cycle. –– Inadequate treatment of pain (monitoring analgesia scales). –– Noisy surrounding environment, with high lighting. –– Organ dysfunction, persistent hypoxia. –– Nutritional deficit: reassess the parenteral or enteral nutritional intake –– Therapy with drugs with direct action on the CNS (sedatives, hypno-inducing drugs, narcotics, anticholinergics) with an elevated plasma concentration, so improvement is observed with dose reduction.

33.1.4 Non-pharmacological Interventions Non-pharmacological interventions include the environment, nursing, and the organizational model of the department, namely: –– Reduction of noise and brightness, especially at night. –– Optimization of nursing maneuvers, avoiding them at night, except those of an urgent nature. –– Keep the ward “open,” if the logistical conditions allow it, or, in any case, encourage the parents to enter and stay next to the child, if in the phase of awakening and pharmacological weaning. –– Food splitting during the day. –– Try to ensure the sleep/wake cycle by introducing melatonin. –– Relaxation techniques/low-volume music therapy. –– On the basis of age, try to accommodate the needs of the child.

33.1.4.1 Pharmacological Interventions (Fig. 33.3) Haloperidol (Serenase): antipsychotic derived from butyrophenone, indicated in hyperactive delirium with hallucinations and agitation. –– Dosage: child and adolescent 0.025–0.1 mg/kg/dose (IM, IV, PO) –– Maximum dose 1 mg/die

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1) Non-pharmacological measures, treat underlying cause (I’M A PERSON) 2) Day-night schedule, sleep routine, use melatonin for sleep disruption 3) Pharmacological - treat according to delirium subtype

Elevated LOC/ Agitated (RASS +1 to +4)

Starting doses HYPERACTIVE DELIRIUM

Agltated, restless, distressing hallucinations

MIXED, FLUCTUATING DELIRIUM

Fluctuates between being agltated, restless, and decreased responsiveness, confused, hallucinations

CAPD =core

Fluctuating LOC

8 or lower

Continue routine monitoring for delirium

Normal/depressed LOC (RASS 0 to -3)

HYPOACTIVE DELIRIUM

Diminished responsiveness, quiet confusion, apathy, difficult to engage

Consider Haloperidol

Consider one atypical antipsychotic ± haloperldol PRN

Consider atypical antipsychotics

Children and adolescents: PO/IV/IM: 0.025-0.1 mg/kg/dose q6h PRN (usual max of 1mg/dose)

Atypical antipsychotics - Starting doses

Infants/children: up to 1.5 mg/kg/day po Queriapine (once daily or divided bid-tid, usual starting (has sedating max dose 25 mg/day) side effects) Adolescents: 12.5.25 mg PO once daily or bid (round dose to nearest 6.25mg)

Children: 0.25-0.5 mg PO daily Risperidone Adolescents: 0.5-1 mg PO daily

Version June 26, 2019

Fig. 33.3  Pharmacological management of delirium

–– Contraindicated in the presence of arrhythmias, hypokalemia, long QT, hepatic insufficiency –– Interferences with carbamazepine, phenobarbital, rifampicin, which cause a significant reduction in plasma levels of haloperidol During therapy, ECG monitoring (dose reduction if QT lengthens. QT administration interruption >500 ms) Daily check of electrolytes Quetiapine (Seroquel): antipsychotic, indicated in the mixed form of delirium. –– Dosage: infant/child: 1.5 mg/kg/die-maximum dose 25 mg/die –– Adolescent: 12.5–25 mg/die P –– Contraindicated if antibiotic therapy with erythromycin or clarithromycin is underway Risperidone (Risperdal): other antipsychotics, indicated in hypoactive delirium. –– –– –– ––

Dosage: child: 0.25–0.5 mg/kg/die Adolescent: 0.5–1 mg/kg/die Contraindicated if therapy with Furosemide is underway Interacts with many drugs, such as Carbamazepine, Phenytoin, Gardenale, Luminale, Mysoline, Rifadin, Rifocin, and Tegretol.

33.2 Neuromuscular Disorder: Breathing and Swallowing Neuromuscular disorder (NMD) may result from injury or metabolic or genetic abnormalities of the central or peripheral nervous system, progressive or not. Cardiac and respiratory complications continue to be the most frequent causes of morbidity and mortality [9].

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Early initiation of noninvasive ventilation (NIV) and therapies to improve cough and manage secretions may preserve muscle function, alter the natural progression of the disease, and reduce hospitalizations [10]. The large use of NIV in children with NMD contrasts with the limited number of studies that have evaluated the benefits of NIV in children. Studies involving a small number of patients have shown that NIV is associated with a correction of nocturnal and daytime gas exchange, improved sleep quality, and reduced symptoms associated with sleep-disordered breathing [11] . Neuromuscular disease can cause feeding and swallowing problems. The common element in all NMDs is muscle weakness, which influences motor abilities and oral motor activities with eating or swallowing problems (dysphagia) [12]. We can identify feeding-related problems: swallowing difficulties (dysphagia, weak suck aspiration, coughing/choking with meal, frequent chest infections) and problems with nutrition and growth (poor appetite, fussy eating, long mealtimes, inadequate weight gain, oral intake, and failure to thrive). Vomiting and gastroesophageal reflux were coexisting factors with swallowing difficulties or nutrition and growth problems in most patients [13] . Common pediatric NMDs include spinal muscular atrophy (SMA), DMD, Charcot-Marie-Tooth disease (CMT), myotonic dystrophy type 1 (DM1), and congenital myopathies (CM). A small number of specific disease-modifying therapies, combined with broader advances in multidisciplinary supportive care, have realized improvements in survival and health outcomes in pediatric NMDs, upheld by disease-­specific care guidelines. In many cases, problems occur in more than one phase. The oral (preparatory) phase is often complicated by structural impairments, such as limited mouth opening, inability to close the mouth due to malocclusions, or structural abnormalities of the tongue. Children with NMDs are at an increased risk for several nutrition and feeding complications related to their neuromuscular diagnosis, its presentation, and severity. These issues include chronic gastrointestinal problems (constipation, reflux, and diarrhea), swallowing difficulties, and abnormal weight and body composition [14]. Evaluation are usually clinical,based on history: clinical, based on history (dysphagia, recurrent pneumonias, mealtimes, longitudinal evaluation of weight, exe…), instrumental (by a Video-fluoroscopic swallow study and a FEES, flexible endoscopic evaluation) and application of scales or interview of parents, can be performed.

References 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Virginia: American Psychiatric Association; 2013. 2. Barr J, Fraser GL, Puntillo K, et  al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:263–306. 3. Traube C, Silver G, Gerber LM, et al. Delirium and mortality in critically ill children: epidemiology and outcomes of pediatric delirium. Crit Care Med. 2017;45:891–8. 4. Maldonado JR. Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Geriatr Psychiatry. 2013;21:1190–222.

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5. Outsen S. Delirium in the Pediatric Intensive Care Unit: recognition, prevention and treatment. In: Newborn pediatric critical care conference, Provo (Utah), 2017. 6. Patel AK, Bell MJ, Traube C.  Delirium in pediatric critical care. Pediatr Clin North Am. 2017;64:1117–32. 7. Traube C, Silver G, Kearney J, et al. Cornell assessment of pediatric delirium: a valid, rapid, observational tool for screening delirium in the PICU. Crit Care Med. 2014;42:656–63. 8. Harris J, Ramelet A-S, van Dijk M, et al. Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals. Intensive Care Med. 2016;42:972–86. 9. Alexiou S, Piccione J. Neuromuscular disorders and chronic ventilation. Semin Fetal Neonatal Med. 2017;22(4):256–9. 10. Yang ML, Finkel RS.  Overview of paediatric neuromuscular disorders and related pulmonary issues: diagnostic and therapeutic considerations. Paediatr Respir Rev. 2010;11(1):9–17. https://doi.org/10.1016/j.prrv.2009.10.009. 11. Young HK, Lowe A, Fitzgerald DA, Seton C, Waters KA, Kenny E, Hynan LS, Iannaccone ST, North KN, Ryan MM. Outcome of noninvasive ventilation in children with neuromuscular disease. Neurology. 2007;68(3):198–201. 12. van den Engel-Hoek L, de Groot IJ, de Swart BJ, Erasmus CE. Feeding and swallowing disorders in pediatric neuromuscular diseases: an overview. J Neuromuscul Dis. 2015;2(4):357–69. 13. Ramelli GP, Aloysius A, King C, Davis T, Muntoni F.  Gastrostomy placement in paediatric patients with neuromuscular disorders: indications and outcome. Dev Med Child Neurol. 2007;49(5):367–71. 14. Mehta NM, Newman H, Tarrant S, Graham RJ.  Nutritional status and nutrient intake challenges in children with spinal muscular atrophy. Pediatr Neurol. 2016;57:80–3. https://doi. org/10.1016/j.pediatrneurol.2015.12.015.

Gastrostomy Insertion, Bronchoscopy

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Marcella Aversa and Daniela Perrotta

34.1 Gastrostomy Insertion 34.1.1 Introduction Gastrostomy is a gastro-cutaneous fistula between the anterior wall of the stomach and the abdominal skin, which bypasses the first digestive tract (mouth and esophagus). Gastrostomy can be packaged surgically or endoscopically; the latter is called PEG (percutaneous endoscopic gastrostomy), which allows you to place a plastic device in the stomach through the abdominal wall to connect the gastric cavity to the outside through a tube of 5–7  mm in diameter. Currently it represents a safe method of insertion [1] preferable in children in the absence of absolute contraindications. PEG is reversible or can be removed when the conditions for which it was indicated do not exist.

34.1.2 Indications In pediatric age, PEG is indicated [2] and represents the preferential way of nutrition when oral feeding becomes insufficient and difficult and fails to cover energy needs, therefore, in the face of malnutrition in patients with dysphagia of

M. Aversa (*) Pediatric Intensive Care, Bambino Gesù Children’s Hospital - Palidoro (Fiumicino), Rome, Italy e-mail: [email protected] D. Perrotta (*) Anesthesiology and Pediatric Intensive Care, Bambino Gesù Children’s Hospital, Rome, Italy e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_34

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pathologies acute neurological (cranio-encephalic trauma, vascular brain damage) or chronic congenital or acquired diseases (tumors, metabolic diseases, epileptiform encephalopathies, genetic syndromes) even in the presence of a preserved intestinal function. In all these circumstances, an artificial nutritional support program must be started, capable of replacing or only completing oral nutrition by establishing a stable and safe long-term nutritional support.

