A Brief History of Time, As It Relates to ARDS

Greg S. Martin, MD, MSc

Jordan A. Kempker MD, MSc

The perpetual enigma that is the acute respiratory distress syndrome (ARDS) can be likened to the layers of an onion. The more layers we peel and the deeper we go, the more we understand and the more we realize how much there is yet to learn. We have had more than five decades of discovery and enlightenment with the condition we call ARDS,[1] [2] yet in many ways ARDS remains as enigmatic and challenging as ever.[3] In this issue of Seminars in Respiratory and Critical Care Medicine, together we review the most recent evidence-based updates on ARDS from experts in the field, covering a spectrum of topics that includes definitions, epidemiology, biomarkers, clinical and biological phenotypes, molecular and genetic epidemiology, as well as state-of-the-art discussion of disease treatment, prevention, and outcomes for both the patient and for society. In this issue, you will find the latest insights into ARDS, and also learn of the many important questions that still need to be answered.

Nearly 200 years since its earliest description as “idiopathic anasarca of the lungs,”[4] ARDS is no longer the obscure condition it once was. The early American–European Consensus Conference (AECC) and subsequent Berlin definitions have facilitated epidemiologic studies that have helped us to understand disease pathogenesis as well as the frequency and outcomes associated with the condition.[5] [6] The advances in ARDS definitions from general expert consensus to data-driven classifications have facilitated high-quality epidemiology studies spanning detailed focus on risk factors and outcomes through multi-decade longitudinal studies and international comparisons. More broadly, the clinically relevant definitions of ARDS have served as a foundation for increased understanding of the condition by producing better tools for diagnosis, treatment, and prognosticating both short-term and long-term outcomes. We now know that ARDS is rare in the population at large but regrettably common among critically ill patients. And, while the most common underlying causes of ARDS, such as pneumonia, aspiration, sepsis, and severe traumatic injuries, have shifted in proportion over time, they remain steadfast as common critical illnesses that lead to lung injury. Most importantly, we now have a small armamentarium of supportive strategies that save lives in ARDS.

These advances in disease identification have enabled more discrete characterization of the condition than ever before possible, but have also opened up new questions as to the validity of a singular characterization of the syndrome under one umbrella. ARDS has long been considered a heterogeneous condition that may be conceptually lumped under one heading to improve early recognition and global awareness, or that may be divided into subgroups to improve prognostic accuracy and enhance targeting of precise treatment strategies. The earlier clinical phenotypes defined by clinical factors such as direct and indirect causes of lung injury have now advanced to include highly complex factors, such as host factors (e.g., biology, genetics, immune status), inciting injury factors (e.g., trauma characteristics or infecting organism) and environmental factors (e.g., mechanical ventilation tidal volume), and the interaction between host, insult, and environment. This deeper characterization of ARDS from differing perspectives permits creation of subphenotypes or endotypes using plasma biomarkers, genetics, and advanced unbiased analytics such as machine learning and latent class analysis. Despite holding great promise, these clinical phenotypes represent one of the greatest challenges to further study of the condition. These challenges are particularly apparent in genome-wide association studies, which have been hampered by the difficulties in clearly distinguishing clinical phenotypes and eliminating heterogeneity. Dissecting these complex phenotypes into less complex intermediate phenotypes is a potential path forward to further understanding ARDS pathogenesis. But until these methods prove to be beneficial in directing treatment, the opposing force of simplifying the diagnostic criteria remains dominant.

A core principle of ARDS clinical care remains the provision of lung protective mechanical ventilation. Mechanical ventilation practices in ARDS patients have progressed by prioritizing tidal volume and plateau pressure limitation through delivery of lung-protective mechanical ventilation. Yet this simple and universally available intervention is not universally applied. Understanding of pulmonary physiology and advances in respiratory monitoring will permit optimized mechanical ventilation by individualizing parameters such as tidal volume and positive end-expiratory pressure, and use of noninvasive ventilation, to foster protection of the lung against incipient or ongoing injury. The monitoring capabilities of modern ventilators are powerful, and improving our understanding and utilization of effective monitoring may contribute to the improved clinical outcomes and more homogeneity of ARDS patients in clinical research studies. With understanding of the complex relationship between the patient and the ventilator, newer ventilation strategies such as airway pressure release ventilation, adaptive support ventilation, high-frequency oscillatory ventilation, and esophageal pressure targeting may prove beneficial despite failing to demonstrate consistent and convincing clinical benefit to date.[7] Furthermore, combining our growing knowledge of ARDS and our ability to monitor clinical features of the disease, we can optimize the use of strategies that confer greater risk or cost within subpopulations most likely to benefit. The refinement of evidence for prone positioning and extracorporeal life support techniques will permit their safe and effective implementation at the bedside.

