Corticosteroids in septic shock: to do or not to do, that is the question

The rationale for the administration of corticosteroids in septic shock 

The use of corticosteroids as adjunctive therapy in septic shock has captivated intensive care physicians for over five decades. Many of the early studies used industrial doses of synthetic glucocorticoids, and predictably, led to poor clinical outcomes. The concept of corticosteroid insufficiency related to critical illness (CIRCI) has arisen more recently. CIRCI is based on the hypothesis that even maximal stimulation of the hypothalamic-pituitary-adrenal axis in disease states such as sepsis results in insufficient corticosteroid levels. Besides, there may be tissue resistance to corticosteroids in the presence of sepsis. Based on this theory, the use of more physiological doses of corticosteroids as adjuvant therapy in sepsis was conceptualized, with several small randomized controlled studies (RCTs) demonstrating improvement in hemodynamic parameters, and a trend to improved survival.^1,2 Many large RCTs have been carried out since then, evaluating the effect of low-dose corticosteroids to replenish insufficient endogenous activity. What does the current evidence suggest regarding the efficacy of corticosteroids in septic shock? 

Earlier randomized controlled trials

Annane et al. conducted the first, adequately powered RCT to evaluate the usefulness of corticosteroids in septic shock. The combination of intravenous hydrocortisone 50 mg every 6 hours and fludrocortisone 50 μg tablet once daily were administered for a week and compared with placebo. A short corticotrophin test was performed in all patients to test adrenal function. Patients with a rise in cortisol level of less than 9 μg/dl in response to corticotrophin were considered as “non-responders”. The 28-d survival, the primary outcome, was significantly higher among non-responders; this suggested that exogenous administration of corticosteroids led to improved survival in patients with relative adrenal insufficiency. The time to cessation of vasopressors was also significantly less among non-responders who were treated with corticosteroids.³ This was followed by the CORTICUS trial, which included 499 patients; in this study, intravenous hydrocortisone alone was administered as adjunctive therapy (not in combination with fludrocortisone) and compared with placebo.⁴ No difference was observed in the 28-d mortality in this study; however, a reduced time to shock reversal was noted in corticosteroid-treated patients. The patients in the CORTICUS trial were less severely ill, compared to the Annane et al. study, with relatively fewer patients who fulfilled the criteria for septic shock. 

Recent randomized controlled trials 

Considering the contrasting results of these two studies, the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) study was carried out by the Australian-New Zealand Intensive Care Society Clinical Trials Group.⁵ The largest RCT to address this question, the ADRENAL study recruited 3800 patients involving 69 medical–surgical ICUs in Australia, the United Kingdom, New Zealand, Saudi Arabia, and Denmark. Patients were intubated or on non-invasive ventilation and on vasopressor therapy for  more than 4 h at randomization. In the intervention arm, hydrocortisone was administered as an intravenous infusion of 200 mg/d for 7 d or until death or discharge from the ICU. No difference was observed in the 90-d mortality, the primary outcome, for which the study was powered. Among the secondary outcomes, the investigators observed a significant difference in the median time to shock resolution, the median time to initial of discontinuation of mechanical ventilation, the median time to ICU discharge, and the number of patients who received a blood transfusion. The 28-d mortality, shock recurrence, use of renal replacement therapy, number of days alive and out of ICU, the median time to hospital discharge, and the number of days alive and out of hospital were not different between groups. 

The combination of hydrocortisone, 50 mg/kg intravenously and 50 μg fludrocortisone once daily was evaluated in a recent French multicentric study (APROCCHSS) among patients with septic shock who were on vasopressor therapy for at least 6 hours.⁶ The study was originally designed to assess the efficacy of the combination of drotrecogin alfa and corticosteroids. However, during the course of the study, drotrecogin alfa was withdrawn from the market; thereafter, the study was continued with corticosteroids alone and compared with placebo. In contrast to ADRENAL, a statistically significant difference was observed in the 90-d mortality, which was the primary endpoint. The all-cause mortality at ICU and hospital discharge, and at 180 days were also significantly lower among corticosteroid-treated patients. Earlier shock reversal was also observed; there were more patients alive and off vasopressor support at 28 d with corticosteroids. 

APROCCHSS vs. ADRENAL: Why the difference? 

A relatively large number of patients were excluded in the ADRENAL trial; 21,818 patients were screened, out of which 8,263patients were excluded. Exclusion of a large number of subjects may represent a bias in RCTs. In contrast, in the APROCCHSS trial, 1,671 patients with septic shock were screened, and 1,241 patients were included in the study. Patients in the APROCCHSS trial may have been more severely ill. They were on higher doses of noradrenaline, had higher lactate levels, and renal replacement therapy was more frequent, all suggesting more severe illness at baseline. In the ADRENAL study, patients were enrolled later compared to APROCCHSS, suggesting that earlier administration of corticosteroids may be more efficacious. Administration of hydrocortisone as an infusion may not be optimal, considering that achievement of adequate blood levels may be delayed without an initial bolus. Furthermore, it may be illogical to administer hydrocortisone as an infusion considering its relatively long half-life (8–12 h). Did fludrocortisone make a difference to the final outcome? It is difficult to answer this question based on the current level of evidence. Vasopressin use was much more common in the ADRENAL trial; however, the impact of a combination of vasopressin and corticosteroids needs detailed evaluation in patients with septic shock.  

The bottom line

• There is a strong physiological rationale for the use of corticosteroids as adjunctive treatment in septic shock.
• All major randomized controlled studies that evaluated the use of corticosteroids in septic shock have shown earlier shock reversal and more rapid weaning down of vasopressors.
• Corticosteroid administration may lead to a shorter duration of mechanical ventilation and length of stay in the intensive care unit.
• In the light of the available evidence, it may be appropriate to consider administration of corticosteroids in patients with septic shock.
• Future studies need to be designed to evaluate whether 1) corticosteroids are more efficacious in the more severely ill and 2) addition of a fludrocortisone would make a difference.

References

1.         Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26(4):645-650. doi:10.1097/00003246-199804000-00010

2.         Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27(4):723-732. doi:10.1097/00003246-199904000-00025

3.         Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871. doi:10.1001/jama.288.7.862

4.         Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. doi:10.1056/NEJMoa071366

5.         Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835

6.         Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. doi:10.1056/NEJMoa1705716