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

Summary

The VASSPR pragmatic cluster-crossover randomized trial included 3959 patients with septic shock across 13 hospitals and compared hospital strategies for initiating vasopressin at lower versus higher background vasopressor doses. Twenty-eight-day mortality was similar with lower-threshold and higher-threshold strategies, providing important negative evidence against routine early vasopressin initiation solely to improve survival.

Key Findings

• The trial included 3959 unique patients with septic shock across 13 hospitals using a cluster-randomized, cluster-crossover design.
• Twenty-eight-day mortality was 31.8% with the lower-threshold strategy and 33.0% with the higher-threshold strategy; adjusted marginal odds ratio was 0.98 with P=.62.
• Kidney replacement therapy-free days were similar between strategies, with a median of 29 days in both groups.

Clinical Implications

Starting vasopressin at a lower norepinephrine-equivalent dose should not be expected to reduce 28-day mortality compared with later initiation. Vasopressin decisions should instead consider shock trajectory, vasopressor toxicity, cardiac function, regional perfusion, and treatment goals rather than a universal dose threshold.

Limitations

• The intervention was a hospital-level strategy rather than individually randomized vasopressin administration, so treatment adherence and contamination may have influenced effects.
• The trial was conducted in 13 hospitals in Idaho and Utah, which may limit transportability to other health systems and resource settings.

Future Directions

Future research should identify patient subgroups that may benefit from vasopressin, including those with specific vasoplegic phenotypes or high catecholamine exposure. Comparative studies should also examine organ-specific outcomes, adverse events, cost, and long-term functional outcomes.