34.1.3 Complications and Contraindications PEG is a safe procedure with a low incidence of major complications (2–4%). The most frequent complication [3] is represented by infection of the skin around the stoma, ranging from simple skin rash to abscess and necrotizing fasciitis. More rarely, peritonitis, hemorrhages, intestinal perforations, and gastrocolic fistulas have been described. Minor complications can be obturation, dislocation and decubitus of probes or tubes used, diarrhea, abdominal distension, nausea, and vomiting related to the quality or method of administration of the nutritional formulas. Absolute contraindications: peritonitis, imperviousness of the esophagus, and peritoneal dialysis in progress. Relative contraindications: ascites, coagulopathy, portal hypertension, hepatomegaly, interposed colic loops, previous abdominal surgery, future peritoneal dialysis program, and intrathoracic stomach for severe kyphoscoliosis.

34.1.4 Procedural Technique The procedure is performed in sedoanalgesia, in deep sedation or general anesthesia according to the general clinical conditions of the patient and the operative site in which the procedure is carried out in order to cause minimal discomfort with maximum safety. An antibiotic prophylaxis is generally performed immediately before the procedure to reduce the risk of infectious complications of the gastrostomy via venous access. The patient is continuously monitored with ECG, SpO2, NIBP in the supine position, and a special mouthpiece is inserted to keep open the patient’s mouth. The preliminary phase is represented by a common esophagogastroduodenoscopy (EGDS) to exclude pathologies and/or lesions of the gastric wall. The stomach is then insufflated so as to make the anterior wall of the stomach adhere to the abdominal wall. By means of digital pressure and trans-illumination, the point in which to place the PEG is chosen and verified [4]. Once the suitable point for the positioning of the PEG has been chosen, a local anesthesia is administered and then a small skin incision is done that allows the operator to insert a needle-cannula that penetrates the gastric lumen from the abdominal wall. A guide wire is then inserted inside the

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cannula which is endoscopically grasped and brought externally through the upper digestive tract by extracting the gastroscope. At this stage, the operator has two techniques available for inserting the feeding tube: –– In the Pull Technique, the tube is pulled by the wire, previously brought out by the gastroscope, in the upper digestive tract up to the abdominal wall which is crossed at the level of the previously created channel. –– In the Push Technique, the feeding tube, which has a dilator at its end, is made to slide on the guide wire starting from the abdominal skin and then pushed toward the mouth keeping the guide wire taut. In both cases, at the end of the procedure, the probe is kept in place by means of an internal bumper (plate or button) and an external plate. The whole is free to rotate.

34.1.4.1 Execution in intensive care If the procedure is carried out in I.C. to patients not analgosedation in controlled mechanical ventilation (CMV) but rather alert or with mild sedation in spontaneous breathing or in ventilatory assistance through High Flows or NIV, through venous access, patients are administered in bolus midazolam at 0.1/0.2 mg/kg and ketamine 0.5–2 mg/kg or alternatively propofol 0.2/0.3 mg/kg with paracetamol 7.5/15 mg/kg at the end of the procedure. After the sedation has started, the mouthpiece is positioned and the endoscope is passed through the upper opening of the catheter mount, placed between the face mask with which the patient is assisted with 100% O2 and the oxygen source by occluding the opening almost entirely. It allows assisting the patient during the endoscopic phase. At the moment in which the guide wire must be recovered from the mouth and positioned the probe, assistance is suspended and then resumed after positioning until complete awakening. 34.1.4.2 Operative Room In the operating room, the procedure can be performed with the same type of assistance in a face mask, however, having the possibility of using the anesthetic vapor, 4–5% sevoflurane to induce sleep associated with a bolus of propofol 1–2 mg/kg at the time of the introduction of the gastroscope or the introduction of the needle and guide wire into the abdomen. The patient always maintains spontaneous breathing which is assisted throughout the procedure in a noninvasive way. Obviously, there are clinical conditions for which correct and safe assistance with a face mask is hardly desirable, and in this case, it is possible to resort to the use of orotracheal intubation with invasive ventilatory assistance. The success rate in positioning the PEG is greater than 90% and the procedure takes approximately 15–30 min. The patient will be able to be fed through the probe after 24 h from its placement.

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34.2 Bronchoscopy 34.2.1 Introduction Bronchoscopy is an invasive endoscopic examination that allows you to view the airways starting from the larynx up to the subsegmentary bronchial branches. It is performed through a rigid (bronchoscope) or flexible (fibrobronchoscope-­ videobronchoscope) endoscope with a small diameter made up of optical fibers and equipped with a light source that can be introduced from the nostril or mouth with the patient under deep sedation or under general anesthesia [5]. It must be performed by specialized personnel and only in a protected environment such as an operating room or intensive care.

34.2.2 Indications There are many indications for fibrobronchoscopy [6] as it is an ideal tool for: –– Identification of the cause in the case of difficulty in breathing –– Diagnosis and treatment of airway malformations –– Removal of an accidentally inhaled and potentially dangerous foreign body in an emergency –– Observation, diagnosis, and assessment of the degree of severity in the case of tumor pathology –– Difficult tubing –– Aspiration and collection of secretions for the identification of pathogenic germs in the case of lung infections or rare diseases through bronchial washing, brushing, and washing of the peripheral airways and alveoli [3] –– Biopsy of endobronchial, parenchymal, and mediastinal structures –– Evaluation and tamponade of bleeding from the bronchi or lungs –– Elimination of the narrowing of the airways in the case of tracheo-bronchial stenosis

34.2.3 Contraindications and Complications Absolute contraindications to bronchoscopy in pediatrics include: –– Acute respiratory failure with hypercapnia (unless the patient is intubated and ventilated) –– Severe tracheal obstruction –– Inability to adequately oxygenate the patient during the procedure –– Potentially fatal non-treatable arrhythmias

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The contraindications relating to bronchoscopy in pediatric age are: –– Uncorrectable coagulopathy –– Obstruction of the superior vena cava, or pulmonary hypertension due to the increased risk of bleeding. Serious complications are rare; minimal bleeding from the biopsy site and fever occur in 10–15% of cases. Patients may have increased cough after bronchoalveolar lavage. Rarely, local anesthesia causes laryngospasm, bronchospasm, seizures, or arrhythmias up to cardiac arrest. Bronchoscopy itself can cause –– Arrhythmias (most commonly premature atrial contractions, ventricular premature beats, or bradycardia) –– Hypoxemia in patients with impaired gas exchange –– Edema of the larynx or minor lesions with hoarseness –– Transmission of infections from suboptimal sterilized equipment (very rare)

34.2.4 Procedural Technique Generally the pediatric patient is able to collaborate only at the end of the pediatric age, that is, after 13–14 years while in almost all cases in pediatric patients, it is absolutely recommended to perform the method in the presence of an anesthetist even if the patient is in good general condition, to be ready to deal with the rare onset of complications, such as (transient) respiratory failure. Most endoscopic examinations are now performed with a flexible bronchoscope which has a much wider field of exploration and a better versatility of use than the rigid. The rigid bronchoscope has characteristics (wide operating channel, the possibility of ventilating the patient during the examination under sedation or general anesthesia) that make it indispensable for some therapeutic maneuvers. Thanks to these diagnostic and operative techniques, it is possible, in many pediatric diseases, to avoid a more aggressive surgery that would involve opening the neck and/or thorax to access structures such as larynx, trachea, bronchi, and lungs [7, 8]. It is performed under deep sedation or under general anesthesia in the operating room or in intensive care. The child is placed in the supine position; if not present, a venous access is positioned. The cardiorespiratory parameters such as SpO2, HR, ECG, and NIPB are continuously monitored as well as inspecting and auscultating the chest for the risk of desaturation.

34.2.4.1 Operative Room The head is placed in hyperextension and spontaneous breathing is maintained in ventilatory assistance with 100% O2 + 4–6% Sevoflurane. In the presence of neurological disorders or congenital cardiac alterations, the concentration of sevoflurane

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should be reduced to 3%. The assistance to the airways can take place through various modalities, face mask, nasopharyngeal cannula, laryngeal mask, or endotracheal tube. A “T” tube is positioned above the anesthesia mask, which at the same time ensures both the passage of the endoscope through the patient’s nose and the administration of oxygen in the mask. Before starting the bronchoscopy, even if the method is performed under general anesthesia, it is advisable to instill in the nasal cavities a local anesthetic such as 1–2% lidocaine [9], and another anesthetic will then be instilled through the bronchoscope on the vocal cords and the tracheal keel. In any case, the total dose of lidocaine must not exceed 5 mg/kg body weight, so a 5 mL vial of 2% lidocaine can be used only in a patient weighing 18–20 kg: lidocaine is rapidly absorbed by the mucous membranes and appears in the blood with systemic effects. If the spray preparation is also used on the glottis, it must be considered that a single spray already contains 10 mg of anesthetic. Since the bronchoscope is generally introduced through the nose, it is also useful to use a vasoconstrictor such as phenylephrine to reduce the presence of any edema/inflammation of the nasal mucosa, so as to make the child’s choanas more open to the passage of the instrument.

34.2.4.2 Intensive Care If sevoflurane is not available as in T.I., deep sedation is recommended with a combination of iv benzodiazepines such as midazolam at 0.1–0.2 mg/kg (max 5 mg) for the sedative, amnesic, and hypnotic properties and opioids such as fentanyl at 1–2 μg/kg or ketamine at 1–2 mg/kg for pain control. Additionally, an intravenous anesthetic such as propofol at a dose of 1–2  mg/kg is recommended to increase hypnosis and suppress airway protective reflexes.

References 1. Khdair Ahmad F, Younes D, Al Darwish MB, Aljubain MA, Dweik M, Alda’as Y.  Safety and outcomes of percutaneous endoscopic gastrostomy tubes in children. Clin Nutr ESPEN. 2020;38:160–4. https://doi.org/10.1016/j.clnesp.2020.05.011. Epub 2020 Jun 16. 2. Friginal-Ruiz AB, Lucendo AJ.  Percutaneous endoscopic gastrostomy: a practical overview on its indications, placement conditions, management, and nursing care. Gastroenterol Nurs. 2015;38(5):354–66; quiz 367–8. 3. Balogh B, Kovács T, Saxena AK.  Complications in children with percutaneous endoscopic gastrostomy (PEG) placement. World J Pediatr. 2019;15(1):12–6. https://doi.org/10.1007/ s12519-­018-­0206-­y. Epub 2018 Nov 19. 4. Franco Neto JA, Liu PMF, Queiroz TCN, Bittencourt PFS, Carvalho SD, Ferreira AR.  PERCUTANEOUS ENDOSCOPIC GASTROSTOMY IN CHILDREN AND ADOLESCENTS: 15-YEARS’ EXPERIENCE OF A TERTIARY CENTER.  Arq Gastroenterol. 2021;58(3):281–8. 5. Eber E, et  al. ERS statement: interventional bronchoscopy in children. Eur Respir J. 2017;50(6):1700901. 6. Soyer T. The role bronchoscopy in the diagnosis of airway disease in children. J Thorac Dis. 2016;8(11):3420–6.

