Pharmacological mechanisms and clinical evidence of vasopressin, steroids, and epinephrine triple therapy in in-hospital cardiac arrest.

In-hospital cardiac arrest carries a hospital discharge survival rate of 22.6% in high-income settings, a figure unchanged over the past decade. Epinephrine reliably promotes return of spontaneous circulation (ROSC) but does not consistently improve neurologically intact survival. This limitation motivated the development of the vasopressin, steroids, and epinephrine (VSE) combination. This review examines the pharmacological rationale underpinning VSE and evaluates the clinical evidence across randomised trials, individual participant data analyses, and network meta-analyses. Vasopressin contributes V1a receptor-mediated vasoconstriction independent of adrenergic receptor status. Intra-arrest methylprednisolone enhances vascular reactivity and attenuates post-ROSC vasopressor requirements. Post-resuscitation hydrocortisone targets critical illness-related corticosteroid insufficiency, constituting a two-phase steroid strategy that defines the full Mentzelopoulos protocol. Pooled analysis of three randomised trials enrolling 869 patients assigns moderate certainty to the ROSC benefit and low certainty to survival and neurological outcome endpoints. A network meta-analysis of 36 trials enrolling 21,768 patients ranked VSE above all comparators for haemodynamic outcomes while leaving neurological endpoints unresolved. Individual patient data reanalysis identifies an independent protective effect of the corticosteroid component against post-resuscitation septic shock. The dissociation between ROSC and neurological recovery reflects insufficient statistical power for hard endpoints, protocol differences between trials, compartmentalised neuroinflammation only partially accessible to circulating glucocorticoids, and epinephrine-mediated cerebral microcirculatory impairment. The 2025 American Heart Association, European Resuscitation Council, and International Liaison Committee on Resuscitation guidelines do not recommend routine VSE during in-hospital cardiac arrest. Adequately powered trial evidence on patient-centred outcomes remains pending. Patient phenotype stratification and factorial trial design represent the most promising directions for future investigation.