a b s t r a c t

Background: The effects of aspirin in preventing the occurrence of Acute respiratory distress syndrome / acute lung injury (ALI) among adult patients are controversial. We aimed to further determine the effectiveness of aspirin in reducing the rate of ARDS/ALI.

Methods: The Pubmed, Embase, Medline, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CEN- TRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all controlled studies that research the role of aspirin in adult patients who have the risk of ARDS/ALI. The outcomes were the ARDS/ ALI rate and the mortality. Cochrane systematic review software, Review Manager (RevMan), the R software for sta- tistical computing version 3.2.0, and the metafor package were used to test the hypothesis by Mann-Whitney U test. The heterogeneity test and sensitivity analyses were conducted, and random-effects or fixed-effects model was ap- plied to calculate odds ratio (OR) and mean difference (MD) for dichotomous and continuous data, respectively. Results: Six trials involving 6562 patients were pooled in our final study. No significant heterogeneity was found in outcome measures. Aspirin could reduce the rate of ARDS/ALI (OR 0.71, 95% confidence interval (CI) 0.58-0.86) but not the mortality (OR 0.87, 95% CI 0.71-1.07).

Conclusions: In patients with risk of ARDS/ALI, aspirin could provide protective effect on the rate of ARDS/ALI, but it could not reduce the mortality.

(C) 2018

Background

acute respiratory distress syndrome /acute lung injury (ALI) is an acute, diffuse, inflammatory lung injury that leads to increased pul- monary vascular permeability, increased lung weight, and a loss of aer- ated tissue [1]. Clinical hallmarks of ARDS/ALI are hypoxemia and bilateral radiographic opacities, which result from the pathological pathogenesis of diffuse alveolar damage. It was first described in 1967 as a life-threatening organ failure due to several pulmonary and extraPulmonary injuries with an incidence of 86.2 per 100,000 patient years and in-hospital mortality of up to 40% [2]. Despite intense investi- gations and numerous large-scale clinical trials, no specific therapies or medications have yet been developed, and the mortality still remains as high as 31% [3-5]. Thus, early Prevention strategies may be more effec- tive in addressing this serious problem.

Evidence showed that platelets played an important role in both the onset and progress of lung injury [6-11]. Preclinical studies have shown

* Corresponding authors at: No.37 Guoxue Alley, Chengdu, 610041, China.

E-mail addresses: [email protected], (B.-M. Liang), [email protected] (Y. Wang).

¹ These authors contributed equally to this work.

that the platelet inhibitor aspirin can prevent or treat ARDS/ALI by de- creasing neutrophil activation, tumor necrosis factor-? (TNF-?) expres- sion in pulmonary intravascular macrophages, plasma thromboxane ?₂ level, and platelet sequestration in the lungs [12,13]. However, the exact role of aspirin in reducing the rate of ARDS/ALI in adult patients remains controversial. A propensity-adjusted analysis of 1149 patients conducted by Chen showed that pre-hospital aspirin use was independently associ- ated with a decreased risk of ARDS/ALI. [14] On the contrary, in the study of Kor in 2016, administration of aspirin could not significantly reduce the incidence of ARDS/ALI when compared with the placebo (odds ratio[OR] 1.24; 95% confidence internal[CI] 0.67-2.31) [15].

Therefore, based on the controversial findings on aspirin in adult pa- tients with ARDS/ALI, we conducted a systematic review and meta- analysis of all published trials containing superiority test with placebo or no treatment.

Methods

Search strategies

From 1946 to March 2018, a comprehensive computer search was conducted in Pubmed, Embase, Medline, ClinicalTrials.gov, World

https://doi.org/10.1016/j.ajem.2018.05.017

0735-6757/(C) 2018

Fig. 1. Study flow.

Health Organization-International Clinical Trails Registry Platform, Cochrane Central Register of Controlled Trails (CENTRAL) and Informa- tion Sciences Institute (ISI) Web of Science using the keywords of (“as- pirin” or anti-platelet) and (“acute respiratory distress syndrome” or “acute lung injury” or “ARDS” or “ALI”) without limitations in the publi- cation type or language. We also reviewed the references listed in each identified article and manually searched the related articles to identify all eligible studies and minimize any potential publication bias.

Inclusion and exclusion criteria

Clinical trials were identified based on the following criteria: 1) par- ticipants enrolled in each study included patients with risk of ARDS/ALI;

2) patients were divided into experimental group, in which aspirin was applied, and control group, in which patients were assigned to receive placebo or no treatment; and 3) outcomes included but were not lim- ited to the rate of ARDS/ALI and mortality. We excluded studies if they were performed in animals or in patients under 18 years old, or pub- lished as reviews or case reports.

