Early norepinephrine for patients with septic shock: an updated systematic review and meta-analysis with trial sequential analysis

Abstract

Background: The optimal timing for initiating norepinephrine in septic shock is debated. This updated systematic review and meta-analysis aimed to evaluate the impact of early versus delayed norepinephrine initiation on mortality and clinical outcomes in adults with septic shock.

Methods: A systematic search in Pubmed, EMbase and the Cochrane Library to identify eligible randomized controlled trials, propensity score matching (PSM) and observational studies that compare early norepinephrine initiation with non-early norepinephrine initiation in patients with acute circulatory failure. The primary outcome was mortality in intensive care unit. Secondary outcomes included intensive care unit length of stay, fluid volume received at 6 h, norepinephrine dose, mechanical ventilation-free days, renal replacement therapy free days, and time to achieve a targeted mean arterial pressure (MAP). Meta-analysis and subgroup analysis were conducted to calculate odds ratio (OR) or mean difference with 95% confidence interval (95%CI) using random-effect model. Trial sequential analysis was conducted to evaluate the conclusiveness of evidence.

Results: Ten studies (two RCT, three PSM and five observational studies) involving 4767 patients were included. Early norepinephrine significantly reduced mortality in RCT (OR 0.49, 95%CI 0.25-0.96; I² = 45%, p = 0.04), pooled RCT and PSM (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%). The trial sequential analysis indicated more data are needed. Subgroup analyses showed reduced mortality with early norepinephrine when lactate was ≤ 3mmol/L and administered within 1 h. Secondary outcomes showed a reduced fluid volume at 6h (RCT + PSM: mean difference -502 mL, 95%CI -899 to -106; I² = 91%, p = 0.01), faster MAP target achievement (RCT + PSM: mean difference -1.30h, 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 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 compare to the non-early initiation group.

Conclusion: Early norepinephrine introduction in septic shock is associated with reduced mortality, decreased fluid volume administered at 6 h, faster time to achieve MAP target and more mechanical ventilation-free days. However, the trial sequential analysis indicates that further RCT are still needed to confirm these findings.

Keywords: Acute circulatory failure; Fluids; Hemodynamic; Timing; Vasopressor.

Fig. 1

Flowchart of literature selection

Fig. 2

Forest plot for mortality in (A) RCT and PSM studies, or in (B) observational studies. NE: Norepinephrine; PSM: propensity score matched; RCT: randomized control trial

Fig. 3

Trial sequential analysis for mortality. The cumulative Z-curve neither crossed the futility boundary nor reached the required information size, suggesting insufficient evidence and inconclusive result. A diversity-adjusted required information size of 8 251 patients was calculated. NE: norepinephrine; RIS: required information size

Fig. 4

Forest plot for mortality in different subgroups depending on (A) lactate level and (B) timing of initiation of norepinephrine. NE: Norepinephrine