When to Press on Vasopressin in Septic Shock Patients

Septic shock continues to challenge intensivists worldwide, with mortality rates that remain high despite ongoing advances in resuscitation and supportive care. Vasopressors remain central to management, with norepinephrine as the first-line agent. Yet the timing of vasopressin initiation has long been debated. Should it be introduced early to reduce catecholamine requirements, or should it be reserved only for patients who reach higher norepinephrine thresholds?

This Concise Critical Appraisal discusses the recent article by Sacha et al published in Critical Care Explorations.¹ The investigators set out to determine how norepinephrine-equivalent dose, lactate concentration, and the interval from shock onset to vasopressin initiation influenced in-hospital mortality among patients with septic shock.

The investigators conducted a large retrospective analysis of two major critical care databases, the Medical Information Mart for Intensive Care IV (MIMIC-IV) and the eICU Collaborative Research Database. Together these databases encompass tens of thousands of ICU admissions across 209 U.S. hospitals, providing a broad snapshot of real-world practice. Within these databases, the investigators identified 1409 adults who met modified Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for septic shock and who required continuous catecholamine infusions. The population reflected the diversity of patients commonly admitted to U.S. intensive care units (ICUs), spanning community and academic centers and including a wide mix of ages, comorbidities, and illness severities.

Overall, in-hospital mortality remained high at roughly 40% to 45%, consistent with other contemporary sepsis cohorts.^2,3 At the time vasopressin was started, the median norepinephrine-equivalent dose was 28.4 µg/min. Mortality risk increased dramatically as norepinephrine requirements rose. Compared with those started on vasopressin at 9 µg/min, patients initiated at 28 µg/min had nearly double the odds of death, and those started at 72 µg/min had nearly four-fold higher odds. Lactate was another potent predictor. A lactate level above 4 mmol/L at initiation carried a particularly poor prognosis, with each 1-mmol/L increase in lactate linked to a 16% higher mortality risk.

Perhaps the most striking finding was what did not matter—the absolute time elapsed from shock onset to vasopressin initiation was not significantly associated with in-hospital mortality after adjusting for severity markers. Whether vasopressin was started within six hours or much later, survival outcomes were essentially unchanged once norepinephrine dose and lactate were considered. Earlier randomized trials of vasopressin, such as VASST and VANISH, reached different conclusions about whether adding vasopressin early improved outcomes.^4,5 Sacha et al suggest that the critical factor is not whether vasopressin is initiated early or late, but rather how sick the patient is at the time it is started. Patients who already require very high norepinephrine doses or have high lactate levels are on a much worse trajectory, and adding vasopressin at that stage may not actually impact mortality.

In summary, what appears to matter most is not the clock but the patient’s physiologic state at the time vasopressin is initiated. Patients who required vasopressin at higher norepinephrine-equivalent doses (>30 µg/min) and patients with lactic acidosis had disproportionately worse outcomes, with mortality exceeding 50%. For clinicians, the lesson is that vasopressin may still have value when added thoughtfully to reduce norepinephrine exposure, but outcomes will be driven by the underlying severity of shock—particularly escalating catecholamine requirements and rising lactate—rather than by arbitrary time cutoffs. Early initiation of vasopressin may still be reasonable to limit catecholamine exposure in carefully selected patients, but this reminds us that critical care remains a practice of nuance and individualized decision-making, even in areas where guidelines provide broad algorithms.


References

1. Sacha GL, Duggal A, Reddy AJ, Wang L, Bauer SR. Vasopressin initiation timing and in-hospital mortality in septic shock: an observational study of large public databases. Crit Care Explor. 2025 Aug 22;7(9):e1284. 
2. 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 Nov 1;49(11):e1063-e1143.
3. Kadri SS, Rhee C, Strich JR, et al. Estimating ten-year trends in septic shock incidence and mortality in United States academic medical centers using clinical data. Chest. 2017 Feb;151(2):278-285. 
4. Russell JA, Walley KR, Singer J, et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-887.
5. Gordon AC, Mason AJ, Thirunavukkarasu N, et al; VANISH Investigators. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA. 2016 Aug 2;316(5):509-518.