Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone Among Patients With Septic Shock

Abstract

ImportancePatients with septic shock may benefit from the initiation of corticosteroids. However, the comparative effectiveness of the 2 most studied corticosteroid regimens (hydrocortisone with fludrocortisone vs hydrocortisone alone) is unclear.ObjectiveTo compare the effectiveness of adding fludrocortisone to hydrocortisone vs hydrocortisone alone among patients with septic shock using target trial emulation.Design, Setting, and ParticipantsThis retrospective cohort study from 2016 to 2020 used the enhanced claims-based Premier Healthcare Database, which included approximately 25% of US hospitalizations. Participants were adult patients hospitalized with septic shock and receiving norepinephrine who began hydrocortisone treatment. Data analysis was performed from May 2022 to December 2022.ExposureAddition of fludrocortisone on the same calendar day that hydrocortisone treatment was initiated vs use of hydrocortisone alone.Main Outcome and MeasuresComposite of hospital death or discharge to hospice. Adjusted risk differences were calculated using doubly robust targeted maximum likelihood estimation.ResultsAnalyses included 88 275 patients, 2280 who began treatment with hydrocortisone-fludrocortisone (median [IQR] age, 64 [54-73] years; 1041 female; 1239 male) and 85 995 (median [IQR] age, 67 [57-76] years; 42 136 female; 43 859 male) who began treatment with hydrocortisone alone. The primary composite outcome of death in hospital or discharge to hospice occurred among 1076 (47.2%) patients treated with hydrocortisone-fludrocortisone vs 43 669 (50.8%) treated with hydrocortisone alone (adjusted absolute risk difference, −3.7%; 95% CI, −4.2% to −3.1%; P < .001).Conclusions and RelevanceIn this comparative effectiveness cohort study among adult patients with septic shock who began hydrocortisone treatment, the addition of fludrocortisone was superior to hydrocortisone alone.

Should We Add Fludrocortisone to Hydrocortisone for Treatment of Septic Shock?

“…10 To answer the question of whether adding fludrocortisone to hydrocortisone would have benefit in treatment of septic shock, a very large randomized and prospective trial would be needed to detect a mortality reduction of 3.7% as reported in the current retrospective study. 6 A trial of this kind would also need to be designed to test for heterogeneity of treatment effect in prespecified sepsis subtypes, potentially using real-time biologic classifiers.…”

“…In view of the plausible biological mechanism and prior trial evidence, the results of the study by Bosch and colleagues are not entirely surprising. The study included a large number of patients captured in a database that included approximately 25% of all US hospital admissions over the study period of 2016 to 2020.…”

“…Taken together, these data suggest that mineralocorticoid deficiency in sepsis may contribute to the immunoparalysis described in some patients with sepsis and that mineralocorticoid therapy may be important in restoring homeostasis and enhancing innate immunity. 7 In view of the plausible biological mechanism and prior trial evidence, the results of the study by Bosch and colleagues 6 are not entirely surprising. The study included a large number of patients captured in a database that included approximately 25% of all US hospital admissions over the study period of 2016 to 2020.…”

“…In this issue of JAMA Internal Medicine, Bosch and colleagues 6 report the results of a retrospective cohort study of routinely collected data that aimed to emulate a target clinical trial to compare adding vs not adding fludrocortisone to hydrocortisone for reducing mortality and morbidity from septic shock. Among 384 394 patients with septic shock who received norepinephrine identified in claims data, 88 275 eligible patients were treated with corticosteroids within 3 days of admission; of those, 85 995 received hydrocortisone alone and 2280 received both hydrocortisone and fludrocortisone on the same day.…”

“…An important limitation in giving the results of these observational analyses a causal interpretation is the potential for confounding by unmeasured variables, especially because the analyses compared the addition of an active treatment (fludrocortisone) with a different route of administration than the baseline intravenous hydrocortisone treatment, against no additional treatment. 6 Furthermore, by restricting all analyses to hydrocortisone initiators, the population of patients to whom the results apply becomes harder to define and is not necessarily the same as the population of all individuals with septic shock who are candidates for corticosteroid therapy. To address this issue, while avoiding misalignments between the time of eligibility, treatment initiation, and the start of followup, the investigators could have used analyses that allow for delayed initiation of treatment after meeting eligibility criteria (eg, within a grace period of 3 days after developing shock requiring norepinephrine treatment).…”