Timing of norepinephrine initiation in patients with septic shock: a systematic review and meta-analysis

Background The effect of the timing of norepinephrine initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early and late start of norepinephrine support on clinical outcomes in patients with septic shock. Methods We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of March 2020. We included studies involving adult patients (> 18 years) with septic shock. All authors reported our primary outcome of short-term mortality and clearly comparing early versus late norepinephrine initiation with clinically relevant secondary outcomes (ICU length of stay, time to achieved target mean arterial pressure (>= 65 mmHg), and volume of intravenous fluids within 6 h). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI). Results Five studies including 929 patients were included. The primary outcome of this meta-analysis showed that the short-term mortality of the early group was lower than that of the late group (odds ratio [OR] = 0.45; 95% CI, 0.34 to 0.61;P < 0.00001;chi(2) = 3.74;I-2 = 0%). Secondary outcomes demonstrated that the time to achieved target MAP of the early group was shorter than that of the late group (mean difference = - 1.39; 95% CI, - 1.81 to - 0.96;P < 0.00001;chi(2) = 1.03;I-2 = 0%). The volume of intravenous fluids within 6 h of the early group was less than that of the late group (mean difference = - 0.50; 95% CI, - 0.68 to - 0.32;P < 0.00001;chi(2) = 33.76;I-2 = 94%). There was no statistically significant difference in the ICU length of stay between the two groups (mean difference = - 0.11; 95% CI, - 1.27 to 1.05;P = 0.86;chi(2) = 0.85;I-2 = 0%). Conclusions Early initiation of norepinephrine in patients with septic shock was associated with decreased short-term mortality, shorter time to achieved target MAP, and less volume of intravenous fluids within 6 h. There was no significant difference in ICU length of stay between early and late groups. Further large-scale RCTs are still required to confirm these results.