Proenkephalin A and heterogeneity of hydrocortisone treatment effect in septic shock: a post hoc analysis of the VANISH trial
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Objective: Heterogeneity of treatment effect is thought to drive conflicting results for the benefits of corticosteroids in sepsis. Proenkephalin A (PENK) is a biomarker of renal function. Given the kidney’s role in sepsis pathophysiology and corticosteroid metabolism, we hypothesized that baseline renal function, assessed using PENK, would be associated with hydrocortisone efficacy.
Design: A post hoc analysis of a double-blind, randomized clinical trial in septic shock (VANISH [Effect of Early Vasopressin vs. Norepinephrine on Kidney Failure in Patients with Septic Shock]).
Setting: Intensive Care Units (ICU) across the UK.
Patients: 173 patients admitted to ICU with septic shock.
Interventions: Norepinephrine vs vasopressin and hydrocortisone vs placebo.
Measurements: PENK was measured in plasma and patients were dichotomized using a PENK concentration above 89 pmol/L.
Main Results: PENK ≥89 pmol/L was associated with 28-day mortality (odds ratio (OR) 3.24 (95% confidence interval (CI) 1.62-6.74)).
We found no interaction between PENK and randomization to vasopressin or norepinephrine on outcome. However, there was a significant interaction between the PENK groups and hydrocortisone or placebo use in those patients who reached the maximum vasopressor threshold (n=111) for kidney failure-free days (high PENK (≥89 pmol/L) placebo 26 (13-28), hydrocortisone 11 (0-26); low PENK placebo (28 (15-28), hydrocortisone 28 (28-28), p = 0.01). Patients with high PENK receiving hydrocortisone had the fewest kidney failure free days. Although we found no significant interaction for 28-day mortality (p=0.14) the patients with high PENK who received hydrocortisone had the highest mortality (high PENK hydrocortisone 50%, placebo 32%; low PENK hydrocortisone 14%, placebo 24%).
Conclusion: This exploratory analysis identified a possible interaction between baseline PENK and hydrocortisone treatment on kidney failure-free days. These findings require validation in independent and prospective studies.
Design: A post hoc analysis of a double-blind, randomized clinical trial in septic shock (VANISH [Effect of Early Vasopressin vs. Norepinephrine on Kidney Failure in Patients with Septic Shock]).
Setting: Intensive Care Units (ICU) across the UK.
Patients: 173 patients admitted to ICU with septic shock.
Interventions: Norepinephrine vs vasopressin and hydrocortisone vs placebo.
Measurements: PENK was measured in plasma and patients were dichotomized using a PENK concentration above 89 pmol/L.
Main Results: PENK ≥89 pmol/L was associated with 28-day mortality (odds ratio (OR) 3.24 (95% confidence interval (CI) 1.62-6.74)).
We found no interaction between PENK and randomization to vasopressin or norepinephrine on outcome. However, there was a significant interaction between the PENK groups and hydrocortisone or placebo use in those patients who reached the maximum vasopressor threshold (n=111) for kidney failure-free days (high PENK (≥89 pmol/L) placebo 26 (13-28), hydrocortisone 11 (0-26); low PENK placebo (28 (15-28), hydrocortisone 28 (28-28), p = 0.01). Patients with high PENK receiving hydrocortisone had the fewest kidney failure free days. Although we found no significant interaction for 28-day mortality (p=0.14) the patients with high PENK who received hydrocortisone had the highest mortality (high PENK hydrocortisone 50%, placebo 32%; low PENK hydrocortisone 14%, placebo 24%).
Conclusion: This exploratory analysis identified a possible interaction between baseline PENK and hydrocortisone treatment on kidney failure-free days. These findings require validation in independent and prospective studies.
Date Acceptance
2026-09-03
Citation
Critical Care Explorations
ISSN
2639-8028
Publisher
Wolters Kluwer
Journal / Book Title
Critical Care Explorations
Copyright Statement
Copyright This paper is embargoed until publication. Once published the Version of Record (VoR) will be available on immediate open access.
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Publication Status
Accepted