Acute Respiratory Distress Syndrome

Colloquium series on Integrated Systems Physiology: from molecule to function to disease Series Editors: D. Neil Granger & Joey Granger Acute Respiratory Distress Syndrome Marie Carmelle Elie Donna Carden life sciences MORGAN & CLAYPOOL LIFE SCIENCES

Acute Respiratory Distress Syndrome

ii Colloquium Digital Library of Life Sciences This e-book is an original work commissioned for the Colloquium Digital Library of Life Sciences, a curated collection of time-saving pedagogical resources for researchers and students who want to quickly get up to speed in a new area of life science/biomedical research. Each e-book available in Colloquium is an in-depth overview of a fast-moving or fundamental area of research, authored by a prominent contributor to the field. We call these resources Lectures because authors are asked to provide an authoritative, state-of-the-art overview of their area of expertise, in a manner that is accessible to a broad, diverse audience of scientists (similar to a plenary or keynote lecture at a symposium/meeting/colloquium). Readers are invited to keep current with advances in various disciplines, gain insight into fields other than their own, and refresh their understanding of core concepts in cell & molecular biology. For the full list of available Lectures, please visit: www.morganclaypool.com/page/lifesci All lectures available as PDF. Access to the Collection is free for readers at institutions that license Colloquium. Please e-mail info@morganclaypool.com for more information.

iii Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease Editors D. Neil Granger Louisiana State University Health Sciences Center Joey P. Granger University of Mississippi Medical Center Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology that account for the relative constancy of organ processes and bodily function even in the face o f substantial environmental changes. This constancy results from integrative, cooperative interactions of chemical and electrical signaling processes within and between cells, organs and systems. This ebook series on the broad field of physiology covers the major organ systems from an integrative perspective that addresses the molecular and cellular processes that contribute to homeostasis. Material on pathophysiology is also included throughout the ebooks. The state-of the-art treatises were produced by leading experts in the field of physiology. Each ebook includes stand-alone information and is intended to be of value to students, scientists, and clinicians in the biomedical sciences. Since physiological concepts are an ever-changing work-in-progress, each contributor will have the opportunity to make periodic updates of the covered material. Published titles (for future titles please see the website, www.morganclaypool.com/page/lifesci)

iv Copyright 2014 by Morgan & Claypool All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopy, recording, or any other except for brief quotations in printed reviews, without the prior permission of the publisher. Acute Respiratory Distress Syndrome Marie Carmelle Elie, M.D. and Donna Carden, M.D. www.morganclaypool.com ISBN: 9781615046348 paperback ISBN: 9781615046355 ebook DOI: 10.4199/C00094ED1V01Y201309ISP047 A Publication in the COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULES TO FUNCTION TO DISEASE Lecture #47 Series Editor: D. Neil Granger, LSU Health Sciences Center, and Joey P. Granger, University of Mississippi Medical Center Series ISSN ISSN 2154-560X print ISSN 2154-5626 electronic

Acute Respiratory Distress Syndrome Marie Carmelle Elie, M.D. and Donna Carden, M.D. Department of Emergency Medicine, University of Florida College of Medicine COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE #47 &C M MORGAN & CLAYPOOL LIFE SCIENCES

vi ABSTRACT The acute respiratory distress syndrome (ARDS) is a complex disorder associated with rapidly progressive lung inflammation, non-cardiogenic pulmonary edema, hypoxemic respiratory failure and one or more well-defined risk factors including sepsis and severe trauma. Since its original description in 1967, experimental and clinical evidence has provided considerable insight into the key roles deregulated systemic inflammation and coagulation play in this devastating clinical syndrome. Despite substantial advances in our understanding of the pathogenesis of ARDS, until recently, little progress had been made in uncovering clinical strategies to improve the outcome of patients with ARDS. However, over the past 10 years protective ventilation and other supportive management strategies have been identified that markedly improve the outcome in ARDS. More recently, research has identified patients at risk for the development of the syndrome. Currently, clinical trials are underway that hold promise for preventing the development of this devastating and often fatal disorder. KEYWORDS acute respiratory distress syndrome, sepsis, systemic inflammatory response syndrome, animal models, protective ventilatory strategies, ventilator-induced lung injury, inflammation, coagulation

