Proenkephalin A and Heterogeneity of Hydrocortisone Treatment Effect in Septic Shock: A Post Hoc Analysis of the VANISH Trial.
4 affiliations
- 1Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
- 2Intensive Care Unit, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.
- 3Medical Department, SphingoTec GmbH, Hennigsdorf, Germany.
- 4School of Medicine, University of Surrey and Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Guildford, United Kingdom.
Abstract
Objectives
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 (Effect of Early Vasopressin vs. Norepinephrine on Kidney Failure in Patients with Septic Shock [VANISH]).Setting
ICUs across the United Kingdom.Patients
One hundred seventy-three patients admitted to ICU with septic shock.Interventions
Norepinephrine vs. vasopressin and hydrocortisone vs. placebo.Measurements and main results
PENK 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%).Conclusions
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.
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BibTeX
@article{antcliffe2026proenkephalin,
title = {{Proenkephalin A and Heterogeneity of Hydrocortisone Treatment Effect in Septic Shock: A Post Hoc Analysis of the VANISH Trial.}},
author = {David B Antcliffe and Florian Uhle and Dominic C Marshall and Ashleigh D Green and Anthony C Gordon and Lui G Forni},
journal = {Critical care explorations},
year = {2026},
month = oct,
doi = {10.1097/cce.0000000000001496},
url = {https://europepmc.org/article/MED/42902572},
note = {CC BY},
}
RIS
TY - JOUR
TI - Proenkephalin A and Heterogeneity of Hydrocortisone Treatment Effect in Septic Shock: A Post Hoc Analysis of the VANISH Trial.
AU - David B Antcliffe
AU - Florian Uhle
AU - Dominic C Marshall
AU - Ashleigh D Green
AU - Anthony C Gordon
AU - Lui G Forni
PY - 2026
DA - 2026/10/21
JO - Critical care explorations
DO - 10.1097/cce.0000000000001496
UR - https://europepmc.org/article/MED/42902572
AB - Objectives 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 (Effect of Early Vasopressin vs. Norepinephrine on Kidney Failure in Patients with Septic Shock [VANISH]).Setting ICUs across the United Kingdom.Patients One hundred seventy-three patients admitted to ICU with septic shock.Interventions Norepinephrine vs. vasopressin and hydrocortisone vs. placebo.Measurements and main results PENK 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%).Conclusions 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.
SN - 2639-8028
ER -