Background: Autologous free-flap reconstruction has transformed reconstructive surgery, restoring form and function in complex head, neck, breast, and limb defects. Maintaining stable perfusion during surgery is essential, yet the choice of vasopressor remains controversial. Surgeons have long feared that α-adrenergic vasoconstriction might jeopardise microcirculation, despite increasing evidence to the contrary. Whether specific vasopressor classes differ in their impact on flap survival has remained uncertain. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO-registered). Eligible randomised controlled trials and observational cohort studies compared perioperative phenylephrine (pure α-agonist) with mixed α/β-agonists (norepinephrine or ephedrine) in adult free-flap surgery. Primary outcomes were flap failure and surgical revision for microvascular compromise; secondary outcomes included thrombosis. Pooled estimates were calculated using random-effects models. Results: Nine studies (two randomised controlled trials [RCTs], seven cohorts) comprising 7181 patients and 8626 flaps were included. Overall flap failure was low (3%), but norepinephrine was associated with higher failure (6%) compared to phenylephrine (2%) and ephedrine (2%). Surgical revision occurred in 12% overall, with norepinephrine again higher (15%) versus phenylephrine (2%). Thrombosis occurred in 7% overall, most frequently with norepinephrine (11%). Sensitivity analyses confirmed the robustness of these findings, though heterogeneity was high and publication bias could not be excluded. Conclusions: In contemporary free-flap surgery, vasopressors are not uniformly harmful – but choice may matter. Phenylephrine and ephedrine were associated with fewer surgical revisions and thrombotic events compared to norepinephrine. While absolute differences in flap failure were small, the higher complication rates with norepinephrine warrant caution, and agent selection should be individualised. Further randomised trials are needed to refine hemodynamic management strategies in microvascular reconstruction.
