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The following is a summary of “Early norepinephrine for patients with septic shock: an updated systematic review and meta-analysis with trial sequential analysis,” published in the May 2025 issue of Critical Care by Shi et al. 

Researchers conducted a retrospective study to compare the effects of early vs delayed norepinephrine initiation on mortality and clinical outcomes in adults with septic shock.  

They executed a systematic search of PubMed, Embase, and the Cochrane Library to identify eligible randomized controlled trials (RCT), observational studies, and propensity score matching (PSM) analyses comparing early vs non-early norepinephrine initiation in individuals with acute circulatory failure. The primary outcome was intensive care unit mortality. Secondary outcomes included ICU length of stay (LOS), fluid volume at 6 hours, norepinephrine dose, mechanical ventilation-free days, renal replacement therapy-free days, and time to reach target mean arterial pressure (MAP). Meta-analysis and subgroup analysis were conducted using a random-effects model to estimate the odds ratio (OR) or mean difference with a 95% CI. Trial sequential analysis was used to evaluate the conclusiveness of the evidence.  

The results showed that 10 studies (2 RCTs, 3 PSM studies, and 5 observational studies) involving 4,767 individuals were analyzed. Early norepinephrine significantly reduced mortality in RCTs (OR 0.49, 95% 0.25–0.96; I²  = 45%, P= 0.04), pooled RCT and PSM studies (OR 0.65, 95%CI 0.42–0.99; I²  = 74%, P= 0.05), and observational studies (OR 0.71, 95%CI 0.54–0.94; I²  = 66%). Trial sequential analysis indicated further data was needed. Subgroup analysis showed reduced mortality with early norepinephrine when lactate levels were ≤3 mmol/L and administered within 1 hour. Secondary outcomes included reduced fluid volume at 6 hours (RCT + PSM: mean difference −502 mL, 95%CI −899 to −106; I²  = 91%, P= 0.01), faster MAP target achievement (RCT + PSM: mean difference −1.30 hours, 95%CI −1.75 to −0.85; I² = 0%, P< 0.01), more mechanical ventilation-free days (RCT + PSM: mean difference 3.99 days, 95%CI 2.42–5.57; I² = 32%, P< 0.01), and a smaller cumulative norepinephrine dose (observational: mean difference −3.44 mcg/kg, 95% CI −6.13 to −0.76; I²  = 0%, P= 0.01) in the early initiation group compared to the non-early initiation group.  

Investigators concluded that early norepinephrine administration in septic shock correlated with lower mortality, less fluid administration at 6 hours, quicker achievement of the MAP target, and more ventilator-free days. 

Source: ccforum.biomedcentral.com/articles/10.1186/s13054-025-05400-z