Effect of timing of norepinephrine application on prognosis of patients with septic shock：a prospective cohort study
Authors: Li Yuting , Guo Jianxing , Li Hongxiang , Wang Youquan , Yang Hongmei , Zhang Dong 
Published: May 2023

Abstract
Background Sepsis and septic shock are major healthcare problems, impacting millions of people around the world each year and killing between one in three and one in six of those it affects. Several studies have demonstrated that early administration of norepinephrine(NE) in septic shock patients may be associated with an increased survival rate. However, the timing from septic shock to NE initiation is controversial.Methods A prospective observational cohort study was conducted in an intensive care unit (ICU) of a tertiary general hospital to examine the relationship between timing of initial NE administration and clinical outcomes of adult patients with septic shock. All enrolled patients were divided into early NE group and late NE group according to whether the time interval from the onset of septic shock to the first application of NE was greater than 1 hour. The primary outcome was 28-day mortality. Secondary outcomes included ICU length of stay, hospital length of stay, time to achieved mean arterial pressure(MAP) ≥ 65 mmHg, 24-hour infusion volume, 6-hour lactate clearance, mechanical ventilation days and continuous renal replacement therapy (CRRT) proportion. Multivariate logistic regression analysis was used to evaluate the independent risk factors for 28-day mortality.Results A total of 120 patients were enrolled in the study. 42 patients (35.0%)were assigned into the early NE group, whereas 78 patients (65.0%)were assigned into the late NE group. The primary outcome demonstrated that the 28-day mortality of early group was lower than that of late group(28.6% vs. 47.4%,P = 0.045). The secondary outcomes showed that the time to achieved MAP ≥ 65 mmHg of early group was shorter than that of late group(1(0.95,2)h vs. 1.5(1,2)h, P = 0.01). The volume of intravenous fluids within 24 h of early group was less than that of late group(3605(2593,4488.75)ml vs. 3930.5(3410.75,5102.5)ml, P = 0.03). The 6-hour lactate clearance rate of early group was higher than that of late group(40.73%(13.42%,55.17%) vs. 14.85%(-33.24%,45.63%),P = 0.009). There were no significant differences between early and late group with respect to ICU length of stay(P = 0.748), hospital length of stay(P = 0.369), mechanical ventilation days(P = 0.128) and CRRT proportion(P = 0.637). Multivariate logistic regression analysis of independent risk factors for 28-day mortality showed that male(OR = 2.894,95%CI 1.157–7.241,P = 0.023), time to achieved MAP ≥ 65 mmHg(OR = 0.433,95%CI 0.259–0.722,P = 0.001) and 6-hour lactate clearance rate (OR = 1.679,95%CI 1.032–2.733,P = 0.037) were independent risk factors for 28-day mortality.Conclusions Initial NE administration ≤ 1h is associated with a decline in 28-day mortality in patients with septic shock. The time to achieved MAP ≥ 65 mmHg is shorter, the volume of intravenous fluids within 24 h is less and the 6-hour lactate clearance rate of early group is higher in early group. Male, time to achieved MAP ≥ 65 mmHg and 6-hour lactate clearance rate are independent risk factors for 28-day mortality.