Effect of Vasopressin Initiation Threshold on Septic Shock Mortality: The VASSPR Cluster Crossover Randomized Strategy Trial

Summary

VASSPR was a pragmatic, open-label, cluster-randomized cluster-crossover strategy trial across 13 US hospitals involving 3,959 adults receiving vasopressors for septic shock. Hospitals alternated between recommending fixed-dose vasopressin 0.03 U/min when other vasopressors reached 0.1 versus 0.4 micrograms/kg/min norepinephrine-equivalent. Twenty-eight-day mortality was 31.8% versus 33.0% (adjusted marginal OR 0.98, 95% CI 0.87-1.06; adjusted risk difference -0.4 percentage points, 95% CI -2.7 to 1.3), with no difference in kidney replacement therapy-free days.

Why it matters

A policy of routinely adding vasopressin at a much lower norepinephrine-equivalent threshold did not improve mortality. The trial argues against assuming a universal early threshold is superior, while leaving clinician-specific vasopressin use and the optimal threshold unresolved.

Main findings

• 28-day mortality: 628/1975 (31.8%) with the lower-threshold strategy versus 655/1984 (33.0%) with the higher-threshold strategy; adjusted marginal OR 0.98 (95% CI 0.87-1.06), adjusted risk difference -0.4 percentage points (95% CI -2.7 to 1.3).
• Kidney replacement therapy-free days through day 28 were a median of 29 in both groups.
• Among patients reaching at least 0.07 micrograms/kg/min norepinephrine-equivalent, vasopressin was given to 68.0% versus 42.7%, demonstrating meaningful strategy separation.
• Persistent or new cardiogenic shock occurred in 7.4% versus 6.3% (adjusted marginal OR 1.19, 95% CI 1.01-1.42); this was exploratory and not adjusted for multiple comparisons.

Limitations

The intervention was an open-label hospital strategy rather than mandated patient-level treatment, and strict strategy adherence was imperfect. The 13 hospitals were within two US states, and the possible increase in cardiogenic shock with the lower-threshold strategy was an exploratory safety finding without multiplicity adjustment.