vii Contents 1 Introduction......................................... 1 1.1 ARDS Diagnostic Criteria....................................... 2 1.2 Pathologic Features of ARDS..................................... 3 1.3 Clinical Features of ARDS....................................... 3 1.4 ARDS Risk Factors............................................. 6 2 The Pathogenesis of ARDS................................ 7 2.1 The Alveolar-Capillary Barrier.................................... 7 2.1.1 Structure of the Alveolar Capillary Barrier.................... 7 2.1.2 Deregulation of Microvascular Fluid and Solute Exchange in ARDS 9 2.2 Mechanisms of Alveolar-Capillary Barrier Disruption................. 11 2.2.1 Pathogen-Associated and Damage-Associated Molecular Patterns. 11 2.2.2 The Role of Neutrophils................................. 13 2.2.3 Pulmonary Endothelial Injury... 15 2.2.4 Alveolar Epithelial Injury................................. 18 2.2.5 Inflammation and the Coagulation Cascade.................. 19 2.3 Conclusion................................................... 21 3 Experimental Models of ARDS............................. 23 3.1 Repeated Lavage.............................................. 24 3.2 Oleic Acid Model............................................. 24 3.3 Endotoxin Model............................................. 26 3.4 Inhalational and Burn Injury Model.............................. 27 3.5 Acid Aspiration............................................... 28 3.6 Hyperoxia................................................... 29 3.7 Mechanical Ventilation......................................... 31 3.8 Bleomycin................................................... 32 3.9 N-nitroso-N-methylurethane.................................... 32 3.10 Conclusion................................................... 35

viii 4 Resolution, Treatment, and Prevention of ARDS................... 37 4.1 Repair of the Alveolar-Capillary Barrier and Resolution of ARDS....... 37 4.2 Pharmacologic Therapy in ARDS................................. 37 4.2.1 Surfactant............................................. 37 4.2.2 Nitric Oxide........................................... 40 4.2.3 Prostaglandins.......................................... 41 4.2.4 N-acetylcysteine........................................ 42 4.2.5 Corticosteroids......................................... 43 4.2.6 Β 2 Agonists............................................ 43 4.2.7 Neuromuscular Blocking Agents........................... 44 4.3 Non-pharmacologic ARDS Therapy............................... 45 4.3.1 Fluid Management..................................... 45 4.3.2 Prone Positioning...................................... 46 4.4 Lung Protective Ventilation..................................... 47 4.4.1 Low Tidal Volume... 49 4.4.2 Positive End Expiratory Pressure (PEEP).................... 49 4.4.3 High Frequency Oscillatory Ventilation (HFOV)............. 50 4.4.4 Airway Pressure Release Ventilation (APRV)................. 50 4.5 Future Directions.............................................. 50 4.6 ARDS Prevention............................................. 52 4.7 Patient Selection and Risk Stratification............................ 53 4.8 Early ARDS Intervention....................................... 54 4.9 Sepsis Recognition and Management.............................. 54 4.10 Transfusion.................................................. 55 4.11 Ventilator Management........................................ 55 4.12 Pharmacologic Therapies........................................ 56 4.12.1 Antidiabetic Agents..................................... 56 4.12.2 Statins................................................ 56 4.12.3 Aspirin............................................... 56 4.13 Conclusion................................................... 56 References.......................................... 59 Author Biography...................................... 87

1 CHAPTER 1 Introduction Acute respiratory distress syndrome (ARDS) is a complex disorder associated with rapidly progressive lung inflammation, non-cardiogenic pulmonary edema, one or more well-defined risk factors (e.g., sepsis; severe trauma) and hypoxemic respiratory failure [1]. Recent evidence indicates there are approximately 190,000 cases of ARDS in the United States each year [2, 3]. ARDS incidence increases with patient age from 16 per 100,000 person-years in children aged 15 19 years of age to 306 per 100,000 person-years among those over the age of 75 [2]. In the intensive care unit, 10 15% of admitted patients and 20% of mechanically ventilated patients meet the diagnostic criteria for ARDS [4]. The annual ARDS mortality rate is 25 40% [5, 6]. Since its first description in 1967, substantial progress has been made in uncovering the mechanisms responsible for lung injury in ARDS [1, 7, 8]. Although experimental evidence has contributed to our understanding of the pathogenesis of the disorder, the complexity of the clinical syndrome has made it challenging to translate this evidence into pharmacologic strategies that improve clinical outcomes (see Chapter 4) [9 13]. The severity of lung injury in ARDS requires that most patients be mechanically ventilated. Importantly, recent advances in ventilator management and supportive therapy have reduced the morbidity and mortality of ARDS (see Chapters 3 and 4) [14 17]. Rather than a single and distinct disease entity, ARDS represents the pulmonary response to local or systemic events and manifests as a continuum of lung damage and hypoxemia. Obtaining accurate epidemiologic data has been challenging due to controversies regarding the clinical definition and distinguishing characteristics of ARDS [18 20]. For example, evolving ARDS definitions and grouping of dissimilar initiating events into one clinical syndrome may obscure disease recognition. Further, overlapping clinical, physiologic, and pathologic features of pulmonary responses to diverse precipitating events make the precise timing of ARDS onset difficult. Despite these challenges, significant advances have been made in defining the clinical features, epidemiology, incidence, and management of ARDS. Recent advances in identifying patients at risk for development of ARDS suggest the possibility of strategies to prevent, rather than treat, this devastating clinical disorder (see Chapter 4) [21].

