Vasopressors Combination Therapy (Norepinephrine Plus Vasopressin Receptor Agonists) Improve Septic Shock Outcome: A Systematic Review and Meta-Analysis.

BackgroundStudies showed different results of vasopressors combination therapy in septic shock patients. This meta-analysis aimed to evaluate the outcomes of combination of norepinephrine plus vasopressin receptor agonists in adult septic shock.MethodsCochrane Library, Embase, Web of Science, and PubMed databases were searched up to September 27, 2026, to identify randomized controlled trials (RCTs) comparing the combination of norepinephrine plus vasopressin receptor agonists versus norepinephrine alone in septic shock patients. Two reviewers independently extracted data on mortality, ICU length of stay, renal replacement therapy (RRT) and adverse events. Trial sequential analysis (TSA) was applied to assess random error.ResultsTwenty-one RCTs involving 3873 septic shock patients were included. The results showed that the combination of norepinephrine plus vasopressin receptor agonists was associated with lower mortality at the longest complete follow-up compared with norepinephrine alone (RR = 0.90, 95% CI 0.83 to 0.99, P = .02), but with an increased risk of digital ischemia (RR = 2.21, 95% CI 1.15 to 4.27, P = .02). Subgroup analysis indicated that the combination of norepinephrine plus vasopressin receptor agonists may provide survival benefits for more severe septic shock patients (RR = 0.90, 95% CI 0.81 to 1.00, P = .04). Moreover, compared with norepinephrine alone, the combination of norepinephrine plus vasopressin showed a trend towards reducing the longest follow-up mortality (RR = 0.89, 95% CI 0.80 to 1.00, P = .05). TSA indicated lack of firm evidence for a beneficial effect.ConclusionsIn adults with septic shock, the combination of norepinephrine plus vasopressin receptor agonists may reduce mortality at the longest complete follow-up compared with norepinephrine alone (low quality of evidence), but may increase risk of digital ischemia (low quality of evidence). This benefit mainly appeared in more severe septic shock patients. Moreover, norepinephrine plus vasopressin may confer a survival advantage.