Military practice guidelines recommend REBOA for profound shock (SBP <90mmHg)1 and ACEP along with the American College of surgeons recommend REBOA for traumatic life-threatening hemorrhage below the diaphragm in patients with hemorrhagic shock who are unresponsive or transiently responsive to resuscitation.2 Despite these recommendations there are no randomized clinical trials to help guide practice until now.
Paper: Jansen JO, Hudson J, Cochran C, et al. Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial [published online ahead of print, 2023 Oct 12]. JAMA. 2023;e2320850. PMID: 37824132
Clinical Question: In trauma patients aged 16 years or older with life-threatening torso hemorrhage, does the use of REBOA and standard care (SC) compared to standard care alone (SCA) improve mortality at 90 days.
What They Did:
- UK Resuscitative Endovascular Balloon Occlusion of the Aorta (UK-REBOA) Trial
- Study Design: Multicenter, open-label, Bayesian, group-sequential, registry-enabled, randomized clinical trial.
- Researchers randomly assigned 90 eligible patients over ≈ 4.5 years, in a 1:1 ratio, to receive treatment with REBOA and standard care or standard care alone.
- Sites: Conducted at 16 major trauma centers in the UK.
- Funding Source: National Institute of Health Research
- Trial Registration: isrctn.org Identifier: ISRCTN16184981
Population:
- Inclusion Criteria: Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso hemorrhage deemed amenable to adjunctive treatment with REBOA.
- Exclusion Criteria: Patients known or thought to be pregnant or with injuries clearly not survivable.
Intervention:
- The placement of REBOA for resuscitation in zone I (the descending aorta) or zone III (above the aortic bifurcation) based on clinician judgment.
Comparator:
- The control group received standard care provided at a major trauma center, including intubation, blood product transfusion, interventions like tourniquet application, and early operative or endovascular hemorrhage control.
Outcome:
Primary Outcome: All-cause mortality at 90 days.
Secondary Outcomes:
- Mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours
- The need for definitive hemorrhage control procedures
- Time to commencement of definitive hemorrhage control procedures
- Complications
- Length of stay (hospital-free and intensive care unit-free days)
- Blood product use
- Cause of death
Results:
Patient Recruitment:
- 120 planned—The trial was stopped short due to prespecified stopping rule for harm was met.
- 90 Randomized
- 46 randomized to REBOA+SC group
- 44 randomized to SCA group
- 1 patient decline participation after enrollment
Baseline characteristics
- 69% of enrolled patients across both cohorts were male.
- 97% of patients sustained blunt trauma.
- The median Injury Severity Score was 41
- The median age was 41
- 23% required prehospital CPR
- All were tachycardic and hypotensive prehospital
- REBOA+SC group had lower median SBP compared with in the SCA group 84 mm Hg vs 99 mm Hg
- REBOA group had higher median Abbreviated Injury Scores for the head region.
REBOA Treatment Pathways
- 19 REBOA with balloon inflation
- 9 Arterial access; No REBOA
- 8 Arterial access unsuccessful
- 5 Arterial access; REBOA with no balloon inflation
- 3 No arterial access or REBOA attempted
- Additionally 2 patients in the SCA arm received REBOA with balloon inflation
- Zone I inflation 53%
- Zone III inflation: 47%
- Median time from ED arrival to balloon inflation was 32 minutes
- Median duration of inflation was 29 min
- Partial REBOA (titrated balloon deflation was used in 42%
Primary Outcome: All-cause mortality at 90 days:
- REBOA+SC group: 25/46 (54%)
- SCA group: 18/43 (42%)
- OR 1.58; 95% CI 0.72 – 3.52
- OR > 1 indicates treatment with REBOA and standard care increased odds of death.
- The posterior probability of OR > 1 was 86.9%, again indicating treatment with REBOA+SC increased the odds of death.
- Multivariable regression, adjusting for baseline differences, showed higher odds of 90-day mortality in the REBOA and standard care group.
- OR 1.80 (95% CrI 0.59-5.59).
- 84.9% posterior probability of OR > 1
- Post hoc analyses of individual covariates had minimal impact on results.
- Results of principal stratum analyses and learning curve effects analysis remained consistent and did not change the overall findings.
Secondary Outcomes:
- Treatment with REBOA+SC increased the odds of death across all time points measures in the secondary outcomes, as indicated by the ORs for mortality and posterior probabilities of OR > 1 were elevated in the REBOA+SC group across all time points: 6-month, in-hospital, 24-hour, 6-hour, and 3-hour mortality.
- More deaths due to bleeding were observed in the REBOA+SC group (32% of patients) compared to the SCA group (17% of patients), with most of these deaths occurring within 24 hours.
- Definitive hemorrhage control procedures were performed in 30% of patients in the REBOA and standard care group and 43% in the standard care alone group.
- The median time from randomization to definitive hemorrhage control was 19 minutes longer in the REBOA and standard care group.
