ESICM LIVES 2026: VASSPR Trial: When Should We Add Vasopressin in Septic Shock? Should vasopressin be introduced early during norepinephrine escalation, or should we wait until higher vasopressor requirements develop? The VASSPR trial, presented by Ithan Peltan, addressed this important question in septic shock management. Vasopressin is frequently added to norepinephrine to restore vascular tone and reduce catecholamine exposure. However, the optimal threshold for its initiation remains uncertain. The VASSPR trial investigated whether recommending vasopressin initiation at lower vasopressor doses improves clinical outcomes compared with a higher threshold. This pragmatic, cluster crossover randomized trial involved 3,959 patients across 13 hospitals, comparing two hospital-level strategies. The lower-threshold strategy recommended introducing vasopressin when norepinephrine equivalent doses reached 0.1 µg/kg/min, while the higher-threshold strategy recommended initiation at 0.4 µg/kg/min. What did the trial demonstrate? At 28 days, all-cause mortality was 31.8% in the lower-threshold group compared with 33.0% in the higher-threshold group. The adjusted odds ratio was 0.98 (95% CI 0.87-1.06), with an adjusted absolute risk difference of -0.4 percentage points (95% CI -2.7 to 1.3). Earlier vasopressin initiation recommendations did not demonstrate a mortality benefit. These findings challenge the assumption that earlier addition of a second vasopressor necessarily improves survival. From a physiological perspective, vasopressin addresses vascular dysfunction through mechanisms distinct from adrenergic stimulation. Nevertheless, correcting vasoplegia through additional pharmacological pathways does not automatically translate into improved outcomes. Importantly, VASSPR evaluated hospital-level recommendations rather than mandatory individualized treatment thresholds. It should not be interpreted as evidence that all patients should wait until norepinephrine reaches 0.4 µg/kg/min. The absence of an overall mortality benefit also does not exclude advantages in selected haemodynamic phenotypes. For clinical practice, the findings reinforce the importance of individualizing vasopressor therapy according to vascular tone, perfusion, cardiovascular function and the evolution of shock. The future of septic shock management may depend less on universal vasopressor thresholds and more on identifying which patients benefit from each intervention. #ESICM #LIVES2026 #SepticShock #Vasopressin #Hemodynamics #CriticalCare #IntensiveCare