Septic shock remains one of the primary causes of intensive care admissions and mortality worldwide. For decades, clinicians have debated the role of adjunctive hydrocortisone in septic shock, particularly because clinical trials have reported conflicting outcomes regarding survival and organ recovery. A post hoc analysis of the landmark VANISH trial now provides novel insight into this heterogeneity. By evaluating Proenkephalin A (PENK), a sensitive plasma biomarker of acute renal function, researchers discovered that baseline renal impairment profoundly alters patient response to corticosteroids.

The Challenge of Hydrocortisone in Septic Shock

Historically, major clinical trials evaluating corticosteroid therapy in severe infection have yielded discordant results. While some landmark studies demonstrated faster vasopressor weaning, others revealed negligible mortality benefits alongside increased risks of secondary infection and metabolic disturbance. Consequently, international guidelines recommend adjunctive corticosteroids only for refractory vasopressor-dependent shock. However, this blanket approach treats all septic patients as a biologically uniform cohort. In reality, sepsis encompasses substantial clinical and immunologic heterogeneity. Sepsis pathophysiology involves complex interactions between vascular collapse, endothelial injury, immune dysregulation, and multi-organ failure. The kidneys play an essential role during this cascade because they regulate fluid balance, clear inflammatory mediators, and metabolize active medications. Impaired baseline renal clearance can significantly alter corticosteroid pharmacokinetics and tissue distribution. Furthermore, severe renal tubular injury alters systemic immune responsiveness and cytokine clearance. Therefore, applying standard corticosteroid regimens without considering organ-specific baseline physiology may explain why clinical trials produce divergent results. Clinicians urgently require validated predictive biomarkers to identify which biological subphenotypes derive benefit and which experience harm from steroid administration. Consequently, stratifying patients based on specific end-organ biomarkers could transform sepsis management from generalized protocols into precision critical care.

Proenkephalin A as an Objective Marker of Kidney Injury

Traditional markers of renal function, specifically serum creatinine and urine output, possess notable limitations in the acute intensive care setting. Serum creatinine reflects changes with substantial latency, and aggressive fluid resuscitation often dilutes its concentration. Moreover, muscle wasting, sepsis-induced catabolism, and altered hepatic metabolism in critically ill patients frequently skew creatinine readings. In contrast, Proenkephalin A (PENK) offers an objective, real-time assessment of glomerular filtration. PENK is an endogenous, stable precursor peptide identical to enkephalin opioids that circulates freely in blood. Because the glomerulus exclusively filters PENK without significant tubular reabsorption, circulating concentrations inversely correlate with true glomerular filtration rate. Furthermore, systemic inflammation, muscle breakdown, and active infection do not alter PENK levels. As a result, PENK serves as an unconfounded indicator of acute kidney injury and renal reserve during critical illness. In the VANISH sub-study, investigators established a threshold of 89 pmol/L to stratify patients. Patients exhibiting PENK concentrations above this cutoff faced a more than threefold increase in 28-day mortality. Thus, elevated PENK identifies a high-risk cohort characterized by severe underlying renal insult before overt clinical failure manifests.

Interaction Between PENK and Hydrocortisone in the VANISH Trial

The VANISH trial originally randomized 173 septic shock patients across United Kingdom intensive care units in a factorial design comparing vasopressin with norepinephrine, and hydrocortisone with placebo. In this exploratory post hoc investigation, researchers evaluated whether baseline PENK influenced response to these interventions. Notably, the type of vasopressor showed no statistical interaction with PENK concentrations. However, a striking and unexpected interaction emerged between PENK concentrations and hydrocortisone therapy among 111 patients reaching the maximum vasopressor dose. Specifically, patients with low baseline PENK (below 89 pmol/L) who received hydrocortisone demonstrated favorable outcomes, preserving a median of 28 kidney failure-free days. In contrast, patients with high baseline PENK who received hydrocortisone experienced profound renal worsening, achieving a median of only 11 kidney failure-free days compared to 26 days in high-PENK placebo recipients. Furthermore, high-PENK patients receiving hydrocortisone suffered the highest 28-day mortality at 50 percent, compared to 32 percent in the placebo cohort. Conversely, in low-PENK patients, hydrocortisone lowered mortality from 24 percent to 14 percent. Consequently, these findings suggest that baseline renal status fundamentally modifies the therapeutic trajectory of corticosteroids.

