Abstract. 
Importance: The optimal vasopressor dose at which to initiate a second vasopressor in patients with septic shock is uncertain.
Objective: To compare the effects of hospital-level strategies initiating vasopressin infusion at a lower threshold vs a higher threshold on outcomes in patients with septic shock.
Design, setting, and participants: Cluster-randomized, cluster-crossover, pragmatic clinical strategy trial including adult patients receiving vasopressors for septic shock at 13 hospitals in Idaho and Utah from February 1, 2024, to July 31, 2025. The last day of follow-up for the primary outcome was February 17, 2026.
Intervention: Hospital-level implementation of septic shock management strategies recommending fixed-dose vasopressin initiation when the total dose of other vasopressors reached 0.1 µg/kg/min of norepinephrine or equivalent (lower-threshold strategy) or when the total dose of other vasopressors reached 0.4 µg/kg/min of norepinephrine or equivalent (higher-threshold strategy). Hospitals were randomized for the first month to an initial strategy (6 hospitals to the lower threshold vs 7 hospitals to the higher threshold) and then crossed over to the alternate strategy monthly thereafter.
Main outcomes and measures: The primary outcome of 28-day mortality and the key secondary outcome of kidney replacement therapy-free days through day 28 were analyzed using multivariable generalized linear mixed-effects models, accounting for trial site and baseline patient characteristics.
Results: There were 3959 unique patients with septic shock (median age, 68 [IQR, 57 to 77] years; 1903 [48%] were female). Of the patients more likely to experience differential management under the tested hospital-level vasopressin dose strategies (maximum vasopressor dose ≥0.07 µg/kg/min of norepinephrine or equivalent), 1034 of 1521 (68.0%) cared for under the lower-threshold strategy received vasopressin compared with 651 of 1526 (42.7%) cared for under the higher-threshold strategy. In the hospital-level strategy recommending a lower-dose threshold for vasopressin initiation, the maximum vasopressor dose received prior to vasopressin initiation was a median of 0.14 (IQR, 0.10 to 0.22) µg/kg/min of norepinephrine or equivalent vs 0.34 (IQR, 0.16 to 0.42) µg/kg/min of norepinephrine or equivalent in the hospital-level strategy recommending a higher-dose threshold for vasopressin initiation. Mortality at 28 days occurred in 628 of 1975 patients (31.8%) treated with the hospital-level strategy recommending initiation of vasopressin at a lower-dose threshold of other vasopressors vs 655 of 1984 patients (33.0%) treated with the higher-threshold strategy (adjusted marginal odds ratio, 0.98 [95% CI, 0.87 to 1.06], P = .62; adjusted risk difference, -0.4 [95% CI, -2.7 to 1.3] percentage points). Patients in both strategies for vasopressin initiation had a median of 29 (IQR, -1 to 29) kidney replacement therapy-free days (adjusted marginal odds ratio, 1.01 [95% CI, 0.91 to 1.14]).
Conclusions and relevance: In this large, pragmatic clinical trial comparing the effectiveness of 2 hospital-level strategies for second-line vasopressor management in septic shock, a strategy recommending initiation of vasopressin at a lower dose of other vasopressors did not reduce 28-day mortality compared with a strategy recommending vasopressin initiation at a higher dose of other vasopressors.
Trial registration: ClinicalTrials.gov Identifier: NCT06217562.
