Septic shock is a life-threatening condition characterized by an uncontrolled immune response to infection, leading to organ dysfunction, metabolic abnormalities, and cardiovascular instability. With a high mortality rate of 30-45%, the management of septic shock remains a significant challenge for clinicians. One area of controversy is the use of steroids in septic shock, as studies have yielded inconsistent findings regarding their impact on mortality.
Early Trials and Favorable Outcomes
In the late 1970s, the first prospective, randomized trial investigating the use of steroids in septic shock demonstrated improved mortality outcomes for patients receiving dexamethasone or methylprednisolone. A subsequent study in 1998 by Bollaert et al. showed that a supraphysiologic dose of methylprednisolone resulted in improved hemodynamics and lower mortality rates [1-2].
Follow Up Trials
In 2002, Annane et al. conducted a double-blinded, randomized, placebo-controlled trial in France, which revealed a reduction in 28-day mortality. Interestingly, the authors subdivided patients into ACTH stimulation responders and non-responders, with the most significant benefit observed in patients who responded to ACTH stimulation. This led to the widespread use of hydrocortisone among septic patients showing an ACTH response. However, subsequent studies, such as the CORTICUS trial in 2008, did not find a difference in 28-day mortality between the intervention and placebo groups, although there was a faster resolution of shock and a potential increased risk of superinfection [4].
Prevention of Sepsis Progression
A German study conducted in 2016 examined the effect of continuous infusion of hydrocortisone followed by a tapered regimen on the progression of sepsis to septic shock. The findings of the study indicated that steroids did not prevent the deterioration of sepsis into septic shock and the use of steroid was confined to septic shock patients [5].
Conflicting Results from ADRENAL and APROCCHSS Trials
The ADRENAL trial, the largest among the studies discussed, included 3,658 patients in a multi-centered, double-blinded design and evaluated the 90-day mortality outcomes of a continuous infusion of hydrocortisone versus placebo. The results showed no significant difference in 90-day mortality but indicated a shorter time to resolution of shock [6].
In contrast, the APROCCHSS study, a smaller multi-centered, double-blinded French randomized controlled trial with 1,241 septic shock patients, compared hydrocortisone plus fludrocortisone to placebo. This study demonstrated reduced 90-day mortality, faster shock reversal, and no difference in ventilator-free days. However, the difference in mortality outcomes between the two trials could be influenced by the sample size discrepancy, as an interim analysis of the ADRENAL study at a similar number of enrolled patients revealed a mortality benefit [7].
Fludrocortisone and its Impact
A retrospective study involving 88,275 patients with septic shock receiving norepinephrine and initiating hydrocortisone treatment investigated the addition of fludrocortisone alongside hydrocortisone. The introduction of fludrocortisone showed a 3.7% decrease in the adjusted absolute risk difference for the primary outcome, a combination of mortality or discharge to hospice, compared to hydrocortisone alone [8].
Patient-level Meta-analysis Findings
A recently published patient-level meta-analysis encompassed a total of 24 trials, with 17 trials providing individual patient data and 7 trials providing information on 90-day mortality. The use of hydrocortisone compared to placebo did not yield a significant difference in the risk of 90-day mortality. However, among patients receiving hydrocortisone, the subgroup that also received fludrocortisone demonstrated a statistically significant decrease in 90-day mortality. It is essential to exercise caution when interpreting these findings due to the limited number of trials and unique patient characteristics involved [9].
Treatment Effects and Safety of Glucocorticoid Use
The meta-analysis did not identify significant variations in treatment effects across different subgroups. Hydrocortisone had minimal impact on secondary outcomes, except for a slight increase in vasopressor-free days. The analysis confirmed the safety of glucocorticoid use in critical illness, as it did not increase the risk of complications such as gastrointestinal bleeding, hyperglycemia, or secondary infections. However, there was a possibility of an increased risk of hypernatremia and muscle weakness associated with hydrocortisone, although the certainty of this evidence was low as this outcome was only measured in a small subset of patients [9].
What is your approach to the use of steroids in patients with septic shock and increasing needs of vasopressors?
0%IV hydrocortisone and oral fludrocortisone
0%IV hydrocortisone only
0%No steroids
Conclusion and Further Research
Current guidelines recommend glucocorticoid treatment for patients with persistent shock requiring vasopressors due to the evidence supporting faster shock reversal and decreased vasopressor dependency. The recent meta-analysis suggests a potential benefit of glucocorticoid treatment in a subset of septic shock patients with severe illness and pulmonary infection, but further research is needed to validate these findings and better understand the variations within sepsis syndrome. While there is a promising indication of benefit from combining fludrocortisone with hydrocortisone, limitations in the trials and complex factors make it challenging to draw definitive conclusions. Additional studies are necessary to clarify the potential advantages and investigate the interaction between illness severity and the effects of fludrocortisone.
References
Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976;184(3):333-341.
Bollaert P, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26(4):645-650.
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.
Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124.
Keh D, Trips E, Marx G, et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016;316(17):1775–1785.
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.
Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone Plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378:809-818.
Bosch NA, Teja B, Law AC, Pang B, Jafarzadeh SR, Walkey AJ. Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone Among Patients With Septic Shock. JAMA Intern Med. 2023;183(5):451–459. doi:10.1001/jamainternmed.2023.0258. Link
Pirracchio R, Annane D, Waschka AK, et al. Patient-level meta-analysis of low-dose hydrocortisone in adults with septic shock. NEJM Evid 2023;2(6).
As usual impressive!