- Patients in the standard care alone group had more intensive care unit-free and hospital-free days.
- No significant differences were observed between groups in terms of complications.
- No serious adverse device events were reported.
Strengths:
- The study addressed a highly debated and clinically relevant question.
- The UK-REBOA Trial is the first randomzied clinical trial to evaluate the effectiveness of REBOA in trauma patients with exsanguinating hemorrhage.
- The primary outcome focused on patient-centered outcomes.
- Investigators employed a randomized, controlled, multicenter study design, which minimized the risk of bias and enhanced external validity.
- The trial had a pragmatic design with broad inclusion criteria.
- The study used a concealed centralized web-based randomization process for participant allocation, which can help mitigate selection and allocation bias.
- The statistical analysis plan was completed before data analysis.
- Investigators performed an Intention-To-Treat analysis, which preserves randomization, mitigates attrition bias, and more closely resembles clinical reality where not all patients will adhere to treatment.
- Investigators performed multiple sensitivity analyses to address potential between-group imbalances that may arise in smaller trials.
- Follow-up was nearly complete, with only one patient withdrawing consent after enrollment.
- The outcomes were predominantly binary and objective, reducing the potential for subjective interpretation and bias.
- The baseline characteristics of the patient cohort indicated patients were severely injured trauma patients.
Limitations:
- The trial was conducted within a single county, which may limit generalizability to other geographical regions.
- The relatively small sample size raises the possibility that observed outcome differences between groups could be due to chance.
- Notably, 3 of the 16 participating centers recruited nearly half of the patients, potentially introducing variations in patient characteristics.
- Blinding the trial participants and healthcare providers was impossible due to the nature of the intervention..
- Some important baseline differences in demographics, including blood pressure, were noted between the groups. As a result, it is unclear if patients had the same prognosis at the beginning of the study.
- The study cohort was predominantly male (69%) and predominantly involved blunt trauma cases (97%). Additionally, the median age was 41, with a relatively narrow age range of 30-62. These demographic characteristics may limit the generalizability of the findings to a more diverse patient population.
- There was almost no penetrating trauma making It near impossible to draw conclusions about REBOA use in penetrating trauma patients.
- Case volume for operative hemorrhage control is much lower in UK compared to other countries, reflecting better road safety standards and low levels of interpersonal violence. These unique circumstances may not reflect other countries and healthcare systems.
- Pre Arrival times exceeded 90 minutes for both the intervention and standard care groups. Extended pre arrival duration may not accurately reflect the time frames in all clinical settings, potentially affecting the study’s generalizability.
- The study reported numerous protocol violations, with only 19 out of 46 patients in the REBOA+SC group receiving complete catheter insertion and balloon inflation intervention. Likewise, 2 patients in the SCA cohort received REBOA.
- The authors omitted detailed information regarding the training requirements and experience level of the healthcare providers involved in the procedures. These factors can significantly impact the effectiveness of the intervention.
- The type and size of the device used in the intervention were not controlled or described. Variations in device characteristics, such as size and type, could influence study outcomes.
- The study did not offer information on the duration of occlusion during the intervention. Prolonged occlusion times are known to have adverse effects and may impact the study’s outcomes.
- The early termination of the trial due to potential harm introduces uncertainty and limitations when interpreting the findings.
Discussion:
Protracted Treatment:
In severely injured trauma patients, the timeliness of hemorrhage control is paramount. In the UK-REBOA trial, patients faced extended pre-hospital transit times, with a median time exceeding 90 minutes. No patient experienced a transit time of <70 minutes; some endured periods as lengthy as 125 minutes. Despite both patient cohorts encountering prolonged intervals of hemorrhage control, the REBOA+SC group experienced a median time to hemorrhage control 19 minutes longer than the SCA group (83 minutes vs. 64 minutes)—the overall time from injury to definitive hemorrhage control for both cohorts approached 3 hours.
The enrolled population was severely injured, with a median ISS of 41, and 23% received CPR. While many would likely die under optimal circumstances, protracted periods of exsanguination likely exacerbated their condition, and more patients died due to bleeding in REBOA+SC (32%) vs SCA (17%). The protracted times observed in various metrics measured within the UK-REBOA trial likely reflect the studied healthcare system’s available resources. These times may not be representative of systems with shorter transit times.
Considering the prolonged pre-hospital transit times observed, could the deployment of REBOA in the pre-hospital setting produce earlier definitive hemorrhage control in this study? This proactive approach could address the challenge of delayed access to critical interventions in healthcare systems with long transit times. Exploring the feasibility and effectiveness of pre-hospital REBOA deployment warrants further investigation to enhance trauma resuscitation strategies and potentially improve patient outcomes.
REBOA Placement:
In contrast to randomized clinical trials evaluating medications, this study revolves around a procedural intervention, introducing a distinct set of challenges. Many past procedure based trials have demonstrated that negative outcomes are more likely when implementing procedures that operators are less familiar with (The Beam Trial and Bougie Trial). This underscores the importance of procedural proficiency and operator expertise, suggesting that the success or failure of interventions like REBOA can be significantly influenced by the skill and experience of the clinicians involved.