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7. Raoof S, Mehrishi S, Prakash UB.  Role of bronchoscopy in modern medical intensive care unit. Clin Chest Med. 2001;22:241–61. 8. Facciolongo N, Piro R, Menzella F, Castagnetti C, Zucchi L. Bronchoscopy in intensive care units. Rassegna di Patologia dell’Apparato Respiratorio. 2009;24:212–9. 9. Amitai Y, Zylber KE, Avital A, et al. Serum lidocaine concentrations in children during bronchoscopy with topical anestesia. Chest. 1990;98:1370–3.

Part IV Guide for Drugs Dose Clinical Practical Approach in Special NIV Indications

Pharmacology Approach in Persistent Dyspnea and Noninvasive Ventilation Approach

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Hatice Aslan Sirakaya

35.1 Definition Dyspnea is defined as uncomfortable feeling or difficulty in breathing, which is a common symptom affecting substantial number of patients. It can be first symptom in lung disease, myocardial ischemia, anemia, neuromuscular disorders, obesity and impaired condition. A majority of respiratory discomfort occurs due to impaired ventilation: perfusion ratio, increased volume of dead space, acidosis or stimulation of pulmonary or thoracic wall receptors. Several intra-pulmonary and extra-pulmonary receptors play a role in the detection of depth, pattern and frequency of respiration. Over- or under-stimulation of these receptors leads to respiratory discomfort feeling. Mechanoreceptors are the receptors which monitor pressure, flow and volume changes in the respiratory tract, allowing the assessment of severity of dyspnea. The stimulation of receptors localized at face and upper respiratory tract and innervated by trigeminal nerve can alleviate the severity of dyspnea. In COPD, the expiration of cold air reduces exercise-induced dyspnea and hyper-ventilation by the stimulation of these receptors while topical lidocaine and expiration of warm, humidified air can exacerbate respiratory disorder due to decrease in receptor stimulation [1, 2]. Despite the use of heated air, high-flow nasal cannula (HFNC) diminishes dyspnea by a greater extent than standard oxygen therapy [3]. In lungs, there are three different receptors innervated by vagal nerve. The pulmonary stretch receptors are slowly adapting receptors (SARs) and provide information about increases in pulmonary volume through activation by increased tension in the airway wall. Rapidly adapting receptors (RARs) are directly stimulated by mechanic H. Aslan Sirakaya (*) Department of Internal Medicine, Health Science University Kayseri City Hospital, Kayseri, Turkey © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_35

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stimuli or expiration of irritant particles or chemical. The pulmonary C fibers are unmyelinated, afferent nerve fibers that originate from J-receptors in small airway. These receptors can exacerbate dyspnea in conditions limiting the movements of respiratory system such as breath holding or acute hypercapnia [4–6]. Dyspnea is considered acute if it develops within hours or days and chronic if it lasts longer than 4–8 weeks. Some patients may present with acute exacerbations due to worsening of underlying disease (e.g., asthma, COPD, heart failure) or newly onset problem during the course of chronic dyspnea.

35.2 Clinical Evaluation Although clinical history is generally inadequate to make a diagnosis, it may be guiding for limiting differential diagnosis and selecting diagnostic tests. The duration of dyspnea and association with certain triggers may provide important clues. There are a limited number of conditions that lead to respiratory problems occurring within minutes or hours (Table 35.1). In acute settings, there are findings and symptoms accompanying dyspnea, which provide typical clues for diagnosis, e.g., substernal chest pain in cardiac ischemia; fever, cough and sputum in respiratory tract infection; urticaria in anaphylaxis; and wheezing in bronchospasm. Although there are multiple etiologies in the majority of patients with chronic dyspnea, they can be discussed in five major topics (Table 35.2) [7–9]. Both chronic exertional dyspnea and paroxysmal nocturnal dyspnea (PND) are associated to heart failure; however, PND is more specific to heart failure. In addition, asthma is associated to exertional dyspnea and nocturnal dyspnea but PND is not resolved by sitting or standing up. When heart failure causes an elevation in pulmonary venous pressure, it can lead to dyspnea by either inducing hypoxemia or stimulating pulmonary vascular and interstitial receptors. Cardiac tamponade can also cause dyspnea by increasing pulmonary vascular pressures. In the blood, vast majority of oxygen is transported as bounded to hemoglobin and oxygen delivery can be severely impaired in anemia. However, in anemia, the mechanism underlying dyspnea has not been fully elucidated. Similar to low-output heart failure, failure in maintaining aerobic metabolism can lead to stimulation of “ergoreceptors” [10, 11]. Moreover, anemia results in increased cardiac output, Table 35.1  Causes of acute dyspnea

Cardiovascular system Acute myocardial ischemia Heart failure Cardiac tamponade Respiratory system Bronchospasm Pulmonary embolism Pneumothorax Pulmonary infection Upper airway obstruction

35  Pharmacology Approach in Persistent Dyspnea and Noninvasive Ventilation… Table 35.2 Conditions associated with chronic or recurrent dyspnea

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Upper airway Laryngeal mass Vocal fold paralysis Inducible laryngeal obstruction (also known as paradoxical vocal fold motion) Neck mass compressing airway Chest/abdominal wall Diaphragmatic paralysis Kyphoscoliosis Late pregnancy Massive obesity Ventral hernia Ascites Intra-abdominal process Pulmonary Asthma Bronchiectasis Bronchiolitis COPD/emphysema Interstitial lung disease Mass compressing or occluding airway Pleural effusion Previous major lung resection (e.g., lobectomy, pneumonectomy) Pulmonary right-to-left shunt Pulmonary hypertension Trapped lung Venous thromboembolism (VTE) Cardiac Arrhythmia Constrictive pericarditis, pericardial effusion Coronary heart disease Deconditioning Heart failure (systolic or diastolic dysfunction) Intracardiac shunt Restrictive cardiomyopathy Valvular dysfunction Neuromuscular disease Amyotrophic lateral sclerosis Phrenic nerve disease/dysfunction Glycolytic enzyme defects (e.g., McArdle) Mitochondrial diseases Polymyositis/dermatomyositis Toxic/metabolic/systemic Anemia Metabolic acidosis Renal failure Thyroid disease Miscellaneous Anxiety Early pregnancy (effect of progesterone) COPD chronic obstructive pulmonary disease

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which, in turn, causes increased left ventricular volume and pulmonary vascular pressure. Intermittent dyspnea associated to cold air or allergen exposure suggests asthma. Besides asthma, intermittent symptoms with complete recovery between attacks can also be seen in recurrent aspiration, recurrent pulmonary embolism and heart failure; however, there is a concomitant organ dysfunction in general. The rapidity of symptom onset during exercise may be helpful in the diagnosis. For instance, in patients experiencing dyspnea and wheezing after walking 50–100  ft, pulmonary capillary wedge pressure (due to diastolic dysfunction) or pulmonary pressure will increase acutely. In exercise-induced asthma, symptoms are generally triggered by intense activity; symptoms start on minute 3 min; reach peak severity within 10 and 15 min and regress on minute 60. In patients with chronic dyspnea, baseline description of dyspnea will be helpful in assessing the escalation of symptoms [12]. There are numerous tools to assess the severity of dyspnea, including Baseline Dyspnea Index, Modified Medical Research Council (mMRC) Dyspnea Scale (Table 35.3) and Borg Scale (Table 35.4) [13–16]. It should be kept in mind that scales such as mMRC do not directly quantify dyspnea. Dyspnea severity at presentation can predict mortality and it is possible to assess dyspnea routinely in hospitalized patients [17, 18]. Table 35.3  The Modified Medical Research Council (mMRC) dyspnea scale Grade 0 1 2 3 4

Description of breathlessness I only get breathless with strenuous exercise I get short of breath when hurrying on level ground or walking up a slight hill On level ground, I walk slower than people of the same age because of breathlessness or have to stop for breath when walking at my own pace I stop for breath after walking about 100 yards or after a few minutes on level ground I am too breathless to leave the house or I am breathless when dressing

Table 35.4  The modified Borg Scale for assessing the intensity of dyspnea or fatigue

0 0.5 1 2 3 4 5 6 7 8 9 10

Nothing at all Very, very slight (just noticeable) Very slight Slight (light) Moderate Somewhat severe Severe (heavy) Very severe

Very, very severe (maximal)

Before 6-min walking test, the patient is asked to rate the severity of dyspnea and degree of fatigue using this scale. After exercise, the patient is asked to rate the severity of dyspnea and degree of fatigue using this scale by reminding the patient the grade he or she selected before exercise.

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Symptoms such as cough, sputum, nasal blockage, chest pain, peripheral edema, Raynaud’s phenomenon, arthritis and muscle weakness can be guiding in the diagnosis. For instance, asymmetrical lower extremity edema may suggest venous thromboembolism; Raynaud’s phenomenon is seen in interstitial lung disease or pulmonary hypertension-related rheumatic diseases. Asymmetrical swelling in metacarpophalangeal joints can be a clue for pulmonary involvement caused by rheumatoid arthritis. A comprehensive physical examination is fundamental. In particular, one should pay attention to whether there is stridor, wheezing, rales, tachycardia, arrhythmia, murmurs, gallop rhythm, peripheral edema, muscle weakness, dysphonia and signs of rheumatic disease. Clubbing is associated to bronchiectasis, idiopathic pulmonary fibrosis, lung cancer or cyanotic heart disease. The presence of jugular venous distention may suggest left-sided heart failure or core pulmonale. Decreased cardiac sounds may suggest pericardial effusion; however, it can be due to obesity or hyper-­ inflammation caused by emphysema. While assessing chronic dyspnea, a stepwise approach from least invasive tests with highest likelihood diagnosis to follow-up tests and advanced tests should be employed. In patients with chronic dyspnea, the severity of dyspnea and rate of worsening are major determinants for the timing of diagnostics tests [12]. After clinical assessment, initial tests should include complete blood count, glucose, blood urea nitrogen, creatinine, electrolytes, thyroid stimulating hormone, spirometry and pulmonary function tests, pulse oxymeter, chest radiograph, electrocardiography, plasma brain-natriuretic peptide and N-terminal pro-brain natriuretic peptide (NT-pro BNP). Chest radiograph can identify pleural effusion, kyphoscoliosis, cardiomegaly, interstitial lung disease or pulmonary hypertension. In the case of pleural effusion, diagnostic thoracentesis is needed (e.g., asbestos effusion, malignancy, rheumatoid effusion, infection, heart failure). In kyphoscoliosis detected by chest radiograph and physical examination, hypercapnia is assessed by arterial blood gas if there is moderate-to-severe restriction in pulmonary function test (PFT). Interstitial lung disease is generally assessed by spirometry, diffusing capacity for carbon monoxide (DLCO) and thoracic computed tomography (CT). Transthoracic echocardiography will be required if heart failure is suspected with chest radiograph and NT-pro BNP. The sensitivity of PFT to upper respiratory tract is relatively lower; thus, direct visualization of upper respiratory tract is needed. Spirometry shows whether there is an airway obstruction and the severity of obstruction, if present. When both FEV1 and forced vital capacity (FVC) are decreased in a proportional manner; in other terms, if FEV1/FVC ratio is normal or high, a restrictive disorder is considered. If asthma is suspected, the irreversibility of air flow limitation is tested using post-bronchodilator spirometry. In asthma, air flow limitation is typically reversible; however, inhaler or oral glucocorticoid therapy is needed for the treatment of edema and inflammation in the respiratory tract. The patients with irreversible air flow obstruction and history of smoking longer than 20 package/year are generally treated with the diagnosis of COPD.  If the patient does not respond to empirical therapy for asthma and COPD, other causes of

