Abstract
Analyzing medical records of 979 patients with severe sepsis or septic shock provided some evidence that the use of low-dose aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) was associated with decreased hospital mortality. However, the benefit was abolished when aspirin and NSAIDs were given together.
Various retrospective clinical studies have shown that pre- and in-hospital use of low-dose aspirin was associated with a reduced mortality [1-4], but there is no evidence that NSAIDs may have a similar benefit [1,5]. We studied the medical records of 979 patients with severe sepsis or septic shock who were admitted to a university hospital surgical intensive care unit (ICU). Exclusion criteria were ICU stay of less than 48 hours, age of more than 18 years, and pregnancy. The study was approved by the local ethics committee. Investigators were not required to ask patients for informed consent.
Findings
Ninety-three patients had received NSAIDs (that is, ibuprofen, diclofenac, or indomethacin) during their ICU stay. There was no difference in APACHE (Acute Physiology and Chronic Health Evaluation) II score at ICU admission, but there were significant differences in age, gender, and length of ICU stay. In-hospital mortality was about 10% lower in NSAID users in comparison with non-users (Table 1). Medication during ICU stay with low-dose aspirin, clopidogrel, or statins, all three of which are believed to have a benefit on the outcome in sepsis, is also indicated in Table 1. A model of stepwise logistic regression with in-hospital mortality as a dependent variable and age, gender, APACHE II score, and the administration of NSAIDs, aspirin, clopidogrel, and statins as independent variables indicated that administration of aspirin during ICU stay was associated with a decreased mortality indicated by an odds ratio (OR) of 0.57 (95% confidence interval 0.39 to 0.83) but that NSAIDs, clopidogrel, statins, and gender were without significant effects. However, when patients on aspirin were excluded from the analysis, NSAIDs were also associated with a reduction of the in-hospital mortality (OR = 0.50, 0.26 to 0.94). On the other hand, the benefit of aspirin (acetylsalicylic acid) was completely abolished in those patients who also received NSAIDs (OR = 1.12, 0.55 to 2.25).
Table 1.
Characteristics of the patients included in the study
| Variables | All patients | Without NSAIDs | With NSAIDs | P valuea |
|---|---|---|---|---|
| Number of patients | 979 | 886 | 93 | |
| Age, yearsb | 67 (56-75) | 67 (57-75) | 61 (49-71) | 0.001 |
| Males/Females, percentage | 66.2/33.8 | 64.7/35.3 | 81.6/19.4 | 0.002 |
| APACHE II scoreb | 23 (16-29) | 23 (16-29) | 22 (17-26) | 0.160 |
| Length of stay in ICU, daysb | 13 (6-23) | 12 (5-22) | 25 (14-18) | 0.0001 |
| Hospital mortality, percentage | 42.0 | 42.9 | 33.3 | 0.076 |
| Co-medication, percentage | ||||
| Aspirinc | 28.0 | 26.7 | 39.8 | 0.008 |
| Clopidogrel | 6.2 | 6.5 | 3.2 | 0.208 |
| Statins | 21.2 | 20.4 | 29.0 | 0.054 |
aSignificant differences between patients without and those with non-steroidal anti-inflammatory drugs (NSAIDs); bvalues are presented as mean (range); c100 mg/day. APACHE II, Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit.
The data of the present study indicate that, given separately, both aspirin and NSAIDs may reduce mortality in patients with sepsis. The interaction between aspirin and NSAIDs needs to be considered in forthcoming trials looking for benefits of either compound in patients with sepsis. We speculate that the lack of benefit of parallel use of aspirin and NSAIDs is due to a higher bleeding risk or anti-inflammatory action or both.
Abbreviations
APACHE II: Acute Physiology and Chronic Health Evaluation II; ICU: intensive care unit; NSAID: non-steroidal anti-inflammatory drug; OR: odds ratio.
Competing interests
The authors declare that they have no competing interests.
Contributor Information
Maik Sossdorf, Email: maik.sossdorf@med.uni-jena.de.
Gordon P Otto, Email: gordon.otto@med.uni-jena.de.
Janina Boettel, Email: janina.boettel@med.uni-jena.de.
Johannes Winning, Email: johannes.winning@med.uni-jena.de.
Wolfgang Lösche, Email: wolfgang.loesche@med.uni-jena.de.
Acknowledgements
This study was supported by the German Federal Ministry of Education and Research within the 'Center for Sepsis Control and Care'.
References
- Eisen DP. Manifold beneficial effects of acetyl salicylic acid and non-steroidal anti-inflammatory drugs on sepsis. Intensive Care Med. 2012;17:1249–1257. doi: 10.1007/s00134-012-2570-8. [DOI] [PubMed] [Google Scholar]
- Winning J, Neumann J, Kohl M, Claus RA, Reinhart K, Bauer M, Lösche W. Antiplatelet drugs and outcome in mixed admissions to an intensive care unit. Crit Care Med. 2010;17:32–37. doi: 10.1097/CCM.0b013e3181b4275c. [DOI] [PubMed] [Google Scholar]
- Winning J, Reichel J, Eisenhut Y, Hamacher J, Kohl M, Deigner HP, Claus RA, Bauer M, Lösche W. Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms. Platelets. 2009;17:50–57. doi: 10.1080/09537100802503368. [DOI] [PubMed] [Google Scholar]
- Sanchez MA, Thomas CB, O'Neal HR. Do aspirin and statins prevent severe sepsis? Curr Opin Infect Dis. 2012;17:345–350. doi: 10.1097/QCO.0b013e3283520ed7. [DOI] [PubMed] [Google Scholar]
- Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997;17:912–918. doi: 10.1056/NEJM199703273361303. [DOI] [PubMed] [Google Scholar]