Biological Mechanisms Underlying Steroid-Induced Renal Divergence

Understanding why hydrocortisone might harm patients with preexisting renal dysfunction requires examining steroid biology and kidney hemodynamics. Corticosteroids exert broad biological actions through mineralocorticoid and glucocorticoid receptors. In patients with preserved renal function, hydrocortisone restores vascular tone, blunts overwhelming cytokine storms, and stabilizes endothelial membranes. These actions improve systemic perfusion pressure and support microvascular renal blood flow. In stark contrast, when kidneys experience severe ischemic or endotoxic tubular damage, cellular responsiveness shifts dramatically. Under severe renal stress, corticosteroids can exacerbate tubular oxidative injury, induce cellular catabolism, and promote excessive fluid retention. In addition, the kidney metabolizes and clears steroid metabolites; severe renal impairment alters free cortisol levels, precipitating sustained supraphysiologic tissue toxicity. Furthermore, corticosteroids may suppress essential reparative macrophage phenotypes necessary for tubular re-epithelialization following acute injury. Therefore, administering high-dose hydrocortisone to an already decompensated nephron bed may impair intrinsic regenerative mechanisms. As a result, hydrocortisone appears protective in intact kidneys but detrimental when renal failure is already underway.

Translating Biomarker Phenotypes into Clinical Practice

These findings carry substantial implications for future clinical trials and individualized bedside management in intensive care units. Currently, international guidelines promote a uniform approach, administering hydrocortisone whenever septic shock requires ongoing vasopressor support. However, this one-size-fits-all paradigm ignores crucial subphenotypic divergence. If prospective trials confirm these exploratory findings, routine point-of-care biomarker testing could safeguard vulnerable patients from harm. For instance, bedside measurement of PENK upon ICU admission could divide patients into distinct actionable categories. Clinicians could confidently administer hydrocortisone to patients with low PENK levels, knowing that anti-inflammatory support protects kidney function and reduces mortality. Conversely, intensivists might deliberately withhold hydrocortisone in patients with elevated PENK, choosing alternative strategies such as early renal replacement therapy or specialized decatecholaminisation protocols. In countries like India, where sepsis and acute kidney injury burden critical care units heavily, biomarker-guided therapies could dramatically optimize healthcare resources. Nonetheless, clinicians must treat this post hoc analysis as hypothesis-generating. Independent prospective randomized trials must validate these findings before altering current international protocols.

Frequently Asked Questions

What is Proenkephalin A and why is it important in septic shock?

Proenkephalin A is a stable precursor peptide that serves as an accurate surrogate for endogenous enkephalin opioids. Because glomeruli freely filter it without tubular reabsorption or secretion, plasma concentrations correlate closely with glomerular filtration rate. Unlike traditional creatinine, acute inflammation, age, and muscle wasting do not confound proenkephalin measurements. Consequently, it rapidly identifies acute kidney injury and predicts mortality in septic shock patients long before serum creatinine levels rise noticeably.

Why did hydrocortisone worsen renal outcomes in high-PENK patients?

Elevated baseline proenkephalin levels indicate established acute renal impairment and compromised microvascular reserves. In damaged renal tissue, corticosteroids can induce excessive catabolism, increase tubular oxidative stress, and impair cellular repair mechanisms. Furthermore, impaired kidneys clear steroid metabolites more slowly, leading to supraphysiologic systemic accumulation and worsened tissue injury. Consequently, rather than stabilizing the vasculature, hydrocortisone administration in severely compromised kidneys appears to exacerbate cellular damage, markedly reducing kidney failure-free days and increasing patient mortality.

Should clinicians stop using hydrocortisone in septic shock based on these results?

Clinicians should not immediately alter current guidelines because these findings stem from an exploratory post hoc analysis with a modest sample size. Present Surviving Sepsis Campaign guidelines continue to recommend low-dose hydrocortisone for vasopressor-refractory septic shock. However, these data highlight critical biological heterogeneity and signal potential harm in patients with early renal failure. Therefore, intensive care teams must await prospective randomized validation before routinely using proenkephalin to guide corticosteroid prescribing.

Disclaimer: This content is for informational and educational purposes only. It is not intended to substitute professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or treatment. Refer to the latest local and national guidelines for clinical practice.

References

1. Antcliffe DB et al. Proenkephalin A and Heterogeneity of Hydrocortisone Treatment Effect in Septic Shock: A Post Hoc Analysis of the VANISH Trial. Crit Care Explor. 2026 Oct 01. doi: 10.1097/CCE.0000000000001496. PMID: 42902572.
2. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016;316(5):509-518.
3. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.
4. Caironi P, Latini R, Struck J, et al. Circulating Proenkephalin, Acute Kidney Injury, and Its Improvement in Patients with Severe Sepsis or Septic Shock. Clin Chem. 2018;64(9):1361-1369.