Abstract & Commentary
Synopsis: Relatively low-dose corticosteroid administration to highly selected patients with severe septic shock was associated with improved survival among those found to have limited adrenal reserve as determined by a short corticotropin stimulation test.
Source: Annane D, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862-871.
Annane and colleagues performed a randomized, placebo-controlled, blinded trial in 19 French ICUs to evaluate the efficacy of low-dose corticosteroids as adjunctive therapy in patients with septic shock. Eligible patients had clinical evidence of infection and a systolic blood pressure less than 90 mm Hg for at least 1 hour despite both adequate fluid replacement and receipt of more than 5 mg/kg dopamine or current receipt of epinephrine or norepinephrine. Additional requirements included a urinary output less than 0.5 mL/kg for at least 1 hour or PaO2/FiO2 less than 280 or arterial lactate greater than 2 mmol/L, and need for mechanical ventilation. Reasons for exclusion from the study included pregnancy, acute myocardial infarction, pulmonary embolism, advanced malignancy or AIDS, and contraindication to or "formal indication" for corticosteroid therapy.
Only 300 of 1326 patients assessed proved to be eligible for randomization and 1 of these died prior to receipt of any study drug. Patients assigned corticosteroid therapy received a 50 mg IV bolus of hydrocortisone hemisuccinate every 6 hours and a 50 mg tablet of 9-alpha-fludrocortisone by NG tube every 24 hours—each for 7 days. All patients underwent a short corticotropin test with a 250 mg dose of tetracosactin with sampling immediately before administration and again after 30 and 60 minutes.
Bacteremia was detected in 26% of corticosteroid recipients and 21% of placebo recipients. Blinded retrospective evaluation determined that 95% of placebo and 91% of corticosteroid recipients received appropriate antibiotic therapy within 24 hours of the diagnosis of sepsis. The mean time to receipt of the first antibiotic dose was 6.0 hours in the placebo group and 7.1 hours in the steroid group.
There was no difference in the frequency of adverse effects between the treatment groups. On examination of the entire group of patients without regard to their baseline adrenal responsiveness, there was no statistically significant effect of corticosteroid administration on 28-day mortality, mortality in the ICU, or 1-year mortality. This was also true of the subgroup that was corticotropin responders.
While several analyses of the frequency of fatal events suggests the possibility of trends favoring placebo administration, these were not confirmed when analysis using a Cox model was performed.
Among corticotropin nonresponders (< 9 mcg increase in serum cortisol), the 28-day mortality was 63% in those assigned placebo and 53% in the corticosteroid recipients (P = 0.04); the median times to death in the 2 groups were, respectively, 12 days and 24 days. Corticosteroid recipients also had reduced ICU mortality and end of hospital mortality, as well as duration of vasopressor therapy.
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Comment by Stan Deresinski, MD, FACP
In contrast to this study using relatively low corticosteroid doses, well-performed randomized trials have previously failed to demonstrate a benefit from the administration of large pharmacologic doses of corticosteroids. It has, nonetheless, been recognized that many septic patients have relative adrenal insufficiency, defined as an insufficient response to a corticotropin stimulation test. In addition, some studies have indicated that relatively low-dose short duration corticosteroid administration to such individuals improves responsiveness to vasoactive agents.
This multicenter clinical trial found that, among those with relative adrenal insufficiency, one life is saved (at day 28) for every 7 treated. The results of this study, while requiring confirmation before they can be unequivocally accepted, may prove to be another in a recently published series of advances in the prevention and management of septic shock.1,2 Thus, it has been reported that tight glucose control with insulin is associated with a reduced risk of sepsis in critically ill patients.3 Patients with severe sepsis and septic shock aggressively managed immediately on presentation with the goal of balancing oxygen delivery and demand had improved survival.4 Norepinephrine infusion, when compared to dopamine, was associated with reduced mortality.5,6 Finally, and most threatening to hospital pharmacy budgets, therapy with drotrecogin alfa activated, a recombinant human activated protein C preparation, was associated with significantly improved survival in patients with severe sepsis.2,7
The mean delay in initiation of antibiotic therapy in this trial was 6-7 hours after the diagnosis of sepsis. This is an extraordinarily prolonged period of time in a group of critically ill patients.
Annane et al performed 2 interim analyses, but they do not indicate that their statistical tests of significance were adjusted for these.
The higher mortality among corticosteroid recipients who proved to have adequate adrenal reserve (61% vs 53%), although not statistically significant, signals a need for further investigation. However, in this study, the actual cortisol measurements were not performed until the trial had been completed—all patients surviving for that duration of time received their assigned therapy for 7 days regardless of adrenal status. A more reasonable strategy would be to discontinue corticosteroid administration in those with a normal response to corticotropin.
Thus, Annane et al suggest that all patients with catecholamine-dependent septic shock be given a short corticotropin stimulation test immediately followed by administration of hydrocortisone and fludrocortisone. It must be recognized, however, that subjects included in this study were highly selected critically ill patients receiving mechanical ventilation; only 23% of patients evaluated for entry into the study proved eligible and, in consequence, the applicability to less ill patients remains to be determined. Furthermore, in order to avoid unnecessary corticosteroid administration to patients with adequate adrenal reserve, such treatment can be discontinued in those with an adequate adrenal reserve and continued for up to 7 days in nonresponders to corticotropin.
Dr. Deresinski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.
References
1. Baigorri F. Corticosteroid treatment for septic shock: New insights. Infectious Disease Alert. 2000;20(2): 12-15.
2. Deresinski S. Treatment of severe sepsis—An advance at last! Infectious Disease Alert. 2001;20(11):81-82.
3. Van den Berghe G, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345: 1359-1367.
4. Rivers E, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
5. Martin C, et al. Effect of norepinephrine on the outcome of septic shock. Crit Care Med. 2000;28: 2758-2765.
6. Johnson K. Effect of norepinephrine on the outcome of septic shock. Infectious Disease Alert. 2001;20(7): 55-56.
7. Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709.
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