Annane D, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71
Introduction and background
Historically, clinicians were often beguiled by the potent anti-inflammatory effect of corticosteroids and their putative benefits in septic patients. In the summer of 1976, William Schumer presented the tantalizing findings of his study on high-dose corticosteroid therapy in patients with septic shock at the annual meeting of the American Surgical Association. In a three-armed prospective trial, he compared methylprednisolone 30 mg/kg or dexamethasone 3 mg/kg with placebo. The author defined septic shock based on presumed “septic history” and “falling blood pressure”, along with positive cultures. The mortality among patients who received such massive doses of corticosteroids appeared to be incredibly low. In the control group, the mortality was nearly thrice as much compared to corticosteroid-treated patients. The study was conducted over a protracted period, between 1967–1975, during which the author conceded that “the use of new antibiotics, respirators, and better methods of diagnosis could have reduced mortality…”. Nevertheless, high-dose corticosteroids appeared to dramatically impact sepsis-related mortality.
Almost predictably, the compelling findings of Schumer were never reproduced.
Years later, Sprung et al. conducted a similar study among patients with septic shock (1). In this randomized controlled trial (RCT), patients in septic shock were treated with methylprednisolone 30 mg/kg or dexamethasone 6 mg/kg, and compared with a control group that did not receive corticosteroids. Earlier shock reversal was observed among corticosteroid-treated patients; however, improved blood pressures did not result in a significant impact on hospital survival. Two further RCTs confirmed the lack of beneficial effect of high-dose methylprednisolone on survival in septic shock (1,2), consigning this questionable therapy to the ash heap of history.
The early 1990s witnessed a revival of interest in lower doses of corticosteroids over a longer duration, based on the concept of relative adrenal insufficiency in sepsis. Two RCTs of a relatively small sample size evaluated the effect of low-dose hydrocortisone on shock reversal during this period. The study by Bollaert et al. revealed a higher rate of shock reversal with hydrocortisone 100 mg administered 8 hourly intravenously compared with placebo (3). These findings were reproduced in a later study by Briegel et al., using a loading dose of hydrocortisone 100 mg followed by 0.18 mg/kg/h. Hydrocortisone administration resulted in earlier cessation of vasopressor support, with no increase in the incidence of adverse events (4).
The integrity and activation of the hypothalamic-pituitary-adrenal axis evolved as an important factor determining outcomes in sepsis. A short corticotrophin test measuring cortisol levels at baseline, 30 and 60 minutes, was employed to test the adequacy of the stress response in sepsis. In a prospective observational study, a failure of serum cortisol levels to rise by >9 μg/dl in response to 0.25 mg of tetracosactrin (a synthetic peptide comprised of the first 24 amino acids of adrenocorticotrophic hormone) was one of the independent predictors of mortality in septic shock (5). The stage was set for testing the concept of relative adrenal insufficiency in septic shock and the impact of low-dose corticosteroids on clinical outcomes, in contrast to the unfavorable outcomes associated with the mega-doses used previously.
Population and design
The randomized, placebo-controlled trial was conducted in 19 French ICUs (6). Adult patients were enrolled if they had a documented or strongly suspected focus of infection, the temperature was >38.3°C or <35.6°C, tachycardia >90/min, systolic BP <90 mm Hg for more than 1 hour despite fluid resuscitation, and dopamine > 5 μg/kg/minute or any dose of norepinephrine or epinephrine, urine output <0.5 ml/kg/hour, or a PaO2/FiO2 ratio <280 mm Hg, or lactate levels >2 mmol/L, and the need for mechanical ventilation.
Patients with acute myocardial infarction, pulmonary embolism, advanced malignancy, acquired immunodeficiency syndrome, and contraindications for steroid use were excluded. So were patients with a definite indication for steroids and pregnant patients. Patients who were on etomidate in the 6 hours prior to randomization were also excluded.
