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Adjunctive Therapy in Septic Shock and Severe Sepsis

In two prospective, multicenter trials, researchers examined the roles of adjunctive hydrocortisone, intensive insulin therapy, and colloid resuscitation in patients with sepsis.

Despite the use of antimicrobials, mortality rates remain very high in patients with severe forms of sepsis. The role of adjunctive therapies is uncertain. In two recent multicenter, randomized trials, researchers investigated the use of such therapies.

Sprung and colleagues compared hydrocortisone with placebo in a multinational, double-blind trial involving 499 adults with septic shock. The primary outcome measure was 28-day mortality among patients who did not have a response to a corticotropin test. Mortality also was evaluated in two other cohorts: patients who did respond to a corticotropin test and the overall group. In all three study cohorts, mortality rates were similar between treatment groups.

In an open-label, two-by-two factorial trial conducted with partial industry support, Brunkhorst and colleagues compared insulin therapies (intensive vs. conventional) and resuscitation fluids (colloid [pentastarch] vs. crystalloid [Ringer’s lactate]) among 537 adults in Germany with severe sepsis or septic shock. Hypoglycemia was more common in the intensive-insulin group than in the conventional-insulin group (12.1% vs. 2.1%; P<0.001). Moreover, life-threatening hypoglycemic episodes were more common in the intensive-insulin group than in the conventional-insulin group (5.3% vs. 2.1%; P=0.05). Intensive insulin therapy was terminated after the first safety analysis; all participants received conventional insulin therapy until the next planned interim analysis. Acute renal failure was more common in the pentastarch group than in the Ringer’s lactate group (34.9% vs. 22.8%; P=0.002). The proportion of days during which renal-replacement therapy was required was higher in the pentastarch group than in the Ringer’s lactate group (18.3% vs. 9.2%).

Comment: Sprung and colleagues acknowledged that their study was underpowered because of various factors, including low enrollment. An editorialist calculated that its power was <35% to detect a 20% reduction in the relative risk for death. Nonetheless, the likelihood of seeing differences in outcomes between the study groups was deemed low.

These two trials provide critical data on the role of adjunctive therapies in patients with severe sepsis or septic shock. Based on findings from these and other investigations, the current message is that corticosteroids are probably not effective and that both intensive insulin therapy and pentastarch resuscitation are harmful.

— Larry M. Baddour, MD

Published in Journal Watch Infectious Diseases January 9, 2008

Citation(s):

Sprung CL et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008 Jan 10; 358:111.

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• Medline abstract (Free)

Brunkhorst FM et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008 Jan 10; 358:125.

• Original article (Subscription may be required)
• Medline abstract (Free)

Finfer S. Corticosteroids in septic shock. N Engl J Med 2008 Jan 10; 358:188.

• Original article (Subscription may be required)
• Medline abstract (Free)