Differences exist in the recommended use of norepinephrine in blunt trauma and hemorrhagic shock between the U.S. and Europe. In the U.S., norepinephrine use is generally avoided over concern of increased mortality based on findings from multiple retrospective studies. However, European guidelines recommend the use of the pressor to manage bleeding.

To evaluate the association of early norepinephrine administration with 24-hour mortality among patients with blunt trauma and hemorrhagic shock, a retrospective, multicenter, cohort study was performed. This study included three regional trauma system registries—two from France (TraumaBase in Clichy and TRENAL in Grenoble) and one from the U.S (R Adams Cowley Shock Trauma Center [RACSTC] in Baltimore, Maryland).

The inclusion process involved two steps that were developed via Delphi consensus by 15 international trauma experts. Initially, all consecutive patients with trauma who were admitted between January 1, 2013, and December 31, 2018, were screened. Patients were eligible for inclusion in the study if they had hypotension; were aged 18 to 89 years; had sustained an exclusively blunt mechanism of injury; and presented with a prehospital or trauma center admission systolic blood pressure <100 mg Hg with/out norepinephrine use. Patients were excluded if they were aged younger than 18 years, were pregnant, or had sustained prehospital cardiac arrest.

In the second step, all patients with a hemorrhagic situation who required at least one of the following were included: administration of packed red blood cells either prehospital or in the emergency department; need for procedural hemorrhage control (e.g., interventional radiology); massive transfusion of blood product (>10 units of packed red blood cells) during the first 24 hours after admission; or death from hemorrhage.

The two French regional trauma system registries utilized established guidelines during prehospital care, which called for the use of continuous norepinephrine in blunt trauma and hypotensive patients via electrical syringe pumps without any bolus and no other vasopressor or inotrope. The American facility served as the control and did not utilize norepinephrine, prehospital blood products, or tranexamic acid.

Various methods were utilized to address confounding variables and missing data. Inverse propensity scoring was employed to ensure that patients treated or not treated with norepinephrine were evenly distributed. Average Treatment Effect was used to assess the mean association between norepinephrine administration and 24-hour mortality. The Rubin Cause Model, an approach to statistical analysis of cause and effect based on a framework of potential outcomes, was employed to assess casual inference. The investigators identified five potential outcomes, which represented the potential values of the outcome under each level of the intervention.

A total of 2,164 patients (1,809 from France and 355 from the U.S.) were included in the study with a mean age of 46 years. Emergency hemorrhage control measures were required in 69% of patients. Whereas 6% required a prehospital transfusion of packed red blood cells, one-quarter needed a massive transfusion.

Norepinephrine was administered in 69% of trauma patients. Overall, 24-hour mortality was 18%, and did not differ among the three trauma sites (16% for RACSTC, 17% for TRENALL, and 19% for TraumaBase). In-hospital mortality was 36%.

The authors concluded that norepinephrine administration is not associated with 24-hour mortality in patients with blunt trauma and hemorrhagic shock. However, caution is advised due to the retrospective nature of the study and that the protocol did not examine crystalloid fluid expansion use. The investigators call for further studies to examine these findings more closely.

This study is significant and offers pharmacists some reassurance that the early use of epinephrine is not associated with increased mortality among patients with blunt trauma and hemorrhagic shock.

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