Concise Critical Appraisal: Hydrocortisone and Fludrocortisone Versus Hydrocortisone Only

Previous studies on hydrocortisone and fludrocortisone for patients with septic shock found lower mortality in patients with septic shock who were treated with hydrocortisone plus fludrocortisone versus hydrocortisone alone¹ and in patients with septic shock treated with hydrocortisone and fludrocortisone versus placebo.² A recent study by Bosch et al adds to this steroid use knowledge.³

Bosch et al performed a retrospective cohort study from 2016 to 2020 using routinely collected data in the Premier Healthcare Database representing charts from approximately 25% of U.S. hospitalizations. The primary outcome was the composite of hospital death or discharge to hospice of patients with septic shock who received hydrocortisone versus hydrocortisone plus fludrocortisone. Secondary outcomes were hospital death, vasopressor-free days, and hospital-free days at day 28.

There are several theoretical mechanisms by which mineralocorticoids are effective therapies for septic shock. These include activation of intracellular receptors to increase leukocyte adhesion and tumor necrosis factor/reactive oxygen species production; facilitating clearance of lung edema in acute respiratory distress syndrome; and increased release of histamine, serotonin, bradykinin, and catecholamine. In comparison to other corticosteroids, fludrocortisone has the strongest mineralocorticoid effect.

Bosch et al evaluated 88,275 patients with septic shock, 2280 of whom received hydrocortisone plus fludrocortisone on the same calendar day, while 85,995 received hydrocortisone alone. Covariates including comorbidities and organ dysfunction were similar between the two groups. Patients were followed until hospital discharge for the primary composite outcome, with study day 0 being the first day hydrocortisone was administered. Investigators followed intention-to-treat, so patients who received fludrocortisone more than 24 hours after the first hydrocortisone dose were analyzed in the hydrocortisone-only group. In addition to secondary outcomes, researchers also collected proportions of hypernatremia and healthcare-associated infections (HAIs).

Of the patients who received hydrocortisone plus fludrocortisone, 1076 (47.2%) died or were discharged to hospice compared to 43,669 (50.8%) of patients who received hydrocortisone alone (absolute risk reduction [ARR] = –3.7%, number needed to treat = 28, P < 0.001). The rate of hospital death was also lower, with 39.3% in the combination group versus 42.7% in the hydrocortisone-only group (ARR= –3.7, P < 0.001). Vasopressor-free days and hospital-free days were also higher in the combination group (13.8 vs. 12.9 vasopressor-free days, 8.7 vs. 8.4 hospital-free days), with both being significant (P < 0.001). The proportions of patients with incident hypernatremia and HAIs were similar in both groups.

The authors created a well-designed multicenter observational effectiveness cohort study, demonstrating that the combination therapy of hydrocortisone plus fludrocortisone led to lower 90-day mortality or discharge to hospice, lower rate of hospital death, and fewer days on vasopressors than treatment with hydrocortisone alone. Although the ARR is similar to the results of the underpowered COIITSS trial,¹ the Bosch study’s conclusiveness is limited by the lack of a definitive randomized control trial demonstrating the same results. Additionally, because the study is based on harvesting a vast database devoid of granular patient details, there is a risk of unmeasured confounders obstructing the ability to make significant conclusions.

Furthermore, application of the results is difficult because the study compared patient populations for whom a decision to administer steroids had already been made but did not define the subset of patients with septic shock who would most benefit from mineralocorticoid therapies. The authors acknowledge that an adequately powered clinical trial would be useful in this regard. Despite these limitations, it appears that there is little downside to adding fludrocortisone to hydrocortisone in the treatment of patients with septic shock who can tolerate enteral therapies.

References:

1. COITSS Study Investigators; Annane D, Cariou A, Maxime V, et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010 Jan;303(4):341-348.
2. Annane D, Renault A, Brun-Buisson C, et al; CRICS-TRIGGERSEP Network. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018 Mar 1;378(9):809-818.
3. 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 May 1;183(5):451-459.