Comparison of Early and Late Norepinephrine Administration in Patients With Septic Shock: A Systematic Review and Meta-analysis

Abstract

BACKGROUNDVasopressor administration at an appropriate time is crucial but the optimal timing remains controversial. RESEARCH QUESTIONDoes early versus late norepinephrine (NE) administration impact the prognosis of septic shock? STUDY DESIGN AND METHODSSearches were conducted on PubMed, EMBASE, the Cochrane Library, and KMBASE. We included studies of adults with sepsis and categorized patients into early and late NE group according to specific time points or differences in norepinephrine use protocols. The primary outcome was overall mortality. The secondary outcomes included length of stay in the intensive care unit, days free from ventilator use, days free from renal replacement therapy, days free from vasopressor use, adverse events, and total fluid volume. RESULTSTwelve studies (4 randomized controlled trials [RCTs], 8 observational) comprising 7,281 patients were analyzed. For overall mortality, no significant difference was found between the early NE group and late NE group in RCTs (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.41–1.19) or observational studies (OR, 0.83; 95% CI, 0.54–1.29). In the two RCTs without a restrictive fluid strategy that prioritized vasopressors and lower intravenous fluid volumes, the early NE group showed significantly lower mortality than the late NE group (OR 0.49, 95%, CI, 0.25–0.96). The early NE group demonstrated more mechanical ventilator–free days in observational studies (MD, 4.06; 95% CI, 2.82–5.30). The incidence of pulmonary edema was lower in the early NE group in the three RCTs that reported this outcome (OR 0.43; 95% CI, 0.25–0.74). No differences were found in the other secondary outcomes. INTERPRETATIONOverall mortality did not differ significantly between early and late NE administration for septic shock. However, early NE administration appeared to reduce pulmonary edema incidence, and mortality improvement was observed in studies without fluid restriction interventions, favoring early NE use.