Pharmacotherapy in acute respiratory distress syndrome—the long and winding road

Ashbaugh’s original case series of patients with acute respiratory distress syndrome (ARDS) had a mortality of 58% (1). Significant gains have been made in the treatment of ARDS with contemporary mortality ranging between 25% and 45% depending upon disease severity (2). In part, improvements are due to general advancements in critical care. Since 1967, new antibiotics have become available for treating pneumonia, continuous renal replacement therapies allow for improved volume management in patients with ARDS and acute renal failure, and sepsis resuscitation is more aggressive and protocolized. Changes in mechanical lung ventilation practices have also improved outcomes. The most salient of these is the widespread adoption of low tidal volume, “protective”, mechanical lung ventilation. In a landmark clinical trial, the ARDS network demonstrated a 9% mortality reduction in patients ventilated with a 6 mL per kilogram tidal volume, compared to patients ventilated with a 12 mL per kilogram tidal volume. Subsequently the practice has become widespread (3). Recently, prone positioning was also shown to lower mortality in patients with severe ARDS (4).

Despite these improvements, the role of pharmacotherapy in ARDS remains uncertain. There have been multiple negative studies with pharmacologic agents including rosuvastatin, methylprednisolone, aerosolized surfactant, prostaglandin E1, and ketoconazole (5-10). Recently the lung injury prediction score (LIPS)-A trial published by Kor et al. failed to demonstrate a reduced incidence of ARDS in a cohort of nearly 400 patients who received aspirin or placebo adding to the list of negative studies (11).

Platelets have a critical role in the pathophysiology of ARDS and Kor and colleagues hypothesized that aspirin could be a useful therapeutic. ARDS affects the alveolar space, the interstitium, and the pulmonary vasculature. When platelets are activated in the pulmonary circulation, they increase production of thromboxane A2 and expression of P selectin, propagating platelet-neutrophil aggregation and extravasation into the interstitium and alveolar space (12). Animal studies have repeatedly shown that disruption of platelet signaling decreases neutrophil chemotaxis and platelet-neutrophil aggregation (13-15). Unfortunately these findings have not translated into consistent benefits in human studies of aspirin in ARDS. In fact, several recent studies showed no benefit with aspirin use in cardiac surgery patients and other critically ill patients after using propensity scores to adjust for confounding (16,17).

It is important to consider why aspirin may have failed to show a benefit in the LIPS-A trial. The first and most obvious limitation of the LIPS-A trial is that the incidence of ARDS was unexpectedly low in both the control and treatment groups (8.7% and 10.3% respectively) (11). In their sample size calculation, the authors assumed an ARDS incidence of 18% and an absolute risk reduction of 10% with aspirin. The authors used a LIPS ≥4 for entering patients into the study because previous work identified this threshold as the optimal cutoff point for balancing sensitivity and specificity. In a previous cohort study, patients with LIPS of 4 had a 6% rate of ARDS, patients with LIPS of 5 had an 11% rate, and patients with LIPS of 6 had a 15% rate (18). The median LIPS in the LIPS-A trial was 6, but the rate of ARDS was less than 15%. It seems that using a cutoff of 4 for inclusion into the study may have been too liberal and perhaps too many “low risk” patients were included negating any potential benefits for aspirin. Also, the optimal timing of aspirin administration for preventing lung injury is unknown making the intervention window in the study somewhat arbitrary. Aspirin may have been given either too early or too late to patients. In fact, 20% of patients in the study were already receiving mechanical ventilation at the time of randomization and perhaps these patients were beyond the optimal window for aspirin administration.

Regardless of its negative findings, LIPS-A is an important contribution to the ARDS literature for a number of reasons. First, it shows the difficulty in accurately predicting which patients will develop ARDS in future clinical trials. The LIPS performed differently than it had in prior validation cohorts and ultimately this led to a lower risk cohort than anticipated. LIPS-A also demonstrated that performing a multicenter ARDS prophylaxis trial is feasible, but challenging because the optimal timing for intervention may be uncertain. Finally, the majority of patients in the LIPS-A trial had sepsis, but perhaps aspirin could prevent lung injury in other settings such as transfusion related acute lung injury (TRALI) where animal models have shown that it may be beneficial (19).

Acknowledgements

None.

Footnote

Provenance: This is an invited Editorial commissioned by the Section Editor Zhiheng Xu (State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, Department of Intensive Care, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China).

Conflicts of Interest: The author has no conflicts of interest to declare.

Comment on: Kor DJ, Carter RE, Park PK, et al. Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial. JAMA 2016;315:2406-14.

References

1. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967;2:319-23. [Crossref] [PubMed]
2. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-33. [PubMed]
3. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-8. [Crossref] [PubMed]
4. Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159-68. [Crossref] [PubMed]
5. National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD, Bernard GR, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014;370:2191-200.
6. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-84. [Crossref] [PubMed]
7. Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med 1996;334:1417-21. [Crossref] [PubMed]
8. Abraham E, Baughman R, Fletcher E, et al. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group. Crit Care Med 1999;27:1478-85. [Crossref] [PubMed]
9. Vincent JL, Brase R, Santman F, et al. A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome. Intensive Care Med 2001;27:1578-83. [Crossref] [PubMed]
10. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network. JAMA 2000;283:1995-2002. [Crossref] [PubMed]
11. Kor DJ, Carter RE, Park PK, et al. Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial. JAMA 2016;315:2406-14. [Crossref] [PubMed]
12. Yadav H, Kor DJ. Platelets in the pathogenesis of acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2015;309:L915-23. [Crossref] [PubMed]
13. Grommes J, Alard JE, Drechsler M, et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 2012;185:628-36. [Crossref] [PubMed]
14. Ortiz-Muñoz G, Mallavia B, Bins A, et al. Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood 2014;124:2625-34. [Crossref] [PubMed]
15. Eickmeier O, Seki H, Haworth O, et al. Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol 2013;6:256-66. [Crossref] [PubMed]
16. Kor DJ, Erlich J, Gong MN, et al. Association of prehospitalization aspirin therapy and acute lung injury: results of a multicenter international observational study of at-risk patients. Crit Care Med 2011;39:2393-400. [Crossref] [PubMed]
17. Mazzeffi M, Kassa W, Gammie J, et al. Preoperative Aspirin Use and Lung Injury After Aortic Valve Replacement Surgery: A Retrospective Cohort Study. Anesth Analg 2015;121:271-7. [Crossref] [PubMed]
18. Gajic O, Dabbagh O, Park PK, et al. Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med 2011;183:462-70. [Crossref] [PubMed]
19. Looney MR, Nguyen JX, Hu Y, et al. Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury. J Clin Invest 2009;119:3450-61. [PubMed]