2 ACUTE RESPIRATORY DISTRESS SYNDROME 1.1 ARDS DIAGNOSTIC CRITERIA The fact that the criteria for diagnosing ARDS have undergone a number of revisions underscores the difficulties in defining this complex clinical syndrome. The original description of ARDS in 1967 emphasized rapidly progressive respiratory failure, profound arterial hypoxemia resistant to oxygen therapy, reduced lung compliance, diffuse bilateral lung infiltrates on chest radiograph, and absence of left ventricular failure [8]. In 1988, a 4-point scale was proposed to quantify acute lung injury and ARDS based on the degree of hypoxemia, the level of positive end-expiratory pressure (PEEP) applied during mechanical ventilation, lung compliance, and extent of infiltrates present on chest radiograph [22]. In 1994, the American-European Consensus Conference proposed yet another definition of ARDS intended to clarify the defining characteristics of the syndrome based on the degree of hypoxemia, extent of radiographic infiltrates, and left atrial pressure measurements [23]. The American-European Consensus Conference definition emphasized the acute onset of the syndrome but did not specify the timeframe between symptom onset and precipitating event. Further, the American-European Consensus Conference definition did not include reference to ventilator settings. It did, however, define a continuum of pulmonary damage from acute lung injury to more severe disease, termed ARDS. Despite these limitations, the American-European Consensus Conference definition of ARDS was used to recruit patients for a number of important clinical trials (see Chapter 4). In 2012, the definition of ARDS was revised again [24]. This revision, known as the Berlin Definition of ARDS (Table 1.1), no longer includes a subgroup termed acute lung injury but describes ARDS as a continuum of disease from mild to severe based on the degree of hypoxemia associated with specific ventilator settings. The Berlin Definition defines the time of disease onset, computed tomography (CT) and radiographic imaging characteristics, and outlines exclusion criteria for left-ventricular heart failure [24]. The Berlin definition requires that all criteria be present to diagnose ARDS.

INTRODUCTION 3 TABLE 1.1: The Berlin definition of ARDS Time of Onset Chest Imaging Characteristics Exclusion of Cardiogenic Pulmonary Edema ARDS Severity Respiratory symptoms develop within one week of insult Presence of bilateral opacities consistent with pulmonary edema on chest radiograph or computed tomography (CT). The opacities cannot be fully explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules. Presence of respiratory failure not fully explained by cardiac failure or fluid overload. An objective assessment (e.g., echocardiography) is required to exclude left ventricular heart failure if no risk factors for ARDS are present. Mild ARDS: PaO 2 /FiO 2 * > 200 mm Hg but 300 mm Hg on ventilator settings that include PEEP or continuous airway pressure (CPAP) 5 cm H 2 O Moderate ARDS: PaO 2 /FiO 2 > 100 mm Hg but 200 mm Hg on ventilator settings that include PEEP 5 cm H 2 O Severe ARDS: PaO 2 /FiO 2 100 mm Hg on ventilator settings that include PEEP 5 cm H 2 O *The PaO 2 /FiO 2 is determined by dividing the partial pressure of oxygen (O 2 mm Hg) obtained by arterial blood gas analysis by the fraction of inspired O 2, which is expressed as a decimal between.21 and 1.0. 1.2 PATHOLOGIC FEATURES OF ARDS ARDS is associated with three distinct pathologic stages. The acute, exudative stage is characterized by diffuse alveolar damage [25]. This stage is associated with both endothelial and epithelial injury as well as alveolar flooding with polymorphonuclear leukocytes (neutrophils), red blood cells, and protein-rich edema fluid [26 28]. The classic pathologic description of disrupted endothelium and epithelium by Bachofen and Weibel are evident in this stage [27, 28]. The denuded basement membrane of the alveolar epithelium is covered with collagen-rich hyaline membranes containing cellular debris, and pulmonary capillaries contain thrombi. A proliferative stage characterized by resolution of pulmonary edema, proliferation of type II alveolar epithelial cells, interstitial infiltration by myofibroblasts, and collagen deposition begins after approximately 7 10 days. In some patients, ARDS resolves without sequelae but in others, a protracted fibrotic stage develops associated with destruction of normal lung architecture and development of pulmonary fibrosis. These patients often develop persistent hypoxemia, pulmonary hypertension, and right-ventricular heart failure.