Study selection

Two independent investigators (HY and YN-N) performed the study selection in two phases. In the first phase, they discarded duplicated and non-controlled studies by screening titles and abstracts. In the second, eligible studies were extracted by reviewing full texts in accordance with the previously designed study inclusion criteria. Any disagreement was resolved by mutual consensus in the presence of a third investiga- tor (YM-W).

Data extraction

Independently, the two independent investigators extracted and re- corded the desired information of each enrolled study in a standard form recommended by Cochrane, [16] which consisted of authors, pub- lication year, study design, country, NCT No., population, demographic characteristics (age, gender, etc.), disease conditions (The Acute Physio- logic and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiologic Score II (SAPS II)), outcome measures, and study results. For any missing data or information, corresponding authors were contacted by email to request the full original data. Different opinions between the two investigators were determined by reaching a consensus or consult- ing a third investigator.

Quality assessment

The Newcastle-Ottawa Scale was used to assess the quality of indi- vidual studies (Appendix 1).

Statistical analysis

Statistical analysis of our study was accomplished by an indepen- dent statistician using Cochrane systematic review software Review

Table 1

Details of the six enrolled studies.

Author (Year)	Study design	NCT No.	Country	ARDS/ALI patients	Total population	Outcomea
Chen 2015	Propensity-adjusted analysis	NR	USA	287	1149	(1)(2)
Kor 2011	Multicenter international observational study	NR	USA and Turkey	240	3855	(1)(2)
Kor 2015	Randomized clinical trial	NCT01504867	USA	37	390	(1)(2)
Mazzeffi 2015	Retrospective cohort study	NR	USA	22	375	(1)
O’Neal 2011	Prospective cohort	NR	USA	152	575	(1)(2)
Tuinman 2012	Nested case control study	NR	Germany	109	218	(1)

ARDS, acute respiratory distress syndrome; ALI, acute lung injury; NR, not reported; SIRS, systemic inflammatory response syndrome.

^a Outcome measures include:(1)rate of ALI; (2)mortality.

Table 2

Baseline characteristics of 6562 aspirin patients.

Author Aspirin users (N = 1841) Non-aspirin users (N = 4721)

(Year)	Age, years mean (IQR)	Man n, (%)	SAPS II mean (IQR)	APACHE II mean (IQR)		Age, years mean (IQR)	Man n, (%)	SAPS II mean (IQR)	APACHE II mean (IQR)
Chen 2015	67 (61-74)	167 (58.2%)	NR	NR		58 (50-65)	464 (53.8%)	NR	NR
Kor 2011	70 (59-81)	435 (44.6%)	NR	12 (8-16)		51 (38-66)	1305 (45.3%)	NR	9 (5-14)
Kor 2016	57 (44-67)	107 (54.9%)	NR	NR		57 (47-68)	96(49.2)	NR	NR
Mazzeffi 2015	72 (64-80)	99 (55%)	NR	NR		65 (54-76)	114)58.8)	NR	NR
O’Neal 2011	NR	NR	NR	NR		NR	NR	NR	NR
Tuinman 2012	NR	NR	NR	NR		NRN	NR	NR	NR

APACHE The Acute Physiologic and Chronic Health Evaluation; IQR, interquartile range; NR, not reported; SAPS Simplified Acute Physiologic Score; SIRS, systemic inflammatory response syndrome.

Manager (RevMan; Version 5.3.5; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2014), the R software for statisti- cal computing version 3.2.0 and the meta for package. Adjusted odds ra- tios (ORs) were used to compute a pooled OR. We used Mann-Whitney U test to verify hypothesis and rendered statistical significance as a Z- value and P-value b 0.05, and the results were displayed in Forest plots. Continuous variables were reported as mean and standard deriva- tion (SD), whereas dichotomous variables were shown as frequency and proportion. An initial test for clinical, methodological, and statistical heterogeneities was conducted, and we used the ?² test with P b 0.1 and I² N 50% to indicate significance. We also performed the sensitivity anal- ysis to substitute alternative decisions or ranges of values for decisions that were arbitrary or unclear. Random-effects model was applied in the presence of statistical heterogeneity; otherwise fixed-effects model was used.

Results

Initially 697 records were identified, of which 694 were extracted from electronic databases and 3 were extracted from reference lists re- view. (Fig.1) By screening the titles and abstracts, we discarded 663 studies for duplication (n = 222), Animal experiments (n = 308), non-adult patients (n = 84), and non-controlled studies (n = 49). We searched the full-text articles for the remaining 34 studies, and eventu- ally 6 trials [14,15,17-20] were enrolled in our final analysis because 5 studies did not report related outcomes and 23 were not designed as expected.