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irreversible air flow limitation (e.g., bronchiectasis, bronchiolitis, central airway obstruction) should be considered. If there is a reduction in the FVC but no air flow restriction, the next step is to identify the cause of FVC reduction. Restriction pattern can be caused by interstitial lung disease, pleural disease, chest wall disorder or weakness of respiratory muscles. A broncho-provocation test (using methacholine, histamine or mannitol) is employed in the patients with normal or near-normal spirometry and recurrent, episodic dyspnea. Alternatively, empirical asthma therapy can be attempted; however, the broncho-provocation test is preferred to establish definitive diagnosis. Studies have shown that 30% of patients clinically diagnosed with asthma have no airway reactivity in the tests [19, 20]. Empirical therapy, including glucocorticoids, can lead to gradual escalation of therapy and adverse effects in a patient without asthma. DLCO is helpful in the assessment of dyspnea; in particular, it will help diagnosing interstitial lung disease (indicated by reduced lung volumes), emphysema, bronchiolitis (indicated by obstructive pattern) and pulmonary vascular disorders. Pulmonary vascular disorders (e.g., pulmonary hypertension, chronic thromboembolic disease, pulmonary embolism) manifest with abnormal gas exchange in DLCO and decreased oxygen saturation (≥5%) during exercise in the presence of normal spirometry and pulmonary findings. The interstitial lung disease is assessed using high-resolution computed tomography (HRCT). Causes of obstruction in major respiratory tract (e.g., tumor) is best evaluated by contrast-enhanced CT. Chest radiograph can be normal in the minority of patients with interstitial lung disease; HRCT is highly sensitive in the detection of fine ground-glass infiltration or reticular opacities [21, 22]. Thus, a HRCT scan should be obtained in the patients with rales in physical examination, decreased lung volumes and reduction in DLCO even if chest radiograph is normal. If tracheomalacia is suspected, dynamic CT scan can reveal expiratory collapse of central airway [23]. Additional tests including bronchoalveolar lavage by bronchoscopy and biopsy from pulmonary or mediastinal lymph nodes can be performed to assess interstitial lung disease suspected. The patients with asymmetrical lower extremity edema, thromboembolic risk factors and low DLCO should be referred to computerized tomography pulmonary angiography (CTPA) to detect thromboembolic disease unless there is a contraindication. In the assessment of thromboembolic disease, alternative ancillary tests include ventilation-perfusion scintigraphy, sonography of venous system in lower extremity and magnetic resonance pulmonary angiography. Following pulmonary emboli, persistent dyspnea, functional limitation and impaired quality of life can be seen in 50% of patients [24, 25]. Heart failure or pulmonary hypertension is suspected, and transthoracic echocardiography is performed if there is suggestive clinical findings, elevated BNP or NT pro-BNP levels, cardiomegaly in chest radiography and exertion-induced oxygen desaturation. Transthoracic echocardiography can define diastolic dysfunction (heart failure with ejection fraction preserved), left ventricular hypertrophy, concentric remodeling and left atrial dilatation. There is diastolic dysfunction in approximately two-thirds of elder individuals with unexplained chronic dyspnea at the

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initial evaluation (e.g., history, physical examination, PFT and chest radiograph); diastolic dysfunction can present as dyspnea with minimum exertion [26]. The diagnosis of constrictive pericarditis can be challenging in patients presenting with chronic dyspnea; there is peripheral edema in general in these patients. Transthoracic echocardiography findings suggesting constrictive pericarditis include increased pericardial thickness, lacking or minimal collapse in vena cava inferior during inspiration, and abnormal ventricular filling in diastole. If there is suspected occult constrictive pericarditis, hemodynamic measurements are performed via right-sided cardiac catheterization 1 h before and after the infusion of warm normal saline (1L). The elevated pulmonary artery pressures (resting mean pulmonary arterial pressure [mPAP] > 20 mmHg) by Doppler echocardiography may suggest pulmonary hypertension. Pulmonary artery catheterization is performed to confirm elevated PA pressures and to exclude left ventricular dysfunction. The workload capacity of patient, severity of dyspnea, peak oxygen uptake, cardiac output and relationship between minute-ventilation and carbon dioxide production can be assessed using cardiopulmonary exercise testing (CPET). The patients with low threshold for respiratory disorder discontinue the test due to dyspnea with mild workload; however, these patients show no abnormal cardiopulmonary sign. The cardiopulmonary exercise test with pulmonary artery catheterization, also termed as invasive CPET (iCPET), is performed in specialized units [27]. In the assessment of dyspnea, the role of iCPET has not been fully defined. Typically, it can be used in the assessment of exercise-induced pulmonary hypertension, heart failure with preserved ejection fraction (HFpEF), exercise-induced heart failure and cardiac output restriction due to increased preload. Obesity-related dyspnea is generally related to increased effort for breathing or respiratory workload due to thickened chest wall [28]. Hypoxemia during resting or exercise may result from ventilation-perfusion mismatch at basal regions of lungs as a result of narrowed airway due to increased pleural pressure caused by thickened chest wall. Obesity is related to decreased expiratory reserve volume and functional residual capacity and, in some patients, decreased total lung capacity [29]. It is known that symptoms (cough and dyspnea in 47% and fatigue in 73%) persisted up to 30 days after discharge in 85% of patients hospitalized due to pneumonia; complete recovery may delay up to 6 months [30, 31]. However, in COVID-19 pneumonia, prolonged symptoms (particularly exercise-induced dyspnea) following COVID-19 can represent persistent and even progressive interstitial pulmonary changes and thromboembolic complications triggered by SARS-CoV-2. In hospitalized COVID-19 patients, persistent symptoms (particularly fatigue and exercise-­induced dyspnea) can be observed after 2 months in 30–50% of patients. Persistent dyspnea was reported in 30–40% after 2 months and in 10–25% after 4–6 months, which is generally related to ground-glass infiltrations on CT scan [32]. Pulmonary dysfunction related to symptoms is seen in less frequently with persistent restrictive ventilation disorder or limited diffusion capacity in a minority of patients. However, interstitial lung diseases requiring treatment have been reported in the literature [33–37].

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Dyspnea grading as rated by the patient can represent both sensorial and emotional components. Perceptive reactions for a certain physiological disorder leading to dyspnea can show great individual variability. Other chest symptoms (e.g., heartburn) and psychological factors can lead to perceived dyspnea [38–41]. The increased ventilation by anxiety, anger or pain may approximate a patient with limited pulmonary reserve to his/her respiratory limits and enhance perceived respiratory discomfort for any activity.

35.3 Treatment Although oxygen supplementation is standard therapy in the symptomatic treatment of dyspneic patients with hypoxemia in room air (oxygen saturation 72 h). In addition, control of the depth of sedation is easily achieved in propofol sedation. It will be used in patients requiring intermittent awakenings [13]. However, propofol can cause hypertriglyceridemia, a propofol-related infusional reaction [10]. Propofol infusion syndrome is a rare but potentially lethal complication after long-term, high-dose propofol infusion. This disorder is triggered under unknown circumstances by a propofol infusion of more than 4 mg/kg/h for more than 48 h. This is characterized by a multiorgan failure, rhabdomyolysis, metabolic acidosis, hyperkalemia, arrhythmias, and sudden cardiac death. It is induced by a disturbance in mitochondrial long chain fatty acid oxidation. The treatment of this

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is discontinuation of propofol, rapid correction of lactic acidosis, hyperkalemia and rhabdomyolysis, and cardiovascular support [30]. Propofol has been shown to increase upper airway collapse in a dose-dependent manner [26]. It also has amnesic properties [29]. Propofol minimizes extubation time regardless of the duration of sedation. Propofol can be used as it provides safe sedation of both short and long duration [13].

36.5.2.2 Ketamine Ketamine, an N-methyl-d-aspartate receptor antagonist, has been shown to have analgesic properties, together with bronchodilator effects and cardiovascular stimulation [31]. Ketamine is recognized for its beneficial cardiovascular and respiratory effects when administered as maintenance sedation by continuous infusion. The effect of ketamine on functional residual capacity, minute ventilation, and tidal volume is minimal compared to other sedatives. In addition, it decreases airway resistance and preserves protective pharyngeal and laryngeal reflexes in asthmatic patients with refractory bronchospasm [13]. Ketamine causes hypersalivation. Because of its effects on the sympathetic nervous system, ketamine should not be used in decompensated heart failure [26]. Ketamine can be used as an alternative for sedation in adults in ICU, as it is shown to have an advantage for hypotensive patients and also for patients requiring high doses of vasopressors [13]. Ketamine is recommended as an alternative when long-term continuous sedation is required to reduce the adverse effects of other agents. It is recommended for higher continuous sedation [13].

36.5.3 Opiates Remifentanil is a newly developed, short-acting, anilidopiperidine analogue opioid. Its metabolism is not influenced by renal or hepatic dysfunction, being metabolized by non-specific blood or tissue stearases to a pharmacologically inactive metabolite. The elimination half-life of remifentanil is less than 10 min, which is independent of infusion duration [32]. The pKa of remifentanil is lower than the physiological pH, which allows it to cross the blood-brain barrier and leads to a rapid equilibration of its concentration [32]. Remifentanil has a 1 min onset of action and rapidly achieves steady state. Its characteristics make remifentanil easy to assess and allow administration without concerns about accumulation [32]. Low doses of remifentanil (0.05 μg kg−1 min−1) provide sedation in critically ill patients without decreased respiratory drive [32]. The higher cost of remifentanil would be offset by this reduction in ICU stay [13]. Remifentanil-based sedation during IVN is effective and safe [33].