4 ACUTE RESPIRATORY DISTRESS SYNDROME 1.3 CLINICAL FEATURES OF ARDS The acute, rapidly worsening exudative phase of ARDS develops within 6 to 72 hr of one or more well-defined risk factors (Table 1.2). Rapid onset of dyspnea, tachypnea, tachycardia, and diaphoresis, use of accessory muscles, and diffuse rales on lung exam are typical. Diffuse, bilateral infiltrates are apparent on chest radiograph (Figure 1.1) but computed tomography (CT) imaging reveals a more heterogeneous pattern of opacities interspersed with areas of aerated lung (Figure 1.2) [1, 29]. FIGURE 1.1: Chest radiograph demonstrating diffuse infiltrates and alveolar consolidation in all lung quadrants consistent with pulmonary edema [30].

INTRODUCTION 5 FIGURE 1.2: Computed tomography image of a mechanically ventilated patient with ARDS demonstrating atelectasis in the dependent, dorsal region of the lung adjacent to normal, aerated lung. Hypoxemia requiring high concentrations of supplemental oxygen is usually present in ARDS and most patients eventually require mechanical ventilation. Severe hypoxemia is a result of intrapulmonary right-to-left shunting of blood through edema-filled, atelectatic alveoli. Peri-bronchovascular edema surrounds and collapses small airways and destruction and inactivation of surfactant increases alveolar surface tension. Together these changes in mechanical properties of the lung reduce lung volumes including vital capacity and functional residual capacity and markedly decrease lung compliance. Respiratory failure in ARDS is a result of a number of factors, including arterial hypoxemia secondary to permeability-induced pulmonary edema, decreased lung compliance, and increased pulmonary dead space due to damage to the pulmonary microvasculature [1, 31, 32].

6 ACUTE RESPIRATORY DISTRESS SYNDROME TABLE 1.2: Conditions associated with an increased risk of ARDS Indirect Lung Injury Sepsis Severe Trauma Massive (>15 units of red blood cells) Blood Transfusion Transfusion Related Acute Lung Injury Drug Overdose Aspirin Cocaine Opioids Acute Pancreatitis Direct Lung Injury Pneumonia Bacterial Viral Aspiration of Gastric Contents Near Drowning Pulmonary Contusion Toxic Inhalation Carbon Monoxide Hyperoxia Smoke Inhalation Ventilator-Induced Lung Injury 1.4 ARDS RISK FACTORS A number of events can initiate ARDS but most cases are associated with well-defined risk factors (Table 1.2). Sepsis is the most common cause of ARDS. The risk of sepsis-induced ARDS appears to be especially high (up to 70%) in patients with a history of alcohol abuse [33 36]. Bacterial or viral pneumonia is the most common cause of community-acquired ARDS [37]. Aspiration of gastric contents, severe trauma, massive blood transfusion (>15 units of red blood cells), transfusion-related acute lung injury, pulmonary contusion, smoke inhalation and hyperoxia are all associated with development of the syndrome [33, 38, 39]. Drug overdose with aspirin, cocaine, opioids, phenothiazines, and tricyclic antidepressants can also cause ARDS [40]. Acute pancreatitis and near-drowning are less common but well-documented risk factors [35, 41 43]. Although the incidence of community-acquired ARDS has not changed, the overall incidence of the syndrome may be declining possibly due to decreases in hospital-acquired ARDS and use of protective ventilator strategies (lower tidal volumes, positive end-expiratory pressure) in mechanically ventilated patients (see Chapter 4) [44].