Aside from mechanical ventilation, the most common “intervention” in ARDS is under-recognized: fluid management. This daily intervention can be simply tailored to deliver a conservative fluid management strategy, and in so doing, produce superior outcomes in ARDS patients. More aggressive strategies may further improve outcomes, particularly in patient subsets defined by hemodynamics, hypoxemia, and hypoproteinemia, for which the interventions need further study to determine their safety and efficacy. Among pharmacologic interventions, neuromuscular blockade remains a propitious therapy, with a recently completed trial expected to standardize the current variable use of these medications.[8] [9] One of the most anticipated of biological therapies is stem cells,[10] where our knowledge continues to advance and recent clinical trials support continued development.

As is true with all forms of critical illness, the future of ARDS is in prevention. The confluence of ARDS knowledge, big data, and powerful analytics increasingly permits the early identification of at-risk patients, permitting changes in care such as blood product transfusion, fluid management, and lung protective ventilation to avoid ARDS altogether. ARDS prevention is likely to be the most cost-effective intervention in this condition, given that annual health care costs for ARDS exceed $5 billion in the United States alone,[11] and these estimates fail to account for the cost of lost lives, lost productivity, and the development of persistent comorbidities that negatively affect both patients and families.

The exponential advances we have made in ARDS over the past 200 years, the past 50 years, and the past 5 years are all truly remarkable. But knowledge alone will not serve the purpose behind our desire to peel the onion that is ARDS. There is an important difference between ARDS and an onion. Unlike an onion, which leaves nothing behind after peeling the last layer, at the core of ARDS is a complete understanding of the condition that will enable the optimal care for every afflicted person.

• References

• 1 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2 (7511): 319-323
• 2 Levine BE. Fifty years of research in ARDS. ARDS: how it all began. Am J Respir Crit Care Med 2017; 196 (10) 1247-1248
• 3 Bernard GR. Acute respiratory distress syndrome: a historical perspective. Am J Respir Crit Care Med 2005; 172 (07) 798-806
• 4 Laennec RTH. A Treatise on the Diseases of the Chest. Translated by Forbes. Birmingham, AL: Classics of Medicine Library; 1979
• 5 Bernard GR, Artigas A, Brigham KL. , et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149 (3, Pt 1): 818-824
• 6 ARDS Definition Task Force; Ranieri VM, Rubenfeld GD. , et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307 (23) 2526-2533
• 7 Beitler JR, Sarge T, Banner-Goodspeed VM. , et al. Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure–guided strategy vs an empirical high PEEP-Fio2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome. JAMA 2019; 321 (09) 846-857
• 8 ClinicalTrials.gov. Reevaluation of systemic early neuromuscular blockade (ROSE). Available at: https://clinicaltrials.gov/ct2/show/NCT02509078 . Accessed February 14, 2019
• 9 Huang DT, Angus DC, Moss M. , et al. Reevaluation of Systemic Early Neuromuscular Blockade Protocol Committee and the National Institutes of Health National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network Investigators. Design and rationale of the reevaluation of systemic early neuromuscular blockade trial for acute respiratory distress syndrome. Ann Am Thorac Soc 2017; 14 (01) 124-133
• 10 Cribbs SK, Matthay MA, Martin GS. Stem cells in sepsis and acute lung injury. Crit Care Med 2010; 38 (12) 2379-2385
• 11 Martin GS, Bernard GR. Airway and lung in sepsis. Intensive Care Med 2001; 27 (Suppl. 01) S63-S79