Observational studyCritical care explorations2026
Proenkephalin A and Heterogeneity of Hydrocortisone Treatment Effect in Septic Shock: A Post Hoc Analysis of the VANISH Trial.
Observational study in Critical care explorations, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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6 authors.
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Abstract
objectivesHeterogeneity 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.
designA post hoc analysis of a double-blind, randomized clinical trial in septic shock (Effect of Early Vasopressin vs. Norepinephrine on Kidney Failure in Patients with Septic Shock [VANISH]).
settingICUs across the United Kingdom. PATIENTS: One hundred seventy-three patients admitted to ICU with septic shock.
interventionsNorepinephrine vs. vasopressin and hydrocortisone vs. placebo. MEASUREMENTS AND MAIN
resultsPENK was measured in plasma, and patients were dichotomized using a PENK concentration above 89 pmol/L. PENK greater than or equal to 89 pmol/L was associated with 28-day mortality (odds ratio, 3.24; 95% 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] and 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% and low PENK hydrocortisone 14%, placebo 24%).
conclusionsThis 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.
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