Starting Vasopressin Earlier in Septic Shock Did Not Lower 28-Day Mortality. Cardiogenic Shock Was Slightly More Common.
In JAMA's VASSPR trial of 3,959 patients, 28-day mortality was 31.8 percent with a lower vasopressin start threshold and 33.0 percent with a higher one. The confidence interval does not exclude a small difference.
When to add vasopressin to norepinephrine in septic shock has been a bedside judgment call. A pragmatic trial published online Oct. 14 in JAMA suggests that adding it earlier does not change the 28-day death rate.
The Vasopressin for Septic Shock Pragmatic (VASSPR) trial, led by Ithan D. Peltan, was an open-label, cluster-randomized, cluster-crossover strategy trial run in 13 hospitals in Idaho and Utah. Registration is NCT06217562.
What the trial tested
From Feb. 1, 2024, to July 31, 2025, hospitals were assigned by month to one of two recommended strategies, with monthly crossover. In both, vasopressin was given as a fixed 0.03 units per minute infusion as a second vasopressor. The lower-threshold strategy recommended starting it when other vasopressors reached 0.1 µg/kg/min of norepinephrine equivalent. The higher-threshold strategy recommended 0.4 µg/kg/min.
The analysis included 3,959 adults with septic shock receiving vasopressors: 1,975 under the lower threshold and 1,984 under the higher one. Clinicians kept discretion over individual patients. The trial was funded by the Intermountain Foundation, with additional support from the National Center for Advancing Translational Sciences, according to the JAMA research summary and the paper.
The results
Twenty-eight-day all-cause mortality was 31.8 percent (628 of 1,975) with the lower threshold and 33.0 percent (655 of 1,984) with the higher threshold. The adjusted marginal odds ratio was 0.98 (95% CI, 0.87 to 1.06; P = .62), and the adjusted risk difference was -0.4 percentage points (95% CI, -2.7 to 1.3). Median kidney replacement therapy-free days were 29 in both groups. Ninety-day mortality was 37.9 percent and 38.4 percent.
The question was never whether vasopressin works as a second agent. It was whether starting it sooner changes who survives, and this trial says not by much.
Safety and caveats
Persistent or new cardiogenic shock was more common with the lower threshold: 7.4 percent versus 6.3 percent (odds ratio, 1.19; 95% CI, 1.01 to 1.42). The authors describe this as exploratory and not adjusted for multiplicity, and say it was the only safety outcome that differed between strategies. Arrhythmia, cardiac arrest, ischemia and severe hyponatremia did not differ.
The trial was open-label and adherence was imperfect, which blurs the contrast between arms. Across all enrolled patients, vasopressin was given after enrollment to 52.4 percent under the lower threshold and 32.9 percent under the higher threshold, according to the trial's results tables. Stress-dose steroid use was slightly higher in the lower-threshold arm. The authors note that the confidence interval does not exclude a small mortality difference, and generalizability beyond one integrated health system's hospitals is uncertain.
What it means in clinic
For protocols that call for early vasopressin at low norepinephrine doses, the trial gives no evidence of a mortality gain and a faint signal of cardiac cost. Sepsis committees can review whether the threshold in their order set rests on evidence or habit. For another recent JAMA septic shock trial, see our report on adding dobutamine during source-control surgery.
Reported, fact-checked and edited by The Script Pad's editorial staff.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