The experience level of clinicians in the UK-REBOA Trial remains unclear. The trial reported a median time of 32 minutes from ED arrival to successful balloon inflation. However, arterial cannulation was unsuccessful in 17% of patients randomized to the REBOA+SC arm, emphasizing clinicians’ difficulty in deploying the device effectively. The training protocol mandated a two-day session, later condensed to one day, with unspecified details on simulation attempts and trainer mannequins or animal and cadaver models. The individual sites were responsible for additional education and repeat training. While simulation cannot fully replicate the stress of a real-life attempt, it is crucial, especially for high-acuity and low-occurence procedures.
The trial investigators conducted a learning curve sensitivity analysis, excluding the first REBOA attempt from each site from the dataset. However, this assumes subsequent attempts will involve the same care team. Furthermore, among the 16 centers in the trial, 3 contributed half the patients, while 4 contributed none. Notably, one site enrolled 20% of patients, with only 9 randomized to the REBOA+SC arm over 54 months—or 1 REBOA attempt every six months. This frequency may be significantly lower than in larger trauma centers where providers might be more adept with the device due to more frequent usage.
Small Sample Size:
The findings of this trial hinge on a relatively small number of events. While 46 patients were randomized to the REBOA+SC arm, numerous protocol violations occurred, and only 19 underwent arterial access, catheter insertion, and balloon inflation. The remaining cases varied from incomplete REBOA with arterial access and catheter insertion but no balloon inflation to no attempted access at all. In addition, investigators stopped the trial early at a pre planned interim analysis due to evidence of harm. Trials stopped early are at risk of overestimating the potential effect of the intervention.
Baseline differences in demographics, including variations in heart rate, systolic blood pressure, and head injury, persisted despite randomization, suggesting patients in the REBOA+SC arm had a worse prognosis. While randomization theoretically aims to balance these characteristics it is more common to see differences in trials with small sample sizes. The combination of small trial size, numerous protocol violations, and early termination raises the possibility that the resulting data could be attributed to chance alone.
Author’s Conclusion: “The REBOA and standard care group was observed to have a high probability of higher mortality at 90 days compared with the standard care alone group. The findings were not altered in an adjusted analysis. REBOA may not reduce, and might increase, mortality in trauma patients with exsanguinating hemorrhage.”
Our Conclusion:
The UK-REBOA Trial presents pivotal insights into the use of REBOA in trauma patients with exsanguinating hemorrhage. Contrary to expectations, REBOA in conjunction with standard care did not demonstrate a reduction in mortality rates at 90 days when compared to standard care alone. In fact, the probability of increased mortality was higher in the REBOA group. Suggestsing that REBOA may not be the universally beneficial intervention it was hoped to be.
However, it’s crucial to interpret these findings with caution. The trial faced several methodological challenges, including extended prehospital transport times, limited operator experience, and a smaller-than-anticipated sample size. These factors, alongside early termination of the trial, introduce a degree of uncertainty to the results. The predominantly male and blunt trauma demographic of the study cohort further limits the generalizability of these findings to a broader patient population.
This study underscores the need for more extensive research in diverse clinical settings to fully understand the role of REBOA in trauma care. It highlights that the path to optimizing trauma care is complex and requires continuous evaluation and adaptation of our approaches. While REBOA might not be the one-size-fits-all solution, it could still hold potential for specific patient subsets. Future research should focus on identifying these subsets and exploring the pre-hospital deployment of REBOA, especially in systems with long transit times.
In conclusion, the UK-REBOA Trial is a significant step in our ongoing pursuit to enhance trauma care. It serves as a reminder of the importance of rigorously testing medical interventions in varied settings and populations.
References:
- Butler FK Jr, Holcomb JB, Shackelford SA, et al. Advanced Resuscitative Care in Tactical Combat Casualty Care: TCCC Guidelines Change 18-01:14 October 2018. J Spec Oper Med. 2018;18(4):37-55. PMID: 30566723
- Bulger EM, Perina DG, Qasim Z, et al. Clinical use of resuscitative endovascular balloon occlusion of the aorta (REBOA) in civilian trauma systems in the USA, 2019: a joint statement from the American College of Surgeons Committee on Trauma, the American College of Emergency Physicians, the National Association of Emergency Medical Services Physicians and the National Association of Emergency Medical Technicians. Trauma Surg Acute Care Open. 2019;4(1):e000376. Published 2019 Sep 20. PMID: 31673635
Post By:
Marco Propersi, DO FAAEM
Vice-Chair, Emergency Medicine
Assistant Emergency Medicine Program Director
Vassar Brothers Hospital, Poughkeepsie, New York
Twitter/X: @marco_propersi
Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter/X: @srrezaie)