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36.5.4 Alpha-2 Agonists 36.5.4.1 Dexmedetomidine Dexmedetomidine is a new lipophilic imidazole derivative with a higher affinity for α2 receptors than clonidine [24]. It is potent and highly selective for receptors α2 with a ratio α2:α1 of 1620:1 [34]. It has sedative, anxiolytic, sympatholytic, and analgesic-sparing effects. It exerts its hypnotic action through activation of central pre- and postsynaptic α2 receptors in the locus coeruleus, thus inducing a similar state of unconsciousness, like natural sleep, with the only aspect being that patients remain easily rousable and cooperative [34]. Among the sedative drugs, dexmedetomidine shows the lowest risk of respiratory depression [26]. The inhibition of sympathetic activity in the periphery leads to sequential decreases in blood pressure and heart rate, the most commonly reported adverse events associated with dexmedetomidine [12]. The side effects of dexmedetomidine are mainly restricted to hemodynamics disturbances. These include hypertension, bradycardia, and hypotension, due to activation of pre- and postsynaptic α2 receptors causing vasoconstriction, vasodilatation, and reflex bradycardia [34]. The recommended dose is an initial infusion of 0.7 μg/kg/h with no loading dose, followed by titration of the desired effect using a dose range of 0.2–1.4 μg/kg/h [34]. A Cochrane review covering seven studies compared the long-term use of dexmedetomidine with traditional sedatives in ICU sedation. Dexmedetomidine reduced the duration of mechanical ventilation by 22% and ICU length of stay by 14% [34]. In the MIDEX and PRODEX trials, the sedative properties of midazolam and propofol were compared with those of dexmedetomidine in mechanically ventilated ICU patients. Dexmedetomidine is not inferior in providing light to moderate sedation. In addition, shorter extubation time is observed with dexmedetomidine [34]. When initiated with a low initial loading dose, followed by a continuous infusion, dexmedetomidine can provide both adequate sedation and safer control sedation in patients with NIV [33]. Dexmedetomidine is an appealing alternative to traditional sedatives such as propofol and benzodiazepines. As a highly selective α2-receptor agonist with no effect on the GABA receptor, it interacts with transmembrane G-protein-binding adrenoreceptors in the periphery (α2A), as well as in the brain (α2B) and the spinal cord (α2C). Inducing a sleep-like state without respiratory depression may explain the beneficial effects of dexmedetomidine, since disturbed circadian rhythm is a known contributing factor of delirium [12]. Dexmedetomidine compared to any sedation strategy or placebo reduces the risk of delirium (16% reduction in risk of delirium) and the need for intubation and mechanical ventilation (16% absolute risk). Any benefit of dexmedetomidine must be balanced against the possible undesirable effects of bradycardia and hypotension [31]. Finally, it should be noted that an important feature of dexmedetomidine-based sedation is that patients wake up easily. This, combined with its minimal influence

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on respiration, makes dexmedetomidine an interesting sedative alternative in many procedures [34].

36.5.4.2 Clonidine Clonidine is a centrally acting alpha-2 selective adrenergic agonist similar in action to dexmedetomidine. Clonidine exerts its sedative effects via stimulation of the pre-­ synaptic alpha-2 adrenoreceptors of the locus coeruleus, decreasing norepinephrine release. Clonidine also has action on the cholinergic, purinergic, and serotoninergic pathways, resulting in analgesia [35]. Traditionally, clonidine has been used to treat attention deficit hyperactivity disorder, opioid and alcohol withdrawal, hypertension, vasomotor menopausal symptoms, and for neuraxial anesthesia via epidural administration. In the critically ill pediatric population, clonidine is frequently used as a sedative agent, particularly as an adjunctive agent when there is an inadequate response to opioids and benzodiazepines, or to help facilitate weaning from mechanical ventilation [35]. The side effects of clonidine include hypotension and rarely bradycardia, as well as rebound tachycardia and hypertension after clonidine withdrawal [35]. There is a shortage of evidence to support the use of clonidine due to the lack of randomized clinical trials in critically ill adults [31].

36.5.5 Others Volatile anesthetics (isoflurane, sevoflurane) will induce light or deep sedation, even in patients difficult to sedate with benzodiazepines and opioids [10]. Volatile anesthetics are known to modulate the function of N-metyl-d-aspartate receptors that are involved in the expression of physical dependence on opioids and could be of great value when doses of intravenous sedatives need to be lowered [36]. The rapid onset of sedation with inhaled anesthetics allows for better planning of extubation and may facilitate daily neurological assessment [36]. Tolerance and withdrawal syndrome have been reported after prolonged administration of inhaled anesthetic agents [36]. Sevoflurane is a versatile inhalation agent with non-organ-dependent degradation and easy titration based on measured concentrations. It appears to be an effective alternative to intravenous sedation in general in ICU patients to decrease awakening and extubation times [36]. When sevoflurane was compared to midazolam in ARDS patients, improved oxygenation and systemic inflammation reduced epithelial lung damage [10]. Data suggest that the use of volatile agents for sedation may be useful in postoperative patients, who require short-term ventilation [31]. A synthetic opioid agonist-antagonist analgesic, butorphanol, can agonize the κ and σ opiate receptors principally, but antagonize μ opiate receptor or partially. Because of lower affinity between butorphanol and σ opiate receptors, little dysphoria could be induced by butorphanol. In addition to analgesia, butorphanol also exerts the effect of sedation through agonizing κ opiate receptors without tolerance.

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There is not floaty euphoria and drug dependence during period of use butorphanol because it antagonizes μ opiate receptor or partially. Butorphanol has been used widely for treatment of pain with moderate-to-severe degree, opioid-induced cough, as a supplement to balancing general anesthesia and reducing postoperative shivering [37]. Wang et  al. concluded that continuous intravenous infusion of butorphanol resulted in the same effect of sedation as propofol as NIV; that compared with propofol, both sedation and analgesia were induced by butorphanol; and that continuous intravenous infusion of butorphanol led to a stable state of hemodynamics and less adverse events [37].

References 1. Hilbert G, Clouzeau B, Nam H, Vargas F. Sedation during non-invasive ventilation. Minerva Anesthesiol. 2012;78(7):842–6. 2. Senoglu N, Oksuz H, Dogan Z, Yildiz H, Demirkiran H, Ekerbicer H. Sedation during noninvasive mechanical ventilation with dexmedetomidine or midazolam: a randomized, double blind, prospective study. Curr Ther Res Clin Exp. 2010;72(3):141–53. 3. Kim T, Kim JS, Choi EY, Chang Y, Choi W, Hwang J, et al. Utilization of pain and sedation therapy on noninvasive mechanical ventilation in Korean intensive care units: a multi-center prospective observational study. Acute Crit Care. 2020;35(4):255–62. 4. William D, Schweickert BK, Gehlbach MD, Pohlman AS, Jesse B, et al. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Crit Care Med. 2004;32(6):1272–6. 5. Ni WN, Wang T, Yu H, Liang BM, Liang ZA. The effect of sedation and/or analgesia as rescue treatment during noninvasive positive pressure ventilation in the patients with interface intolerance after extubation. BMC Pulm Med. 2017;17(1):125. 6. Rasheed AM, Amirah MF, Abdallah M, Parameaswari PJ, Issa M, Alharthy A. Ramsay sedation scale and Richmond agitation sedation scale. Dimens Crit Care Nurs. 2019;38(2):90–5. 7. Kayir S, Ulusoy H, Dogan G. The effect of daily sedation-weaning application on morbidity and mortality in intensive care unit patients. Cureus. 2018;10(1):2062. 8. Swart E, Van Schijndel R, Van Loenen A, Thijs L. Sedation with lorazepam is easier to manage and is more cost effective. Crit Care Med. 1999;27(8):1461–5. 9. Namigar T, Serap K, Esra AT, Can OA, Aysel A, Achmet A.  The correlation among the Ramsay scale, Richmond agitation sedation scale and Riker sedation agitation scale during midaziolam-­remifentanil sedation. Rev Bras Anestesiol. 2017;67(4):347–54. 10. Chanques G, Constantin JM, Devlin JW, Ely EW, Fraser GL, Gélinas C, et al. Analgesia and sedation in patients with ARDS. Intensive Care Med. 2020;46(12):2342–56. 11. Matsumoto T, Tomii K, Tachikawa R, Otsuka K, Nagata K, Otsuka K, et al. Role of sedation for agitated patients undergoing noninvasive ventilation: clinical practice in a tertiary referral hospital. BMC Pulm Med. 2015;15:71. 12. Flükigeer J, Hollinger A, Speich B, Meier V, Tontsch J, Zehnder T, et al. Dexmedetomidine in prevention and treatment of postoperative and intensive care unit delirium: a systematic review and meta-analysis. Ann Intensive Care. 2018;8(1):923. 13. Neme D, Awake Z, Mola S, Jemal B, Regasa T. Evidence-based guideline for adult sedation, pain assessment, and analgesia in a low resource setting intensive care unit: review article. Int J Gen Med. 2020;13:1445–52. 14. Kress JP, Pohlman AS, O’Connor MF, Hall JB.  Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471–7.

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15. Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003;168(12):1457–61. 16. Brattebo G, Hofoss D, Flaatten H, Muri AK, Gjerdde S, Plsek PE. Effect of a scoring system and protocol for sedation on duration of patients’ need for ventilator support in a surgical intensive care unit. Qual Saf Health Care. 2004;13(3):203–5. 17. Nies RJ, Müller C, Pfister R, Binder PS, Nosseir N, Nettersheim FS, et al. Monitoring of sedation depth in intensive care unit by therapeutic drug monitoring? A prospective observation study of medical intensive care patients. J Intensive Care. 2018;6:62. 18. Sessler CN, Grap MJ, Ramsay MAE. Evaluating and monitoring analgesia and sedation in the intensive care unit. Crit Care. 2008;12(3):S2. 19. Olson D, Lynn M, Thoyre SM. The limited reliability of the Ramsay scale. Neurocrit Care. 2007;7:227–31. 20. Hilbert G, Navalesi P, Girault c. Is sedation safe and beneficial in patients receiving NIV? Yes. Intensive Care Med. 2015;41(9):1688–91. 21. Khan BA, Guzman O, Campbell NL, Waldroth T, Tricker JL, Hui SL, et  al. Comparison and agreement between the Richmond agitation-sedation scale and the Riker sedation-­ agitation scale in evaluating patients’ eligibility for delirium assessment in the ICU. Chest. 2012;142(1):48–54. 22. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the sedation-agitation scale for adult critically ill patients. Crit Care Med. 1999;27(7):1325–9. 23. Luo A, Muraida S, Pinchotti D, Richardson E, Ye E, Hollingsworth B, et  al. Bispectral index monitoring with density spectral array for delirium detection. J Acad Consult Liaision Psychiatry. 2021;62(3):318–29. 24. Triltsch AE, Welte M, Von Homeyer P, Grobe J, Genähr A, Moshirzadeh M, et al. Bispectral index-guided sedation with dexmedetomidine in intensive care: a prospective, randomized double blind, placebo-controlled phase II study. Crit Care Med. 2002;30(5):1007–14. 25. Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam isoflurane, and alfentanil in healthy volunteers. Anesthesiology. 1997;86(4):836–47. 26. Longrois D, Conti G, Mantz J, Faltlhauser A, Asntaa R, Tonner P. Sedation in non-invasive ventilation: do we know what to do (and why)? Multidiscip Respir Med. 2014;9(1):56. 27. Fraser GL, Devlin JW, Worby CP, Alhazzani W, Barr J, Dasta JF, et al. Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials. Crit Care Med. 2013;41(9):S30–8. 28. Cavus MA, Bektas SG, Turan S. Comparison of clinical safety and efficacy of dexmedetomidine, remifentanil, and propofol in patients who cannot tolerate non-invasive mechanical ventilation: a prospective randomized, cohort study. Front Med. 2022;9:995799. 29. Clouzeau B, Bui HN, Vargas F, Grenouillet-Delacre M, Guilhon E, Grusson D, et al. Target-­ controlled infusion of propofol for sedation in patients with non-invasive ventilation failure due to low tolerance: a preliminary study. Intensive Care Med. 2010;36(10):1675–80. 30. Carrillo-Esper R, Garnica-Escamilla MA, Bautista-León RC. Síndrome por infusión de propofol. Rev Mex Anestesiol. 2010;33(2):97–102. 31. Page V, McKnzie C.  Sedation in the intensive care unit. Curr Anesthesiol Rep. 2021;11(2):92–100. 32. Constantin JM, Schneider E, Cayot-Constantin S, Guerin R, Bannier F, Futier E, et  al. Remifentanil-based sedation to treat noninvasive ventilation failure: a preliminary study. Intensive Care Med. 2007;33(1):82–7. 33. Huang Z, Chen Y, Yang Z, Liu J.  Dexmedetomidine versus midazolam for the sedation of patients with non-invasive ventilation failure. Intern Med. 2012;51(17):2299–305. 34. Weerink MAS, Struys MMRF, Hannivorrt LN, Barends CRM, Absalom AR, Colin P. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 2017;56(8):893–913.