Study description

All 6 studies compared the outcomes of patients treated with aspirin and the ones who were not. The rate of ARDS/ALI was reported in 6 studies [14,15,17-20], and the mortality was reported in 4 studies [14,15,17,19]. One study was a multicenter randomized clinical trial

(RCT) [15], 4 were prospective studies [14,17,19,20], and the remaining one was a retrospective study [18]. Details of each study were summa- rized in Table 1.

A total of 6562 patients were pooled from all the included trials in our final systematic review and meta-analysis, among which 1841 pa- tients were treated with aspirin and the other 4721 patients received placebo or no treatment. Details of baseline characteristics of patients in each enrolled study were presented in Table 2.

Quality assessment

In brief, a maximum of 9 points was assigned to each study: 4 for se- lection, 2 for comparability, and 3 for outcomes. A final score ?6 was regarded as high quality. Among the 6 studies, 1 study [15] scored 8 and the other 5 [14,17-20] scored 7 (Fig.2). The funnel plot is in Fig. 3 and no publication bias was found.

Heterogeneity

No significant statistical heterogeneity was found either in the rate of ARDS/ALI between the patients treated with aspirin and not (I² = 0%, P = 0.419) or in the mortality (I² = 26.7%, P = 0.251).

Rate of ARDS

Significant differences were not found in the rate of ARDS/ALI be- tween patients who were treated with aspirin and those who received placebo or no treatment. (OR0.71, 95% CI 0.58-0.86). (Fig. 4).

Mortality

We did not find any significant difference in mortality between treatment with aspirin and not (OR 0.87, 95% CI 0.71-1.07). (Fig. 5).

Fig. 2. Risk of bias summary.

Discussion

Fig. 3. Funnel plot.

leukotriene synthesis [30]; and 5) increasing the restitution of pulmo- nary barrier function and promoting resolution of injury through lipoxins [31,32], which elicits distinct anti-inflammatory and pro- resolution bioactions [33] Functioning through these mechanisms, aspi- rin could help minimize intrapulmonary shunt, prevent pulmonary hy- pertension, reduce pulmonary edema and inflammation, and finally decrease the rate of ARDS/ALI [34,35].

Nevertheless, our meta-analysis also indicated that aspirin could not further decrease mortality in adults. Numerous factors, especially the treatment strategy towards ARDS/ALL, contribute to the mortality. Only one RCT was included in our final analysis, and the treatment strat- egy was not consistent in patients who received aspirin with those who did not in the cohort and retrospective study. In addition, the reason why the clinicians used aspirin in the selected patients was not clear in the cohort and retrospective study, which might have influenced the mortality as well. Moreover, other factors, especially the concomi- tant complications such as acute kidney dysfunction and cardiac impair- ment, may have contributed to the mortality besides the respiratory status itself [36,37].

The present study has four limitations that should be mentioned.

In this meta-analysis, we found that the preventive use of aspirin could provide a protective effect for patients who have risk of ARDS/ ALI.

A significant lower rate of ARDS/ALI has been reported to be found in patients who received preventive aspirin, and several mechanisms could be used to explain the protective effect of aspirin. It is known that ARDS/ALI is a multifactorial disease in which immune cell migra- tion and endothelial cell activation within the lung will ultimately re- sults in injury to the alveolar-capillary membrane [7,21,22]. platelet activation with resultant secretion of platelet granule contents and changes in platelet shape [6,23] can modulate the immune function and contribute to the onset and progress of ARDS/ALI [24]. Aspirin is a kind of anti-platelet drug which could prevent the onset and process of ARDS through the following mechanisms: 1) reducing the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activity, and decreasing intracellular adhesion molecule 1 (ICAM-1) and platelet P-selectin expression [25-28]; 2) irreversibly acetylating the active site of cyclooxygenase-1, which is required for the production of thrombox- ane A2, a promoter of platelet and aggregation neutrophil in the lung [8,28]; 3) preventing the activation of Endothelial cells induced by platelets and thus reducing the number of[ok??] inflammatory media- tors and inflammatory cells, and the expression of adhesion molecules such as TNF-a, IL-8, and lipoxygenase products [29]; 4) inhibiting the cy- clooxygenase and downstream inhibiting the prostaglandin and

The first is the clinical heterogeneity. On the one hand, the causes of ARDS/ALI in our enrolled studies were heterogeneous; but we could not make corresponding subgroup analyses because data on the cause of individual respiratory failure was not independently available. On the other hand, the severity of ARDS/ALI and the dose of aspirin in the six studies were mixed. Second, only one of the studies enrolled in our meta-analysis was RCT and the total number of the studies was small, which limits the application of our results. Third, one of the six studies was conducted before the Berlin definition and the most recent study was published in 2016. The treatment strategy of ARDS/ALI and the patients who have the risk of ARDS/ALI vary neces- sarily over time, which could contribute to the rate of ARDS/ALI and mortality. Finally, although no publication bias has been identified, we cannot deny that still some studies may have not been published due to reasons unknown.

