• Chiwon Ahn, Gina Yu, Tae Gun Shin, Youngsuk Cho, Sunghoon Park, and Gee Young Suh.
• Department of Emergency Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea.
• Chest. 2024 Jul 5.

BackgroundVasopressor administration at an appropriate time is crucial, but the optimal timing remains controversial.Research QuestionDoes early vs late norepinephrine 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 an early and late norepinephrine 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 ICU, days free from ventilator use, days free from renal replacement therapy, days free from vasopressor use, adverse events, and total fluid volume.ResultsTwelve studies (four randomized controlled trials [RCTs] and eight observational studies) comprising 7,281 patients were analyzed. For overall mortality, no significant difference was found between the early norepinephrine group and late norepinephrine group in RCTs (OR, 0.70; 95% 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 IV fluid volumes, the early norepinephrine group showed significantly lower mortality than the late norepinephrine group (OR, 0.49; 95%, CI, 0.25-0.96). The early norepinephrine group demonstrated more mechanical ventilator-free days in observational studies (mean difference, 4.06; 95% CI, 2.82-5.30). The incidence of pulmonary edema was lower in the early norepinephrine 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 norepinephrine administration for septic shock. However, early norepinephrine administration seemed to reduce pulmonary edema incidence, and mortality improvement was observed in studies without fluid restriction interventions, favoring early norepinephrine use.Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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