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. 2024 Jun 25;9(1):e001465.
doi: 10.1136/tsaco-2024-001465. eCollection 2024.

Characterization of adverse events in injured patients at risk of hemorrhagic shock: a secondary analysis of three harmonized prehospital randomized clinical trials

John M Lorence  1 , Jack K Donohue  1 , Nidhi Iyanna  1 , Francis X Guyette  2 , Elizabeth Gimbel  1 , Joshua B Brown  1 , Brian J Daley  3 , Brian J Eastridge  4 , Richard S Miller  5 , Raminder Nirula  6 , Brian G Harbrecht  7 , Jeffrey A Claridge  8 , Herb A Phelan  9 , Gary Vercruysse  10 , Terence O'Keeffe  11 , Bellal Joseph  12 , Matthew D Neal  1 , Jason L Sperry  1
Affiliations

Characterization of adverse events in injured patients at risk of hemorrhagic shock: a secondary analysis of three harmonized prehospital randomized clinical trials

John M Lorence et al. Trauma Surg Acute Care Open. .

Abstract

Background: The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials focusing on traumatic injury. In the setting of prehospital traumatic injury trials, no literature currently exists analyzing the clinical implications of AEs and their associations with mortality and morbidity. We sought to analyze AEs from three prehospital hemorrhagic shock trials and characterize their time course, incidence, severity, associated clinical outcomes, and relatedness.

Methods: We performed a secondary analysis of three prehospital randomized clinical trials. We analyzed AEs at both the patient level as well as the individual AE level. We categorized patients who had no AEs, a single documented AE and those with multiple events (>1 AE). We characterized AE timing, severity, relatedness and attributable mortality outcomes.

Results: We included 1490 patients from the three harmonized clinical trials, with 299 (20.1%) individual patients having at least a single AE documented with 529 AEs documented overall as a proportion of patients had multiple events. Over 44% of patients had a death-related misclassified AE. Patients with at least a single documented AE had a significantly higher 28-day mortality (log-rank χ2=81.27, p<0.001) compared with those without an AE documented. Patients with a single AE had a significant higher mortality than those with multiple AEs, potentially due to survival bias (log-rank χ2=11.80, p=0.006). When relatedness of each individual AE was characterized, over 97% of AEs were classified as 'definitely not related' or 'probably not related' to the intervention.

Conclusions: AEs in hemorrhagic shock trials are common, occur early and are associated with mortality and survival bias. The potential for inaccurate reporting exists, and education and training remain essential for appropriate treatment arm comparison. The current results have important relevance to injury-related clinical trials.

Trial registration numbers: NCT01818427, NCT02086500 and NCT03477006.

Level of evidence: II.

Keywords: Clinical Protocols; Shock, Hemorrhagic; classification; guideline.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Timing of first recorded adverse event (AE) and attributable mortality rate.
Figure 2
Figure 2
Kaplan-Meier survival analysis comparing patients with any adverse event (AE) versus those patients without a documented AE.
Figure 3
Figure 3
Kaplan-Meier survival analysis comparing patients with one adverse event (AE) versus those with multiple AEs (>1 AE).
See this image and copyright information in PMC

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