Non-adrenergic vasopressors for vasodilatory shock or perioperative vasoplegia: a meta-analysis of randomized controlled trials

Background: Excessive exposure to adrenergic vasopressors may be harmful. Non-adrenergic vasopressors may spare adrenergic agents and potentially improve outcomes. We aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of non-adrenergic vasopressors in adult patients receiving vasopressor therapy for vasodilatory shock or perioperative vasoplegia. Methods: We searched PubMed, Embase, and Cochrane Library for RCTs comparing non-adrenergic vasopressors with adrenergic vasopressors alone or placebo in critically ill or perioperative patients. Each eligible study was categorized into septic shock, cardiac surgery, or non-cardiac surgery. Non-adrenergic vasopressors included vasopressin, terlipressin, selepressin, angiotensin II, methylene blue, and hydroxocobalamin. The primary outcome was mortality at longest follow-up. We conducted a random-effects meta-analysis. We registered the protocol in PROSPERO International Prospective Register of Systematic Reviews (CRD42024505039). Results: Among 51 eligible RCTs totaling 5715 patients, the predominant population was septic shock in 30 studies, cardiac surgery in 11 studies, and non-cardiac surgery in 10 studies. Cochrane risk-of-bias tool for randomized trials version 2 identified 17 studies as low risk of bias. In septic shock, mortality was significantly lower in the non-adrenergic group (960/2232 [43%] vs. 898/1890 [48%]; risk ratio [RR], 0.92; 95% confidence interval [95% CI], 0.86–0.97; P = 0.03; I2 = 0%), with none of the individual non-adrenergic vasopressors showing significant survival benefits. No significant mortality difference was observed in patients undergoing cardiac surgery (34/410 [8.3%] vs. 47/412 [11%]; RR, 0.82; 95% CI, 0.55–1.22; P = 0.32; I2 = 12%) or those undergoing non-cardiac surgery (9/388 [2.3%] vs. 18/383 [4.7%]; RR, 0.66; 95% CI, 0.31–1.41; P = 0.28; I2 = 0%). Conclusions: Administration of non-adrenergic vasopressors was significantly associated with reduced mortality in patients with septic shock. However, no single agent achieved statistical significance in separate analyses. Although the pooled effects of non-adrenergic vasopressors on survival did not reach statistical significance in patients undergoing cardiac or non-cardiac surgery, the confidence intervals included the possibility of both no effect and a clinically important benefit from non-adrenergic agents. These findings justify the conduct of further RCTs comparing non-adrenergic vasopressors to usual care based on noradrenaline alone.