LandmarkRCT

VASST

Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock

New England Journal of Medicine, 2008 · Multicenter, randomized, double-blind trial.

Clinical question

In septic shock already requiring norepinephrine, does adding low-dose vasopressin instead of continuing to titrate norepinephrine alone improve mortality?

Population: 778 adults with septic shock already receiving norepinephrine (≥5 μg/min).
Intervention: Low-dose vasopressin infusion added to open-label norepinephrine.
Comparator: Additional norepinephrine alone (vasopressin infusion replaced with more norepinephrine).
Primary outcome: 28-day all-cause mortality.
Result: No significant difference in 28-day mortality overall between vasopressin and norepinephrine-only strategies. (28-day mortality 35.4% (vasopressin) vs 39.3% (norepinephrine), p = 0.26)

What the trial found

Adding vasopressin to norepinephrine did not significantly reduce 28-day mortality compared with norepinephrine alone in the overall trial population. A pre-specified subgroup analysis suggested a possible mortality benefit in patients with less severe shock (lower baseline norepinephrine dose), but subgroup findings in a formally neutral trial are hypothesis-generating, not confirmatory.

Current guideline position

The 2026 Surviving Sepsis Campaign guideline conditionally suggests adding vasopressin in patients with escalating norepinephrine doses, consistent with VASST's design (add-on, not replacement) but without claiming a proven mortality benefit.

Clinical interpretation

VASST is the main trial-level basis for using vasopressin as an add-on agent in septic shock rather than as a norepinephrine replacement, but it did not establish a mortality benefit for the overall population — the rationale for adding it (reducing norepinephrine dose requirements, catecholamine-sparing) is physiologic and practical rather than a demonstrated survival benefit.

Limitations

Overall trial result was neutral for mortality; the less-severe-shock subgroup signal is exploratory.
Excluded patients requiring very high-dose norepinephrine at enrollment.

Moderate certainty

Clinical Context & Relevant Topics (1)

Disease Reference

Septic Shock

The subset of sepsis with profound circulatory and cellular/metabolic abnormality — clinically identified by a vasopressor requirement to maintain MAP ≥ 65 mmHg plus lactate > 2 mmol/L despite adequate fluid resuscitation.

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