Conclusions

The preventive administration of aspirin could reduce the rate of ARDS/ALI but not the mortality in patients who have the risk of ARDS/ALI.

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2018.05.017.

Fig. 4. Rate of ARDS/ALI. ARDS, acute respiratory distress syndrome; ALI, acute lung injury; SD, standard deviation.

Fig. 5. Mortality. CI, confidence interval; SD, standard deviation.

Abbreviations

APACHE Acute Physiologic and Chronic Health Evaluation ARDS acute respiratory distress syndrome

ALI acute lung injury

CENTRAL Cochrane Central Register of Controlled Trails CI confidence interval

ICU intensive care unit

ISI Information Sciences Institute LOS length of stay

MD mean difference

OI oxygen index

OR odds ratio

RCT randomized controlled trial SaO₂ Arterial oxygen saturation

SAPS Simplified Acute Physiologic Score SD standard derivation

Author contributions

HY designed the study and drafted the manuscript; HY and Y-NN conducted literature search and data analysis; Y-MW and HY revised the manuscript critically for important intellectual content; B-ML and Z-AL made the decision to submit the report for publication. All authors read and approved the final manuscript.

Financial/nonfinancial disclosures

None of all authors have any financial or non-financial competing in- terests in this manuscript.

Funding

This study was partly supported by Sichuan Science and Technology Agency Grant (2015JY0716 and 2017JY0271).

Competing interests

None of all authors have any financial or non-financial competing in- terests in this manuscript.

Other contributions

We thank Professor Dongtao Lin (College of Foreign Languages and Cultures, Sichuan University), who is specialized in biomedical writing and editing, for copyediting this manuscript.

Acknowledgements

Guarantor

YH takes responsibility for the content of the manuscript, including data and analysis.

