July 18, 2016

 LIPS – A trial review

Relatively recent evidence has suggested an important role of platelet activity both on onset and resolution of lung injury (1, 2). Together with inflammation, micro-thrombosis and vascular occlusion also seem to play a role in ARDS; moreover, modulation of anti-inflammatory lipid mediators, including leukotrienes, thromboxane, and prostaglandins, have been implicated as important mediators of ARDS progression and severity (1, 2).

Interestingly pre-hospital aspirin therapy has been associated both with lower incidence of ARDS (3) and with lower ICU mortality in patients developing ARDS (4, 5). A large multi-centric study found univariate significant association between aspirin therapy and lower incidence of lung injury (p=0.01), but a propensity score analysis attenuated such association (p=0.07) (6). 

With this background, a phase-2b, multi-centre, double-blind, placebo-controlled RCT was designed and enrolled adult patients presenting to the emergency department (ED) with high risk of progression to ARDS, as defined by a LIP Score of at least 4 points. In order to avoid the risk of under-dosing, the authors decided to randomise the intervention group to receive a loading dose of aspirin (325 mg) within 24 hours from the presentation to hospital. The loading dose was followed by a daily dose of 81 mg until day-7, hospital discharge or death (whichever occurred first). Patients already on antiplatelet therapy were excluded, while shortly after the beginning of the trial, the board decided to also include patients with chronic kidney disease or acute kidney injury (initially exclusion criteria).

The primary outcome was the progression to ARDS according to the Berlin definition, which was modified to require mechanical ventilation (8). The time frame of development of ARDS was set at one week from hospital admission, since the median time to ARDS onset has been shown within couple of days of hospital admission (9). Secondary outcomes included ventilator-free days until day 28, intensive care unit and hospital lengths of stay, and 28-day and 1-year mortality. The authors conducted also a series of analyses on plasma biomarkers and reported adverse events.

There was no significant difference in ARDS between the aspirin-treated group (10.3%) and the placebo group (8.7%), nor any differences in the secondary outcomes although aspirin group had a higher rate of ICU admission (59% vs 50%). Mortality at 28 day was around 9%. 

Adverse events were uncommon, with bleeding-related events occurring more frequently with aspirin (5.6%) than with placebo (2.6%), although this difference was not statistically significant. Among all biomarkers, only IL-2 was higher in the aspirin group while the others showed no significant differences. 

This RCT has many strengths. Indeed, although of theoretically difficult design for the need of early identification, screening and intervention, the investigators were able to randomise patients in about 7 hours from ED presentation, and to administer aspirin/placebo in about 12 hours from ED presentation! The trial design is very robust and the methodology is well-described. Of note, chest radiographs were also reviewed blindly by one (or more) reviewers a part from the recruiting site. 

Important co-interventions, including mechanical ventilation, aspiration precautions, infection control, fluids and transfusions, were standardised across sites using the web-based tool Checklist for Lung Injury Prevention (CLIP) (10). This standardised approach may have helped in reducing the incidence of ARDS (estimated progression to ARDS: 18%, observed progression: 9.5%). Thus, although the RCT enrolled the target number of patients, it seems underpowered by the lower-than-expected progression of disease. Nonetheless, taking the whole results of the RCT, further investigations for aspirin as a preventive measure for patients admitted to hospital with high risk of developing ARDS do not seem warranted.

Article review was submitted by Filippo Sanfilippo on behalf of the ESICM Journal Review Club.


1. Looney MR, 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(11):3450-3461.
2. Fukunaga K, et al.  Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol 2005;174(8):5033-5039.
3. Boyle AJ, et al.  Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis. Crit Care 2015;19:109.
4. Chen W, et al.  Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis. Crit Care Med. 2015;43(4):801-807.
5. Erlich JM, et al.  Prehospitalization antiplatelet therapy is associated with a reduced incidence of acute lung injury: a population-based cohort study. Chest 2011;139(2):289-295.
6. Kor  DJ,  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(11):2393-2400.
7. Kor  DJ, 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 Jun 14;315(22):2406-14.
8. Ranieri VM, et al.  ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307(23):2526-2533.
9. Gajic O, et al; U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS). 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(4):462-470.
10. Litell JM, et al. Multicenter consensus development of a checklist for lung injury prevention. Crit Care 2012;(16)(suppl 1):504.

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