DOI: 10.1097/cce.0000000000001496 ISSN: 2639-8028

Proenkephalin A and Heterogeneity of Hydrocortisone Treatment Effect in Septic Shock: A Post Hoc Analysis of the VANISH Trial

David B. Antcliffe, Florian Uhle, Dominic C. Marshall, Ashleigh D. Green, Anthony C. Gordon, Lui G. Forni
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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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