Patients received hydrocortisone 50 mg 6 hourly, intravenously as a bolus dose, combined with one tablet of 9- α- fludrocortisone 50 μg once daily administered through the nasogastric tube. Corticosteroids were administered for 7 days.
In the control group, identical placebos were administered.
A short corticotrophin test was performed to identify patients with relative adrenal insufficiency. Cortisol levels were measured at baseline and following 30 and 60 minutes after a 250 μg intravenous dose of tetracosactrin, an analogue of adrenocorticotrophic hormone (ACTH). Relative adrenal insufficiency was diagnosed if the serum cortisol levels failed to rise by >9 μg/dL after tetracosactrin administration; these patients were classified as non-responders. Patients in whom the cortisol levels rose by >9 μg/dL were classified as responders.
The authors assumed that 40% of patients would be non-responders. They also assumed 95% mortality in the control group among non-responders. A sample size of 270 patients was meant to detect a 20% difference between groups in the 28-day mortality with a 90% probability, and a type I error of 0.05.
The general characteristics and severity of illness were similar in the corticosteroid and the placebo groups. Pulmonary infections were most common, followed by intra-abdominal infections. The causative organism was also similar between the two groups of patients. Appropriate antibiotic therapy was administered with most patients – nearly 95% in the placebo and 91% in the corticosteroid group.
Two hundred ninety-nine patients were included in the final analysis; 229 were classified as non-responders and 70 as responders. Among the non-responders, the main focus of the study, 114 belonged to the corticosteroid and 115 to the placebo group.
The primary outcome: 28-day mortality in non-responders
Among the non-responders, the 28-day mortality was significantly lower in the corticosteroid group. In the corticosteroid group, 60/114 (53%) had died at 28-days compared with 73/115 (63%) in the placebo group (odds ratio, 0.54; 95% CI, 0.31–0.97; p = 0.04). In contrast, among the responders, the 28-day mortality was not significantly different [Placebo: 18/34 (53%) vs. corticosteroid: 22/36 (61%); p = 0.96].
The overall 28-day mortality was 82/150 (55%) in the corticosteroid group and 91/149 (61%) in the placebo group; the difference was not statistically significant.
ICU, hospital, and 1-year mortality
Among the non-responders, the ICU mortality was also significantly lower in the corticosteroid compared to the placebo group. The ICU mortality was 66/114 (58%) in the corticosteroid group compared with 81/115 (70%) in the placebo group (p = 0.02). The hospital mortality was also lower in the corticosteroid group (corticosteroid vs. placebo, 61% vs. 72%; p = 0.04). Mortality at 1 year of follow-up was lower in the corticosteroid group; however, the difference was not statistically significant (68% vs. 77%; p = 0.07).
There was no difference in the 28-day, ICU, hospital, and 1-year mortality between the corticosteroid and placebo groups among responders. Analysis including all patients (responders and non-responders) also did not show a difference in mortality at any of the above time points.
Time to cessation of vasopressors
Among non-responders, vasopressors could be withdrawn earlier in the corticosteroid group compared to the placebo group (median duration: 10 days vs. 7 days). At 28 days, more patients were off vasopressors in the corticosteroid group (57% vs. 40%). The time to cessation of vasopressors was not significantly different among responders.
The incidence of superinfections, including catheter-related infection, nosocomial pneumonia, urinary infection, and surgical site infection, was similar in both groups. Gastrointestinal bleeding occurred in a similar number of patients in both groups. Adverse events attributable to vasopressors, including myocardial infarction, arrhythmias, and limb ischemia, were also similar.
The authors concluded that a 7-day treatment with hydrocortisone combined with fludrocortisone reduced the 28-day mortality in patients with relative adrenal insufficiency, with no obvious adverse effects. They went on to recommend that patients with catecholamine-dependent septic shock should be commenced on this combination, pending the results of the short corticotrophin stimulation test, following which corticosteroid treatment may be ceased in non-responders.
