Statins for Treatment of Severe Sepsis
By Amesh A. Adalja, MD, FACP, May 3, 2013
The pathophysiology of many infectious diseases often involves a complicated interplay between a host’s immune system and the virulence factors of an invading pathogen. The current conceptual model begins with a systemic inflammatory response syndrome (SIRS) that is provoked by a pathogen, which leads to sepsis. In some cases, organ dysfunction ensues, giving rise to severe sepsis. As infection and inflammation progress, a state of net immune suppression is entered (compensatory anti-inflammatory response syndrome or “CARS”).1 Several interventions to modulate the immune response and the delicate relationship between inflammation and anti-inflammation have been tested, with varied results. One such intervention is treatment with statins, a class of lipid-lowering agents known for their pleiotropic immune-modulating activity.
Statins have also been considered as an adjunct treatment for influenza, but as we have noted in the past, data are insufficient for development of definitive guidelines for use of statins to treat influenza. Results of a recent study by the ANZICS Clinical Trials Group in Australia and New Zealand provide new data about use of statins for treating patients with severe sepsis, which many patients with severe influenza develop.2
250 Patients Studied
This phase II double-blind randomized control trial (RCT) was conducted from 2007-2010 in 21 ICUs in New Zealand and Australia. Eligible subjects were critically ill patients aged 18-90 who had severe sepsis. Prior statin users who had not taken them within the previous 2 weeks were eligible for enrollment. The study protocol involved randomizing patients to either 20 mg of atorvastatin or placebo, irrespective of prior use. Of the 250 study patients, 31% had received statin treatment previously and were included in the trial. The treatment group was statistically younger and less likely to have COPD. Bacteremia was present in 31% of patients.2 The primary outcome was plasma IL-6 levels; secondary outcomes included CRP level, lipid levels, atorvastatin levels, SOFA score changes, length of stay, and mortality.2
Limited Benefit from Statins
IL-6 levels, which are highly related to mortality and SOFA scores, did not differ among groups, including those started on statins de novo. Similarly, mortality differences were not appreciable among groups, including those started on atorvastatin at randomization. However, in prior statin users in the treatment group, 28-day mortality was lower (5% vs. 28%). This difference was not statistically significant at 90 days, though the trend persisted. ICU length of stay was shorter among those first prescribed statins at randomization (5.7 days vs. 8.5 days), but hospital length of stay was not affected.2
Atorvastatin levels, expectedly, were higher in those receiving atorvastatin; cholesterol levels were accordingly lower. Similar to IL-6 levels, CRP levels were not different among groups. Importantly, no adverse events were reported as definitely arising from the atorvastatin in this study group.2
Role of Statins Still Unclear
This RCT provides some answers to the clinical question of whether statins should be used to treat infectious diseases complicated by severe sepsis. The ANZIC researchers have demonstrated that de novo statin use may decrease ICU length of stay, but has no effect on mortality. These results suggest that de novo statin use may not always be warranted, but patients taking statins should continue to receive them during hospitalization, given the mortality benefit and safety profile.
These results also bring up additional important questions that warrant further investigation:
- Do statins have a role in the management of severe influenza?
- Would higher doses of atorvastatin change the outcome?
- Would treatment with other statins produce similar outcomes?
- Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008;4:617-625.
- Kruger P, Bailey M, Bellomo R, et al. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 2013;187:743-750.