BACKGROUND: Vasopressor administration at an appropriate time is crucial, but the optimal timing remains controversial.

RESEARCH QUESTION: Does early vs late norepinephrine administration impact the prognosis of septic shock?

STUDY DESIGN AND METHODS: Searches were conducted in PubMed, EMBASE, the Cochrane Library, and KMbase databases. 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.

RESULTS: Twelve 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.

INTERPRETATION: Overall 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.

Specialty	Relevance to Practice	Is this News?	Score
Infectious Disease
Hospital Doctor/Hospitalists
Internal Medicine
Intensivist/Critical Care

Infectious Disease rater

The lack of observed difference suggest that, if needed, there is value to the late use. Unfortunately, the definition of late and early varies (indeed, it is not disclosed for every study) making interpretation difficult.

Infectious Disease rater

This is more confirming evidence of the harms caused by fixed (and excessive) administration of IV fluids in septic shock. Highly relevant for clinical practice.

Intensivist/Critical Care rater

Not a helpful meta-analysis for clinical practice.

Internal Medicine rater

If I understand the methods correctly, this was not the actual topic of randomization; if a subgroup analysis, this is hypothesis-generating only.