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

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.