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35. Wang GJ, Belley-Coté E, Burry L, Duffet M, Karachi T, Perri D, et al. Clonidine for sedation, in the critically ill: a systematic review and meta-analysis (protocol). Syst Rev. 2015;4:154. 36. Pavcnik M, Groselj M. Sevoflurane sedation for weaning from mechanical ventilation in pediatric intensive care unit. Minerva Anestesiol. 2019;85(9):951–61. 37. Wang X, Meng J. Butorphanol versus propofol in patients undergoing noninvasive ventilation: a prospective observational study. Int J Gen Med. 2021;14:983–92.

Pharmacological Therapy for the Management of Patient Ventilator Asynchrony During Noninvasive Ventilation

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Mohanchandra Mandal, Pradipta Bhakta, John Robert Sheehan, Brian O’Brien, and Dipasri Bhattacharya

37.1 Introduction Patient ventilator asynchrony (PVA) is a challenging reality of noninvasive ventilation (NIV) therapy [1–4]. It is a common cause of NIV intolerance and can lead to NIV failure [2, 3]. To discuss its pharmacological management of PVA, we will first define the spectrum of PVA through NIV intolerance and NIV failure. After briefly outlining the non-pharmacological interventions, we will discuss pharmacological ones and the evidence for their use.

M. Mandal (*) Department of Anaesthesiology and Intensive Care, Institute of Postgraduate Medical Education and Research, Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India P. Bhakta Department of Anaesthesiology and Intensive Care, Hull University Teaching Hospital NHS Trust, Hull, East Yorkshire, UK e-mail: [email protected] J. R. Sheehan · B. O’Brien Department of Anaesthesiology and Intensive Care, Cork University Hospital, Cork, Ireland D. Bhattacharya Department of Anaesthesiology, Pain Medicine, and Critical Care, R. G. Kar Medical College, Kolkata, West Bengal, India © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Esquinas et al. (eds.), Pharmacology in Noninvasive Ventilation, Noninvasive Ventilation. The Essentials, https://doi.org/10.1007/978-3-031-44626-9_37

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37.2 Patient Ventilator Asynchrony The patient’s ability to cooperate and thus synchronize with NIV ultimately determines the success of this therapy and influences patient outcome [1]. Clinicians must be able to assess the efficacy of NIV therapy and patient’s comfort to prevent PVA. The term “asynchrony” is defined as “Disruption of the coordination between two subsequent events that are expected to happen in a coordinated manner one after the another” [2]. PVA is defined as the mismatch between the patient’s respiratory effort and the assisted breath delivered by the ventilator [3, 5]. The incidence of PVA during NIV has been reported to vary widely, between 20% and 80% [6–8]. An asynchrony index (number of dyssynchronous breathing efforts per minute divided by the total respiratory rate including wasted breaths × 100) more than 10% has been classified as severe form of PVA and is associated with higher mortality [5, 9]. A high AI has been reported to occur in about 40% of patients [10, 11]. Several types of PVAs are reported during NIV therapy [2, 3, 12, 13]. PVA can occur due to delays between breath delivery and the patient’s respiratory effort. This uncoordinated interaction (mismatch or delay) between patient and ventilator can occur either at the beginning of inspiratory cycle (triggering phase) or at the end of the inspiratory effort (cycling phase) [2, 14]. Among them, ineffective triggering is most commonly observed [5]. Underlying pathophysiological conditions (commonly restrictive or obstructive lung disease), ongoing air leaks, the level of ventilatory support, type of interface, humidification, and anxiety or discomfort of patient can contribute to the development of PVA [12]. It usually develops when the patient’s respiratory effort is relatively elevated, such as in acute respiratory failure (ARF) [1, 7, 11, 14–16]. Clinicians need to be able to differentiate between an insufficient breathing effort requiring escalation in ventilatory support (which may be due to the disease state or excessive sedation) and an acute disease state as cause of the problem necessitating sedation.

37.3 NIV Intolerance NIV intolerance is defined as cessation of continuous or intermittent NIV therapy due to refusal by the patient to continue it, usually because of discomfort [17]. In addition to the etiologies of PVA, several other factors contribute to the development of NIV intolerance, these including the type and severity of acute respiratory failure, the status of the underlying disease, type of interface (mask) being used, the presence of any hemodynamic instability, and the patient’s neurological status, be that agitation or anxiety, and even PVA [2, 18]. Mask intolerance due to pain, pressure, disruption of facial skin, or claustrophobia may lead to refusal in a further NIV in 9–22% of cases [19]. Inappropriate choice and application of masks can lead to these complications and so to NIV failure [6, 20]. Some 10–38% of patients refuse to continue NIV therapy owing to discomfort resulting from NIV interfaces [21]. In pediatric populations, the availability

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of suitable types and sizes of NIV interfaces is often an issue. Fragile skin, especially in neonates and preterm infants, leaves them vulnerable to pressure damage with consequent NIV failure [16]. Neurocognitive impairment (such as developmental delay and/or delirium) can pose additional challenges in the management of NIV intolerance [2, 4]. Some patients, especially those with claustrophobia, become overtly anxious and thereby develop NIV intolerance with the application of the NIV interface [22].

37.4 Diagnosis of PVA and NIV Intolerance Close monitoring of these patients, especially during the initial period of NIV therapy is the best way to diagnose PVA [3, 15, 23–25]. Earlier diagnosis allows targeted interventions to be instituted in a timely manner which improves NIV tolerance [3, 15, 23–25]. This can prevent subsequent NIV failure, which necessitates endotracheal intubation (ETI) and institution of invasive mechanical ventilation (IMV) [3, 23, 25]. PVA can be diagnosed by visual inspection of flow and pressure waveforms displayed on the screen of modern NIV machines [5, 13, 15]. This, however, can be time consuming, and there is high inter-individual variation, with significant underestimation, when relying on waveform interpretation to diagnosis PVA [5, 13, 15, 26]. To diagnose it more accurately, visual waveform observations have been combined with objective respiratory activity measurements [i.e., esophageal pressure monitoring, electrical activity of diaphragm (Edi), ultrasonographic evaluation of diaphragmatic thickening] [5, 15, 27–33]. Recently, electronic software-based algorithms have been developed which diagnose PVA with higher specificity and sensitivity when compared to waveform analysis [13, 27, 31, 34–36]. For example, SyncSmart, Better Care™, and NeuroSync Index use this technology to diagnose PVA [26, 35, 37]. Typically, when the AI is greater than 10%, adjustment of the ventilator settings is indicated [26]. However, auto-triggering may contribute to 40% of all these PVA events [26]. Software which detects interface-related air leaks and auto-adjust flow to compensate greatly reduces the occurrence of PVA [26]. The use of such software has been found to reduce auto-triggering, the delivery of ineffective inspiratory supports, and delayed expiratory cycling [38]. Continuous monitoring of air leakage, tidal volume delivery, respiratory rate, minute volume, mismatch between inspired and expired air, patterns of synchronization with NIV, trends in lung compliance, and pressure-volume loops are all now possible on the NIV machine screens and can be used to diagnose PVA [13, 15, 26, 27, 31, 34, 35–37]. These parameters, combined with the patient’s clinical status and arterial blood gas (ABG) results can be used to adjust strategies when managing NIV-dependent patients [15]. It is recommended to continuously monitor all these variables during the initial period of NIV, until the patient is stabilized and improving [3, 15, 23, 24, 39]. This can prevent PVA, improving the success of therapy and therefore patient outcomes [24]. Although most experienced physicians and nurses can accurately recognize PVA, they often experience difficulties identifying the exact mechanism [3, 26]. After

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this, the degree and details of monitoring will depend on the patient’s condition and progress [39]. The level of monitoring may determine where the patient is cared for, as some are only suited to an intensive care unit (ICU) environment [39]. The location where the patient will be treated [i.e., ICU, high dependency unit (HDU), general ward, or at home] is also determined by the severity of the illness, the presence of associated comorbidities, prognosis, and the availability of experienced staff [39]. Most patients requiring NIV are now managed in the general wards and some even at home [39].

37.5 NIV Failure NIV failure is diagnosed when escalation of therapy to ETI and institution of IMV is required, or in the most extreme case, when the patient dies while they remain on NIV [40]. The incidence varies from 5% to 60% [4, 17, 41]. The most common causes of NIV failure are poor patient co-operation, mask intolerance, poor patient selection, severe ARF, a disordered sensorium, and unrealistic expectations for the patients [40, 42].

37.6 Management Considering the varied etiology and presentation, and patients’ variability, the management of PVA must suit the patient. This can be achieved by selecting from different non-pharmacological and pharmacological strategies the best options without compromising the safety of the patients [1–4, 22, 30, 43–55]. The following considerations guide such decision-making.

37.6.1 Non-pharmacological Means While sedation is the mainstay of management of PVA, clinicians should first consider modifiable factors and non-pharmacological means. Current evidence recommends minimization of the stress and discomfort by using different nonpharmacological strategies [43, 56]. These include the use of the proper size and type of mask, with humidification, head up position, a comfortable ambient temperature, and the provision of a peaceful environment (reduction of noise and strong light) [3, 30, 43–45, 56]. Also adopting lower initial ventilatory pressure settings, changing of modes (switching from pressure support mode to NAVA and proportional assist ventilation), the adjustment of sensitivity and trigger setting, maintenance of normal sleep cycle, provision family, and psychological support are desirable measures [3, 30, 43–45, 56]. Using digital software-based diagnosis of PVA and auto-correction of NIV flow can reduce the occurrence of PVA, avoiding the use of pharmacological means [26, 38].

