Lower Vasopressin Initiation Threshold Does Not Reduce 28-Day Mortality in Septic Shock

A hospital-level strategy of starting vasopressin at a lower dose of other vasopressors did not reduce 28-day mortality in patients with septic shock, compared with a higher-threshold strategy. The results come from the Vasopressin for Septic Shock Pragmatic (VASSPR) trial, published online in JAMA.

The investigators noted that the optimal vasopressor dose at which to start a second vasopressor in septic shock is uncertain. The cluster-randomized, cluster-crossover, pragmatic trial enrolled adults receiving vasopressors for septic shock at 13 hospitals in Idaho and Utah from February 2024 to July 2025. Hospitals used strategies recommending fixed-dose vasopressin (0.03units/min) once the total dose of other vasopressors reached either 0.1µg/kg/min of norepinephrine or equivalent or 0.4µg/kg/min. Hospitals switched strategies monthly.

The trial included 3959 patients (median age, 68 years; 48% female). Mortality at 28 days was 31.8% with the lower-threshold strategy and 33.0% with the higher-threshold strategy (adjusted marginal odds ratio, 0.98; 95% CI, 0.87-1.06; P = 0.62). Patients under both strategies had a median of 29 kidney replacement therapy–free days, the key secondary outcome.

The two strategies did lead to different vasopressin use. Among patients whose maximum vasopressor dose was at least 0.07µg/kg/min of norepinephrine or equivalent, 68.0% under the lower threshold received vasopressin, compared with 42.7% under the higher threshold. Persistent or new-onset cardiogenic shock was possibly more common with the lower threshold (7.4% vs 6.3%). However, the investigators said this analysis was exploratory and not adjusted for multiple testing.

The authors noted that the trial allowed clinician discretion, crossover, and imperfect adherence, so it is unknown whether strictly enforced thresholds would have produced different results. They also said the 95% CI for the adjusted risk difference (−2.7 to 1.3 percentage points) does not rule out a small difference in 28-day mortality. The results may not apply to less integrated health systems or resource-limited care settings.

Source: Peltan ID, Groat D, Jacobs JR, et al. Effect of vasopressin initiation threshold on septic shock mortality: the VASSPR cluster crossover randomized strategy trial. JAMA. Published online October 14, 2026. doi:10.1001/jama.2026.21333