Association of Early Norepinephrine Administration With 24-Hour Mortality Among Patients With Blunt Trauma and Hemorrhagic Shock

Abstract

Importance: Hemorrhagic shock is a common cause of preventable death after injury. Vasopressor administration for patients with blunt trauma and hemorrhagic shock is often discouraged.

Objective: To evaluate the association of early norepinephrine administration with 24-hour mortality among patients with blunt trauma and hemorrhagic shock.

Design, setting, and participants: This retrospective, multicenter, observational cohort study used data from 3 registries in the US and France on all consecutive patients with blunt trauma from January 1, 2013, to December 31, 2018. Patients were alive on admission with hemorrhagic shock, defined by prehospital or admission systolic blood pressure less than 100 mm Hg and evidence of hemorrhage (ie, prehospital or resuscitation room transfusion of packed red blood cells, receipt of emergency treatment for hemorrhage control, transfusion of >10 units of packed red blood cells in the first 24 hours, or death from hemorrhage). Blunt trauma was defined as any exposure to nonpenetrating kinetic energy, collision, or deceleration. Statistical analysis was performed from January 15, 2021, to February 22, 2022.

Exposure: Continuous administration of norepinephrine in the prehospital environment or resuscitation room prior to hemorrhage control, according to European guidelines.

Main outcomes and measures: The primary outcome was 24-hour mortality, and the secondary outcome was in-hospital mortality. The average treatment effect (ATE) of early norepinephrine administration on 24-hour mortality was estimated according to the Rubin causal model. Inverse propensity score weighting and the doubly robust approach with 5 distinct analytical strategies were used to determine the ATE.

Results: A total of 52 568 patients were screened for inclusion, and 2164 patients (1508 men [70%]; mean [SD] age, 46 [19] years; median Injury Severity Score, 29 [IQR, 17-36]) presented with acute hemorrhage and were included. A total of 1497 patients (69.1%) required emergency hemorrhage control, 128 (5.9%) received a prehospital transfusion of packed red blood cells, and 543 (25.0%) received a massive transfusion. Norepinephrine was administered to 1498 patients (69.2%). The 24-hour mortality rate was 17.8% (385 of 2164), and the in-hospital mortality rate was 35.6% (770 of 2164). None of the 5 analytical strategies suggested any statistically significant association between norepinephrine administration and 24-hour mortality, with ATEs ranging from -4.6 (95% CI, -11.9 to 2.7) to 2.1 (95% CI, -2.1 to 6.3), or between norepinephrine administration and in-hospital mortality, with ATEs ranging from -1.3 (95% CI, -9.5 to 6.9) to 5.3 (95% CI, -2.1 to 12.8).

Conclusions and relevance: The findings of this study suggest that early norepinephrine infusion was not associated with 24-hour or in-hospital mortality among patients with blunt trauma and hemorrhagic shock. Randomized clinical trials that study the effect of early norepinephrine administration among patients with trauma and hypotension are warranted to further assess whether norepinephrine is safe for patients with hemorrhagic shock.

Figure 1.. Flow Diagram of Study Participation

RACSTC indicates R Adams Cowley Shock Trauma Center; and TRENAU, Trauma System of the Northern French Alps Emergency Network.

Figure 2.. Average Treatment Effect (ATE) Estimation of Association of Norepinephrine With 24-Hour Mortality

Model 1: ATE estimation in the combined US and French cohort with no correction. Model 2: ATE estimation in the combined US and French cohort through regression adjustment. Model 3: weighted regression adjustment for all untreated patients and US patients weighted according to their similarity with untreated French patients. Model 4: ATE estimation in the US cohort matching each US patient with a treated French patient with similar baseline confounders combined with ATE estimate in the French cohort to generate a global ATE in the combined cohorts (US and French). Model 5: ATE in the US cohort matching each US patient with a treated French patient with a similar probability of belonging to the US cohort given confounders combined with ATE estimate in the French cohort to generate a global ATE in the combined cohorts (US and French). Models used the doubly robust approach and multivariate imputation by chained equations.

Figure 3.. Average Treatment Effect (ATE) Estimation of Association of Norepinephrine With In-Hospital Mortality

Model 1: ATE estimation in the combined US and French cohort with no correction. Model 2: ATE estimation in the combined US and French cohort through regression adjustment. Model 3: weighted regression adjustment for all untreated patients and US patients weighted according to their similarity with untreated French patients. Model 4: ATE estimation in the US cohort matching each US patient with a treated French patient with similar baseline confounders combined with ATE estimate in the French cohort to generate a global ATE in the combined cohorts (US and French). Strategy 5: ATE estimate in the US cohort matching each US patient with a treated French patient with a similar probability of belonging to the US cohort given confounders combined with ATE estimate in the French cohort to generate a global ATE in the combined US and French cohorts. Models used the doubly robust approach and multivariate imputation by chained equations.