Norepinephrine Versus Vasopressin as First-Line Vasopressor Therapy in Septic Shock: Implications for Patients Presenting to the Emergency Department

Background: Septic shock requires rapid restoration of perfusion with infection treatment. Norepinephrine is the recommended initial vasopressor, while vasopressin offers an alternative mechanism of vascular support. This review examines comparative clinical outcomes and their relevance to emergency department treatment. Methods: A systematic review was reported according to PRISMA 2020 guidelines. PubMed, Scopus, Web of Science Core Collection, and Cochrane CENTRAL were searched from inception to May 2026. Two authors independently screened studies, extracted data, and assessed risk of bias, resolving disagreements through consensus. We include comparative studies of adults with septic shock, renal outcomes, hemodynamic responses, and adverse events. Initial and adjunctive treatment comparisons were distinguished, and overlapping trial reports were linked. Results: Ten original articles represented seven independent study populations, including three secondary analyses of VASST. In VASST, involving 778 treated patients, mortality at 28 days was 35.4% with vasopressin and 39.3% with norepinephrine. VANISH enrolled 409 patients and demonstrated no improvement in its primary kidney outcome, despite lower renal replacement therapy use with vasopressin. VANCS II enrolled 250 patients with cancer and found no significant mortality difference. Smaller investigations documented blood pressure responses and selected renal physiological improvements. Differences in treatment timing, concomitant vasopressors, and patient selection restricted direct comparison across studies. Conclusion: Renal and catecholamine-sparing findings support further investigation of selected treatment strategies. Emergency department recommendations remain largely extrapolated from intensive care evidence, with a need for trials specifically evaluating initial vasopressor selection during early emergency resuscitation.