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37.6.2 Pharmacological Means Medications are commonly used to manage PVA [1, 4, 19, 47–49, 51–54, 57–67]. The use of sedation and sedo-analgesics during NIV therapy is standard, first-line therapy as recommended by most existing guidelines [1, 4, 47–49, 51–54, 57–74]. They are broadly used for the management of accompanying pain, discomfort, anxiety, agitation, and delirium linked to PVA [4, 47–50]. Although increasing the depth of sedation is common practice, it is associated with adverse consequences [5]. Deeper levels of sedation can increase the incidence of ineffective triggering and the duration of NIV, length of ICU and hospital stay, and ultimately mortality [5, 55, 75–77]. Evidence-based data on the safety of sedatives and/or sedo-analgesics remains controversial [4, 22, 47, 49, 55, 64, 68, 71, 78–84]. Thus, when pharmacological means are selected, some reflection is warranted. Summary of the relevant literature review can be found in Table 37.1.

37.6.3 Sedative Agents 37.6.3.1 Benzodiazepines There is a paucity of evidence on the use of benzodiazepines to prevent PVA in the literature. They lack analgesic properties and can cause hypotension and respiratory depression [4, 66, 68]. Their continued use at higher doses has been found to be associated with delirium [4, 6, 85, 86]. In spite of this, benzodiazepines are the most commonly used sedative during management of NIV based on the experience gained, albeit largely with IMV, in ICU [4, 47, 51, 53, 54, 61, 62, 87–89]. Midazolam is the most common choice, followed by lorazepam [4, 61, 62]. Midazolam is useful if anxiety is clearly the cause of PVA, provided the respiratory status is closely monitored [4, 87]. Infusion has been successfully used [51, 53, 54, 88]. 37.6.3.2 Propofol Propofol has been widely used in the management of PVA, especially in patients who are electively placed on NIV after weaning from IMV and endotracheal extubation [4]. Because of propofol’s unique pharmacokinetic profile, it has been used in a target-controlled infusion (TCI) successfully to manage PVA [52, 90]. Propofol has also been used as a supplementary sedative in this setting [61, 80]. However, during monitoring of Edi in patients being managed with pressure support ventilation (PSV), propofol was found to reduce respiratory drive [90]. Using either propofol, an opioid (mostly remifentanil), or dexmedetomidine has been reported to reduce overall mortality and the incidence of NIV failure in patients with NIV intolerance compared to those not receiving sedation [80]. 37.6.3.3 Dexmedetomidine Dexmedetomidine is a highly selective α2 agonist which has both sedative and analgesic properties [4, 51, 53, 54, 62, 63, 69, 91, 92]. It is primarily used as a sedative agent [51, 53, 54, 62, 63, 91, 92]. Used judiciously, it can preserve respiratory drive

Dexmedetomidine infusion as sole sedative

Case report (n = 2)

Single-center, retrospective observational cohort study

Retrospective cohort study

Retrospective study

Venkatraman et al. [62]

Piastra et al. [92]

Shutes et al. [63]

Type of study Prospective observational study

Takasaki et al. [91]

Author (s) Akada et al. [69]

Children (n = 382, aged ≤18 years). Received dexmedetomidine infusion for >24 h Abrupt discontinuation of infusion (n = 336), infusion weaned off (n = 37), sedation changed to oral clonidine (n = 9)

Pediatric patients (n = 40, median age 16 months) who received NIV in PICU

A man (65 year) and a woman (32 year) respectively with ARF resulted from severe asthma Children (median age 2 years, n = 202) received NIV, dexmedetomidine infusion was used up to 48 h

Study population Hypercapnic ARF patients (n = 10)

Dexmedetomidine was used as a part of ‘Usual care practices’; hence may be considered as ‘Prophylactic’

For prevention of NIV intolerance

For the purpose of managing NIV intolerance. Dexmedetomidine infusion was used within 48 h of PICU admission

For presumptive management of agitation

Reason for using sedation and/or analgesia For the purpose of managing NIV intolerance

Table 37.1  List of clinical studies using sedatives/analgesics for management of NIV intolerance

Comfort-B score titrated between 11 and 22; RASS score≤1

SBS score kept between 0 and 1

RSS score titrated between 2 and 3

Methods used for titration of sedation RSS score ≥2; RASS score ≤0 within 1 h

Adequate tolerance was achieved

NIV was well tolerated [Rarely needed interventions for bradycardia (13%), hypotension (20%), and hypopnea (5%)] NIV was well tolerated

Adequate tolerance was achieved

Tolerance of NIV Adequate tolerance was achieved

Even longer duration of infusions of dexmedetomidine monotherapy found to have predictable hemodynamic effects in critically ill pediatric population

Dexmedetomidine infusion provided an effective level of sedation

Study outcome Dexmedetomidine infusion is found to be an efficacious option for management of NIV intolerance Dexmedetomidine infusion was found to be a valuable sedative to facilitate induction of NIV Dexmedetomidine infusion is an effective sedative in pediatric patients for NIV

364 M. Mandal et al.

Rocco et al. [1]

Remifentanil

Prospective observational study

Prospective, double-blind randomized controlled trial

Prospective randomized. Controlled trial

Huang et al. [53]

Devlin et al. [54]

Prospective, double-blind randomized controlled trial

Senoglu et al. [51]

Dexmedetomidine vs. placebo and/or midazolam and fentanyl

Dexmedetomidine vs. midazolam

Hypercapnic patients with ARF (n = 33) Dexmedetomidine (n = 16) vs. placebo (n = 17) ± midazolam (for agitation) and/or fentanyl (for pain) ARF patients having persistent hypoxia (n = 36)

Hypercapnic patients with CPE and ARF (n = 62) Dexmedetomidine (n = 33) vs. midazolam (n = 29)

Hypercapnic (COPD) patients with ARF (n = 40). Dexmedetomidine (n = 20) vs. midazolam (n = 20)

For the purpose of managing NIV intolerance

For prevention of NIV intolerance

For the purpose of managing NIV intolerance

For the purpose of managing NIV intolerance

RSS score titrated to 2 and 3

SAS score titrated between 3 and 4

RSS score titrated to 2–3

RSS score titrated to 2–3, RASS to 3–4, and BIS >85

Adequate tolerance as achieved

NIV tolerance was not achieved

Adequate tolerance was achieved

Adequate tolerance was achieved

(continued)

Both sedatives were found to be equally effective during NIV except dexmedetomidine required fewer dose adjustments Desired level of arousable sedation, shorter duration of ventilation, and shorter length of ICU stay was achieved with dexmedetomidine compared to midazolam Routine early use of dexmedetomidine was found neither to improve NIV tolerance nor able to maintain the desired level of sedation Remifentanil-based sedation was found to reduce incidence of NIV failure in patients who were initially intolerant to it

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Constantine et al. [72]

Propofol and remifentanil

Prospective observational study

Prospective observational study

Type of study Patients who developed NIV failure due to discomfort, agitation and/ or refusal (n = 10) Propofol TCI was administered in hypoxemic (n = 7) or hypercapnic (n = 3) patients with ARF Patients with ARF (n = 13); hypoxemic (n = 10), and hypercapnic (n = 3) Propofol was used only in 3 patients while remifentanil was used in all 13 patients

Study population

For the purpose of managing NIV intolerance

For the purpose of managing NIV intolerance

Reason for using sedation and/or analgesia

RSS score was titrated between 2 and 3

OAA/S score was titrated to 3 or 4

Methods used for titration of sedation

Adequate tolerance was achieved

Adequate tolerance was achieved

Tolerance of NIV

This study proved the feasibility and safety of remifentanil-based sedation in patients with NIV failure

Propofol TCI was found to be safe and effective in managing NIV failure due to low tolerance

Study outcome

RSS Ramsay sedation score, RASS Richmond Agitation-Sedation Scale, PICU Pediatric Intensive Care Unit, CPE cardiogenic pulmonary oedema, COPD chronic obstructive pulmonary disease, ARF acute respiratory failure, TCI target-controlled infusion, SAS Sedation-Agitation Scale, OAA/S Observer Assessment of Alertness/Sedation Scale

Clouzeau et al. [52]

Propofol TCI

Author (s)

Table 37.1 (continued)

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and maintain hemodynamic stability, thus facilitating faster weaning from mechanical ventilation (MV) [4, 58]. This can significantly reduce the risk of delirium and agitation, the duration of MV, and length of ICU and hospital stay and perhaps improve overall mortality [53, 54, 58, 61, 62, 69, 70, 80, 91, 93–102]. Its favorable cardiorespiratory profile makes it a suitable agent for the provision of sedation as well as analgesia for the management of PVA [58, 95]. Akada et al. conducted a prospective observational study to investigate the role of dexmedetomidine in patients on NIV who developed PVA attributable to agitation [69]. They successfully weaned all patients from NIV without further respiratory deterioration. Subsequently published case report [102] and retrospective chart review [103] have also echoed this. Hao et al. evaluated the comparative efficacy of remifentanil and dexmedetomidine for the management of moderate to severe PVA in patients on prophylactic or therapeutic NIV after cardiac surgery [70]. While remifentanil was deemed better than dexmedetomidine in the initial period, the overall effect during treatment was similar. Dexmedetomidine infusion has been found to be superior to haloperidol and midazolam for management of NIV-related delirium [61, 95]. It was found to reduce duration of mechanical ventilation, length of ICU stay, and need for ETI and IMV compared to other agents [4]. Dexmedetomidine infusion also required less supplemental sedatives and analgesics compared to haloperidol. However, it was reported to be associated with a much higher incidence of bradycardia and hypotension, although not typically necessitating any intervention [61, 95]. Shutes et al. used dexmedetomidine for management of NIV intolerance, safely and effectively in pediatric patients [63]. These reports have helped establish the safety as well as the efficacy of dexmedetomidine in the management of PVA.