References

1. Definition Task Force ARDS, Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute re- spiratory distress syndrome: the Berlin definition. JAMA 2012;307(23):2526-33.
2. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung in- jury. N Engl J Med 2005 Oct 20;353(16):1685-93.
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.
4. Guerin C, Reignier J, Richard J-C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159-68.
5. Papazian L, Forel J-M, Gacouin A, et al. ACURASYS study investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-16.
6. Zarbock A, Ley K. The role of platelets in acute lung injury (ALI). Front Biosci (Land- mark Ed) 2009 Jan 1(14):150-8.
7. Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 2007 Mar;21(2):99-111.
8. Looney MR, Nguyen JX, Hu Y, Van Ziffle JA, Lowell CA, Matthay MA. Platelet deple- tion and aspirin treatment protect mice in a two-event model of transfusion- related acute lung injury. J Clin Invest 2009 Nov;119(11):3450-61.
9. El Kebir D, Jozsef L, Pan W, Wang L, Petasis NA, Serhan CN, et al. 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. Am J Respir Crit Care Med 2009 Aug 15;180(4):311-9.
10. Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD. Cyclooxygenase 2 plays a piv- otal role in the resolution of acute lung injury. J Immunol 2005 Apr 15;174(8):5033-9.
11. aderna P, Godson C. Lipoxins: resolutionary road. Br J Pharmacol 2009 Oct;158(4): 947-59.
12. Chelucci GL, Boncinelli S, Marsili M, Lorenzi P, Allegra A, Linden M, et al. Aspirin ef- fect on early and late changes in acute lung injury in sheep. Intensive Care Med 1993;19(1):13-21.
13. Yasuda O, Takemura Y, Kawamoto H, Rakugi H. Aspirin: recent developments. Cell Mol Life Sci 2008 Feb;65(3):354-8.
14. Chen W, Janz DR, Bastarache JA, May AK, O’Neal Jr HR, Bernard GR, 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 Apr;43(4): 801-7.
15. Kor DJ, Carter RE, Park PK, Festic E, Banner-Goodspeed VM, Hinds R, et al. US critical illness and injury trials group: lung injury prevention with aspirin study group (USCIITG: LIPS-A). Effect of aspirin on development of ARDS in at-risk patients pre- senting to the emergency department: the LIPS-A randomized clinical trial. JAMA 2016 Jun 14;315(22):2406-14.
16. Higgins JP, Green S, editors. Cochrane handbook for systematic reviews of interven- tions Version 5.1.0. Oxford: The Cochrane Collaboration; 2011 Updated March 2011 www.cochrane-handbook.org, Accessed date: 20 March 2011.
17. O’Neal Jr HR, Koyama T, Koehler EA, Siew E, Curtis BR, Fremont RD, et al. Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/ acute respiratory distress syndrome. Crit Care Med 2011 Jun;39(6):1343-50.
18. Mazzeffi M, Kassa W, Gammie J, Tanaka K, Roman P, Zhan M, et al. Preoperative as- pirin use and lung injury after aortic valve replacement surgery: a retrospective co- hort study. Anesth Analg 2015 Aug;121(2):271-7.
19. Kor DJ, Erlich J, Gong MN, Malinchoc M, Carter RE, Gajic O, et al. Injury trials group: lung injury prevention study investigators. Association of prehospitalization aspirin therapy and acute lung injury: results of a multicenter international observational study of at-risk patients. Crit Care Med 2011 Nov;39(11):2393-400.
20. Tuinman PR, Vlaar AP, Binnenkade JM, Juffermans NP. The effect of aspirin in transfusion-related acute lung injury in critically ill patients. Anaesthesia 2012 Jun;67(6):594-9.
21. Kodama T, Yukioka H, Kato T, Kato N, Hato F, Kitagawa S. Neutrophil elastase as a predicting factor for development of acute lung injury. Intern Med 2007;46(11): 699-704.
22. Perl M, Lomas-Neira J, Chung CS, Ayala A. Epithelial cell apoptosis and neutrophil re- cruitment in acute lung injury-a unifying hypothesis? What we have learned from small interfering RNAs. Mol Med 2008 Jul-Aug;14(7-8):465-75.
23. Tabuchi A, Kuebler WM. Endothelium-platelet interactions in inflammatory lung disease. Vascul Pharmacol 2008 Oct-Dec;49(4-6):141-50.
24. Yadav H, Kor DJ. Platelets in the pathogenesis of acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2015 Nov 1;309(9):L915-23.
25. Papadakos PJ. An aspirin a day keeps the acute respiratory distress syndrome away. Crit Care Med 2013 Feb;41(2):659.
26. Tuinman PR, Muller MC, Jongsma G, Hegeman MA, Juffermans NP. High-dose acetylsalicylic acid is superior to low-dose as well as to clopidogrel in preventing lipopolysaccharide-induced lung injury in mice. Shock 2013 Oct;40(4):334-8.
27. Eickmeier O, Seki H, Haworth O, Hilberath JN, Gao F, Uddin M, et al. Aspirin- triggered resolving D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol 2013 Mar;6(2):256-66.
28. Grommes J, Alard JE, Drechsler M, Wantha S, Morgelin M, Kuebler WM, et al. Disrup- tion of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 2012 Mar 15;185(6):628-36.
29. Marik PE. Aspiration pneumonitis and Aspiration pneumonia. N Engl J Med 2001 Mar

    1;344(9):665-71.

    Awtry EH, Loscalzo J. Aspirin. Circulation 2000 Mar 14;101(10):1206-18.

30. Chiang N, Arita M, Serhan CN. Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins Leukot Essent Fatty Acids 2005 Sep- Oct;73(3-4):163-77.
31. Claria J, Serhan CN. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci U S A 1995 Oct 10; 92(21):9475-9.
32. Jin SW, Zhang L, Lian QQ, Liu D, Wu P, Yao SL, et al. Posttreatment with aspirin- triggered lipoxin A4 analog attenuates lipopolysaccharide-induced acute lung injury in mice: the role of heme oxygenase-1. Anesth Analg 2007 Feb;104(2):369-77.
33. Sigurdsson GH, Vallgren S, Christenson JT. Influence of aspirin and steroids on acute lung injury after i.v. Injection of a sclerosing agent. Acta Chir Scand 1989 Mar;155 (3):163-70.
34. Leeman M, Delcroix M, Vachiery JL, Melot C, Naeije R. Blunted hypoxic vasoconstric- tion in oleic acid lung injury: effect of cyclooxygenase inhibitors. J Appl Physiol (1985) 1992 Jan;72(1):251-8.
35. Li G, Cook DJ, Thabane L, et al. risk factors for mortality in patients admitted to in- tensive care units with pneumonia. Respir Res 2016 Jul 11;17(1):80.
36. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995 Oct;23(10):1638-52.