Should we add fludrocortisone to patients with septic shock who are treated with hydrocortisone?

Although previous clinical trials have shown reduced mortality with combined hydrocortisone-fludrocortisone, guidelines recommend hydrocortisone alone in septic shock patients with persistent vasopressor requirements. The recommendation for hydrocortisone alone is based on the "negative" findings of the COIITSS clinical trial and the potentially adequate mineralocorticoid effects of hydrocortisone. However, published mineralocorticoid equivalences do not account for pleotropic mineralocorticoid effects that may explain the lower mortality associated with the combination of hydrocortisone-fludrocortisone. These effects include activation of innate immunity and facilitation of clearance of increased alveolar fluid, which is a hallmark of acute respiratory distress syndrome, a common comorbidity in septic shock patients [1].

Using a large, multicenter, enhanced claims-based database, a recently published cohort study in JAMA emulated a clinical trial to compare the effectiveness of fludrocortisone added to hydrocortisone versus hydrocortisone alone in septic shock patients. The results showed that the addition of fludrocortisone to hydrocortisone was associated with increased hospital survival, shorter length of stay, and decreased shock duration compared to hydrocortisone alone. The risk reduction was similar to the previous COIITSS clinical trial, which also compared the two treatments. These findings provide additional evidence that combining fludrocortisone with hydrocortisone may be a more effective treatment for septic shock patients than hydrocortisone alone [2].

The authors acknowledge limitations to their study, which is observational and may have residual confounding despite sensitivity analyses. The database used did not contain comprehensive physiological and vasopressor data (dose and mechanical ventilation needs). However, a sensitivity analysis showed similar results to the primary analysis. The database also only had granularity to the level of the calendar day, potentially leading to misclassification of covariates. The authors suggest that initiation of fludrocortisone may not have occurred concurrently with hydrocortisone, increasing the risk of immortal time bias, but note that survival curves continue to separate through study day 4, consistent with prior trial findings.

Despite these limitations, the findings provide additional evidence that the addition of fludrocortisone to hydrocortisone may be superior to hydrocortisone alone among patients with septic shock. The authors suggested that further studies, including randomized trials, are needed to validate the results and identify optimal treatment strategies for patients with septic shock.

Does this study change your practice? will you add fludrocortisone to hydrocortisone in the management of septic shock patients?

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Based on the available evidence, clinicians may consider using fludrocortisone in combination with hydrocortisone for patients with septic shock who require vasopressors. However, individual patient factors and clinical judgment should always guide treatment decisions.

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REFERENCES

1. COIITSS Study Investigators; Annane D, Cariou A, Maxime V, Azoulay E, D'honneur G, Timsit JF, Cohen Y, Wolf M, Fartoukh M, Adrie C, Santré C, Bollaert PE, Mathonet A, Amathieu R, Tabah A, Clec'h C, Mayaux J, Lejeune J, Chevret S. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010 Jan 27;303(4):341-8. doi: 10.1001/jama.2010.2. Erratum in: JAMA. 2010 May 5;303(17):1698. PMID: 20103758.

2. 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. Published online March 27, 2023. doi:10.1001/jamainternmed.2023.0258