1. Annane D, Bellissant E, Briegel J, et al. Corticosteroids for severe sepsis and septic shock: a systematic review and metaanalysis. BMJ. 2004;329:480.
Severe sepsis is a common cause of ICU admissions and continues to have mortality rates as high as 30%. As research has evolved, the role of corticosteroids in sepsis has changed. Annane and colleagues systematically reviewed corticosteroid treatment for severe sepsis and septic shock. The authors found 15 randomized trials that evaluated their main outcome of all-cause mortality at 28 days. When these results were pooled there was no significant improvement in mortality (RR 0.98; 0.87 to 1.10). However, the analysis showed very significant heterogeneity, so the authors appropriately performed a sensitivity analysis based on an a priori hypothesis that low-dose, long-course steroids (≤ 300 mg hydrocortisone/day and ≥ 5 days) would provide greater benefit than short-course, high-dose corticosteroids. The sensitivity analysis of five studies with low-dose, long-course corticosteroids showed a clear reduction in 28-day mortality (RR 0.80; 0.67 to 0.95) with no heterogeneity. There was no statistically significant difference in GI bleeds, superinfections, and hyperglycemia.
This is a very well-done review, which included an exhaustive search for all available evidence. The authors conclude based on the findings of an individual study in the review that patients with septic shock should undergo adrenal insufficiency testing prior to starting empiric therapy with low-dose hydrocortisone (200-300 mg/day). Hydrocortisone should then be stopped if there is no evidence of adrenal insufficiency. However, none of the studies in this review were limited to patients with adrenal insufficiency. Also, although none of the studies individually showed a statistically significant improvement with corticosteroids, they all favored the steroid treatment group with RRs < 1. Although there is good evidence that septic shock patients with adrenal insufficiency should be treated with corticosteroids, it remains unclear if therapy should be generalized to all septic patients. The ongoing European CORTICUS trial should help answer some of these questions.
2. Baddour L.,Yu, V. and the International Pneumococcal Study Group. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Resp Crit Care Med; 2004;170:440-444.
Three retrospective studies indicate that patients with pneumococcal bacteremia are less likely to die if treated with combination antibiotics. The combination of a beta-lactam and a macrolide appear to be especially protective. Based upon this soft data, multiple societies now recommend combination antibiotic therapy with a beta-lactam and a macrolide as first-line therapy for hospitalized patients with CAP. This large, multi-center, prospective observational study analyzed outcomes for all patients with pneumococcal bacteremia. Critically ill patients were eight times more likely to die than non-critically ill patients (mortality: 54.6% vs. 7.3%, p=0.0001). Combination therapy was defined as any two or more antibiotics used concurrently: multiple different regimens were used. The 14-day mortality difference between pneumococcal bacteremic patients receiving monotherapy vs. those receiving combination therapy was not significant (10.4 vs. 11.5%, p-value not disclosed) However, in critically ill patients, combination antibiotic therapy was associated with a marked decrease in mortality (23.4 vs. 55.3%, p=0.0015).
This study has significant limitations. It is not randomized, combination therapy was broadly defined as any two or more antibiotics, and 16% of critically ill patients received only one antibiotic, a major deviation from the standard of care. Nonetheless, this is the first prospective trial that attempts to ascertain which patients with pneumococcal bacteremia benefit from combination therapy. The marked mortality reduction in critically ill patients who received combination therapy reinforces the current recommendation that septic patients with pneumococcal bacteremia should receive combination therapy. However, these findings also underscore the fact that current guidelines for the treatment of an exceedingly common and serious disease are based upon weak retrospective data. Further randomized prospective trials are needed to determine which patients with pneumococcal pneumonia may actually benefit from combination antimicrobial therapy and what combination is most efficacious.