At the time of the Annane et al. trial, corticosteroids had been in use among patients with sepsis for several decades. However, there had been few controlled trials that systematically evaluated their efficacy, and the results were conflicting. The authors conducted the first large, multicentric RCT across 19 centers in France. The study was adequately powered and double-blinded, with a low likelihood of bias. In contrast to some earlier studies that had used higher doses of corticosteroids with adverse outcomes, a low-dose strategy was followed, based on the hypothesis of relative adrenal insufficiency. The severity of illness was high among the study population. All patients were on mechanical ventilation, were oliguric, had increased serum lactate levels, and acute respiratory distress syndrome. Corticosteroid treatment in seven non-responders led to one additional life being saved at 28 days. The study was the harbinger of future clinical trials on steroids in septic shock, including the CORTICUS and the ADRENAL trials.
The study excluded a large number of patients –1326 patients were screened; only 300 were randomized. The overall mortality (58%) was high by present- day standards, even considering the high severity of illness in the study population. The mean time to administration of antibiotics was 7.1 hours in the corticosteroid group and 6.0 hours in the placebo group, which may be considered suboptimal in patients presenting with severe sepsis or septic shock. Etomidate, an inhibitor of steroid synthesis, was administered in 24% of patients and may have led to adrenal insufficiency. The protocol was amended during the study by excluding patients who had received etomidate in the 6-hour period preceding randomization.
The CORTICUS trial was published 6 years later, including a larger sample size of 499 patients. Intravenous hydrocortisone alone was administered as (fludrocortisone was not used) and compared with a placebo among patients with septic shock (7). The authors observed no difference in the 28-d mortality; however, a reduced time to shock reversal was observed in corticosteroid-treated patients.
The Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) study (8) has been the largest RCT thus far to address this question. The study included 3800 patients in septic shock, involving 69 medical-surgical ICUs in Australia, the United Kingdom, New Zealand, Saudi Arabia, and Denmark. Hydrocortisone was administered as an intravenous infusion of 200 mg/day for 7 days and compared with placebo. There was no significant difference in the 90-d mortality, the primary outcome. Among the secondary outcomes, the investigators observed a significant difference in the median time to shock resolution, the median time to initial discontinuation of mechanical ventilation, the median time to ICU discharge, and the number of patients who received a blood transfusion.
Considering its powerful anti-inflammatory properties, clinicians resorted to high-dose corticosteroid administration in patients with severe sepsis for over three decades from the 1950s. Some early reports suggested benefit with such high-dose therapy. However, by the 1980s, it was evident that such heavy-handed use of corticosteroids was more likely to cause harm. A resurgence of interest in low-dose therapy occurred in the 1990s arising from the concept of relative adrenal insufficiency in sepsis. Following up on small RCTs, Annane et al. conducted their landmark trial involving multiple ICUs in France to test this hypothesis. They evaluated the efficacy of a 7-day treatment regime, including hydrocortisone 50 mg 6 hourly combined with fludrocortisone 50 μg once daily in patients with septic shock. Failure of serum cortisol levels to rise by >9 μg/dL following tetracosactrin was considered to suggest relative adrenal insufficiency (non-responders). Among non-responders, the hydrocortisone-fludrocortisone combination resulted in significantly lower 28-day mortality, with no apparent adverse effects. This study was the first large RCT to evaluate the hypothesis of relative adrenal insufficiency in sepsis and the impact of low-dose corticosteroid therapy in septic shock.
1. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984 Nov 1;311(18):1137–43.
2. Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med. 1987 Sep 10;317(11):659–65.
3. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998 Apr;26(4):645–50.
4. Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999 Apr;27(4):723–32.
5. Annane D, Sébille V, Troché G, Raphaël JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000 Feb 23;283(8):1038–45.
6. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock.
7. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111–24.
8. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar;378(9):797–808.
9. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809–18.
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