37.6.4 Sedo-analgesic Agents 37.6.4.1 Opioids Opioids are still the main pharmacological intervention for the management of dyspnea in ARF [1, 4, 68, 71, 72, 104]. Their ability to reduce respiratory drive and suppress air hunger improves patient’s comfort [4, 104, 105]. As opioids are commonly used in the ICU during IMV, that experience has been extrapolated to NIV [4, 68]. However, respiratory depression associated with opioids is undesirable as NIV is dependent on patient’s spontaneous respiratory effort [4, 71, 78, 79, 106]. Although newer machines offer backup ventilation lest the patient becomes apneic, it is clearly undesirable and should not be relied upon as it eliminates many of the advantages of NIV [4]. Several opioids (such as morphine, hydromorphone, fentanyl, sufentanil, and remifentanil) have been used in the management of PVA [61, 62, 68, 80, 88, 107]. The intravenous infusion of morphine was found to alleviate respiratory distress thereby improving NIV tolerance [88, 105, 107]. It is thus recommended by the British Thoracic Society, including in patients who are not terminally ill [48]. Enders et  al. conducted an observational study on preterm neonates managed with NIV and found significant improvements in cardiorespiratory parameters and

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comfort scores after single dose of morphine (0.05–0.1 mg/kg), although patients born 61%. Initially developed in a German ICU, it has subsequently been validated in an international cohort. However, as up to 25% of critically ill patients develop delirium within the first 24 h of admission, it is necessary to detect it as early as possible. Thus E-PRE-DELIRIC was directly validated in an international cohort, with an AUROC of 0.76 out of 9 predictors; age, cognitive impairment prior to admission, alcohol abuse, reason for admission (medical, surgical, trauma or neurology/neurosurgery), emergency admission, respiratory failure, BUN, mean arterial pressure (MAP), and corticosteroid use on admission to the ICU [13]. In a study analyzing the characteristics of both tools, with reported good or moderate performance, although the predictive value is higher in PREDELIRIC. However, the need for early diagnosis, and the ease of its use, lead the authors to favor the E-PRE-DELIRIC [14].

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38.7 Rationale Delirium Assessment Being an underdiagnosed problem, and given the high comorbidity, the assessment of delirium through scales is a recommendation of the international society of intensive care [15]. The Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) are the most commonly used scales. Both require an adequate level of consciousness (RASS ≥−2). Given that patients undergoing NIV need an adequate level of consciousness to cooperate with the technique and the high prevalence of delirium in NIV, it is unacceptable today not to investigate the existence of delirium in this type of patient. To implement the effectiveness of delirium screening, it is suggested to incorporate it into the daily routine of the ICU, so that some authors speak of the “brain roadmap,” which is a simple questionnaire (100 mmHg), intravenous nitroglycerin rather than oral or transdermal can lead to early improvement in symptoms in combination with diuretics. The medication is often initiated at 5–10 μg/min and titrated in 5 μg/min increments based upon clinical response and repeated hemodynamic assessment (dose range 5–400 μg/min). The other alternative is NTG given as 3 mg IV boluses every 5 min. 39.2.2.2 Diuretics Furosemide is the most commonly used diuretic. Loop diuretics are presumed to decrease preload through two mechanisms: diuresis and direct vasoactivity (venodilation). Furosemide reduces preload by diuresis in 20–60 min. Diuretics are indicated for patients with evidence of fluid overload. Numerous cases with CPE do not have fluid overload. Continued use of diuretics in these patients after their acute symptoms have resolved may be associated with adverse outcomes, including electrolyte derangements, hypotension, and worsening renal function (GFR) as a result of tubuloglomerular feedback. Intravenous administration for furosemide is preferred, with the dose of furosemide ranging from 40 to 80 mg (0.5–1.0 mg/kg) [13]. The higher doses in the range are used for patients already taking oral diuretics or with chronic kidney disease. An initial bolus can be given slowly intravenously and repeated 20 min later if required [14]. After the bolus, a continuous intravenous infusion may be considered, commencing at a rate of 5–10 mg/h. A small randomized controlled trial did not find any difference in outcomes between bolus and continuous infusion [15]. A dose of 40 mg of furosemide is considered equivalent to 1 mg of bumetanide or 20 mg of torsemide. 39.2.2.3 Morphine Morphine sulfate administration has been the cornerstone in the treatment of acute decompensated heart failure for many years. Morphine is known to have a mild preload reducing effect and relieves anxiety, possibly blunting catecholamine production, but good evidence supporting a beneficial hemodynamic effect is lacking. However, data suggest that morphine sulfate may contribute to a decrease in cardiac output and that it may be associated with an increased need for ICU admission and endotracheal intubation.

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Morphine, 1–5 mg iv once or twice is believed to reduce the work of breathing, but because of poor outcome with its use, it is not recommended except in palliative care. Given the availability of drugs that are more effective than morphine (e.g., NTG) for reducing preload, adverse effects of morphine (such as nausea and vomiting, local or systemic allergic reactions, and respiratory depression) may outweigh any possible benefits. Respiratory and central nervous system depression, decreased cardiac output, and hypotension are all serious side effects of morphine. The use of morphine for CPE has been linked to negative outcomes including drastically higher rates of mechanical breathing, intensive care hospitalizations, and mortality. Any beneficial hemodynamic effects of morphine are likely the result of anxiolytics, which cause catecholamine levels to drop and reduce systemic vascular resistance [16]. In the absence of high-quality randomized trial data, the best current evidence suggests that morphine may cause harm. Morphine is therefore no longer recommended for routine use in acute pulmonary edema. The European Society of Cardiology does not recommend routine use of morphine, suggesting that it should only cautiously be used in patients with severe dyspnea and predominately in those with acute CPE [17] (recommendation class IIB; level of evidence B). Also, the American Heart Association/American College of Cardiology Heart Failure guidelines does not mention morphine in their guidelines from 2013, which reserve this therapy only for palliative care of end-stage heart failure patients [13]. It may be beneficial if there is ongoing chest pain resistant to nitrates. Low doses of morphine (1–2.5 mg) can be useful to facilitate the tolerance of noninvasive ventilation, but the patient needs to be monitored for sedation [13]. Alternatively, for patients who are severely anxious, low-dose benzodiazepines, such as lorazepam 0.5 mg IV, can be an option as anxiolytic drug. In individuals whose health improved after receiving initial treatment, this alternative lowers the chance of respiratory depression. Data from the ADHERE registry, encompassing 147,632 individuals hospitalized to US acute care hospitals for AHF, were reported by Peacock et al. (Acute Heart Failure). They showed that the administration of morphine during AHF was a reliable indicator of higher hospital mortality (OR 4.8, 95% CI: 4.52–5.18) [18]. The retrospective and observational nature of this study and the fact that the authors did not do PS analysis are both limitations. However, Gray et al. conducted a secondary analysis of 1052 patients who participated in the UK 3CPO trial from 2003 to 2007. The authors find no relation between morphine and 7-day mortality [19]. Retrospective studies have linked the use of morphine to worse outcomes in people with pulmonary edema. It should not come as a surprise. Patients who are sicker are considerably more prone to be air-hungry, which necessitates morphine medication. Additionally, it is feasible that morphine could conceal the signs of pulmonary edema, causing medical professionals to be less aggressive with other treatments (for example, a patient could not appear unwell enough to require CPAP). Midazolam and Morphine efficacy in patients with acute pulmonary edema (MIMO) was compared in a multicenter, prospective, open-label, randomized study

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[20]. Morphine was given in doses of 2–4 mg IV if the patient continued to experience severe anxiety or distress as a result of acute CPE, up to a total dose of 8 mg. Midazolam has been administered in 1 mg IV increments if the patient continues to experience severe anxiety or distress as a result of acute CPE, up to a total dose of 3  mg. While there was no difference in mortality between midazolam and morphine, the morphine group had a significantly higher rate of serious adverse events. While there was no difference in mortality between midazolam and morphine, the morphine group had a significantly higher rate of serious adverse events. To summarize, using morphine in CPE is a metaphor for the limitations of modern AHF approaches. There appears to be a strong link between morphine use and a worsening outcome. Because of the poor research methodology, proving causality is difficult. The quality of the evidence makes it impossible to conclude that it is completely useless in this context. Its main effect appears to be anxiolytic, but some authors recommend benzodiazepines instead because they are much more potent and cause less respiratory depression. As a result, the MIMO trial is likely to answer any remaining questions about the subject. The study was called off early due to safety concerns, with patients in the morphine group experiencing higher rates of cardiovascular adverse events (including cardiac arrest and shock). This is only one small trial, but it contains the highest quality data available. As a result, opioids should be avoided in the setting of acute CPE.

39.2.3 Afterload Reduction Elevated level of catecholamine in cardiogenic pulmonary edema patient causes increase in systemic vascular resistance afterload. Afterload reducers increase cardiac output and improve renal perfusion, allowing for diuresis.

39.2.3.1 ACE Inhibitors The use of ACE inhibitors in cardiogenic pulmonary edema is associated with following [21]: • Reduced admission rates to ICUs • Decreased endotracheal intubation rates • Decreased length of ICU stay Enalapril 1.25  mg IV or Captopril 25  mg administered sublingually produces subjective and hemodynamic improvements within 10  min. Improvements occur much more slowly when administered orally. Studies have suggested a role for ACE inhibitors and ARBs in preventing structural and electrical remodeling of the heart, leading to a reduced incidence of arrhythmias.

39.2.3.2 Sodium Nitroprusside Nitroprusside results in a simultaneous reduction in preload and afterload by inducing direct smooth muscle relaxation, with a greater effect on afterload. The

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reduction in afterload is associated with an increase in cardiac output. The initial infusion rate is 0.3  μg/kg/min with titration up to 5  μg/kg/min. The potency and rapidity of onset and offset of effect make this an ideal medication for patients who are critically ill. It can cause steep drops in blood pressure and unstable fluctuations in blood pressure. Intra-arterial blood pressure monitoring is often recommended. Nitroprusside should generally be avoided in acute myocardial infarction [21]. Due to its use associated with shunting of blood from the ischemic to the healthy myocardium (i.e., coronary steal syndrome), potentiation of ischemia, and prolonged use at high doses, it is associated with thiocyanate and cyanide toxicity, particularly in patients with severe hepatic impairment or renal dysfunction.

39.2.4 Inotropic Support Inotropic support is usually used when preload- and afterload-reduction strategies are not successful or when hypotension precludes the use of these strategies. These agents produce vasodilatation and increase the inotropic state. Two main classes of inotropic agents are available: catecholamine agents and phosphodiesterase inhibitors (PDIs). • Catecholamine agents –– Dobutamine (2–20 μg/kg/min) –– Dopamine –– Norepinephrine (0.01–3 μg/kg/min) • Phosphodiesterase inhibitors (PDIs)

39.2.4.1 Dobutamine Dobutamine, a synthetic catecholamine drug, serves primarily as a beta1-receptor agonist, although it has some activity at the beta2-receptor and minimally at the alpha-receptor. IV dobutamine given with an infusion rate of 2–3 μg/kg/min without a loading dose induces significant positive inotropic effects with mild chronotropic effects. It also induces mild vasodilation (decreased afterload). The combined effect of increased inotropy with decreased afterload significantly increases cardiac output. Combined use with intravenous NTG may be ideal for patients with MI and CPE and mild hypotension to simultaneously reduce preload and increase cardiac output [22]. In general, avoid dobutamine in patients with moderate or severe hypotension (e.g., systolic blood pressure