This study is the first to our knowledge to investigate and compare simplified and readily applicable bedside protocols for performing intermittent REBOA for NCTH due to severe solid organ injury. The clinical syndrome of NCTH has only recently been defined and characterized and includes physiologic disturbance in the setting of a source of major torso hemorrhage.21 Additional work has characterized the epidemiology and high mortality and morbidity with NCTH in both civilian and military cohorts.22–24 Although the use of this “catch-all” terminology is helpful epidemiologically, it is important to appreciate each specific cause of NCTH as a separate entity when studying interventions and treatment adjuncts, such as REBOA. The majority of translational studies examining REBOA for NCTH have utilized major abdominal vascular injury models, which may behave significantly differently than models utilizing other common causes of NCTH, such as severe solid-organ injury or major pelvic fractures. We performed this study using a major solid organ injury model as a follow-on to our previously reported analysis of intermittent REBOA in a vascular NCTH model.14 As suspected, based on our prior anecdotal experience, we found significant differences in the behavior and response to interventions between these two models. These areas of similarity and significant differences should be considered in any clinical applications of these data and in the testing and validation of REBOA or other interventions for NCTH.
Within the past few years, the trauma community has continued to investigate and better characterize optimal use of the REBOA catheter as a useful adjunct for NCTH.14,17,25–27 This has included efforts to improve the device and the associated algorithms and techniques for placement to minimize time to deployment and optimize it for use earlier in the immediate post-injury phase. Appropriate imaging free placement was one of the first examples of improving the time needed from placement to safe and effective inflation of the balloon. These techniques range from extracorporeal measurements, to population-based blind placement target distances and even smart phone based infrared technologies.28–30 The advent of a 7-Fr wire-free catheter (ER REBOA Catheter, Prytime Inc.) has enabled providers to be more comfortable placing these devices and decreased the overall morbidity of surgical intervention.31–33 Studies out of Japan have found survival was improved with early prehospital placement which they report doing in nearly 2% of cases.34,35 Further, rapid placement of a femoral arterial line (typically 5 Fr) is reasonable for all hemodynamically unstable patients and can be easily exchanged over a wire with a 7-Fr sheath for REBOA deployment should the clinical scenario call for it, effectively decreasing precious intervention time.34 These advances in both the technology as well as provider experience have made REBOA a more common and viable option to control hemorrhage in patients with NCTH.
The association of reperfusion injury, particularly with zone 1 placement has become a well-described phenomenon with prolonged inflation times beyond 45 minutes to 60 minutes being largely fatal.14,36–38 Zone 1 placement can also create significant supra-celiac pressure that may contribute to morbidity after REBOA use and definitive intervention.39 Intracranial pressures alone have been thought to create or worsen devastating intracranial hemorrhage.31,40 Thus, mitigation to avoid the consequences of zone 1 REBOA use has now become an important area of focus in the literature surrounding REBOA. One of the first studies to evaluate possible strategies was by Russo et al.41 in 2016 who were able to develop a model where complete occlusion was compared with a REBOA balloon that was deflated to a 50% blood pressure gradient across the occlusion in a controlled hemorrhage swine model. They were able to demonstrate improved physiology in terms of proximal MAP, duodenal necrosis, and final lactate levels over their 45-minute study time. They demonstrated similar findings when a 30% liver injury (similar to the one in our study) was created.6 One of the most significant limitations discussed is these studies is that the REBOA balloon utilized is a noncompliant balloon, and partial deflation of the currently available balloon is not clinically applicable.6,41 A study evaluating controlled restoration of distal flow to minimize the effects of rebound hypotension and potential clot destabilization showed that benefits to incremental deflation of the balloon.12 Based on their findings, they further recommended continued investigation of augmenting the way the REBOA balloon is utilized to improve outcomes.
More recently, a highly sophisticated system entitled endovascular variable aortic control, developed by Williams et al.42 utilizes concomitant bicannulation of the carotid and femoral arteries allowing carotid pressure dependent extracorporeal oxygenated blood flow distal to the REBOA occlusion during zone 1 occlusion to aide in distal perfusion. Their studies have found that use of endovascular variable aortic control may result in the need for less resuscitation, lower lactate levels, and higher levels of angiotensin II.43,44 Although these results are provocative from an academic standpoint, the need for large bore access of an additional two arteries and the requirement of a novel extracorporeal perfusion device, one can foresee profound difficulties in transitioning this system to a clinical setting much less a deployed or prehospital setting.
Clinically, partial balloon inflations have begun to be more formally evaluated as well. Although anecdotal use is common in many trauma centers in both the United States and Japan, the majority of published clinical data comes from the multicenter DIRECT-IABO investigators of Japan.32,34,35 This group has reported that partial occlusion is utilized in up to 70% of cases and is associated with a more consistent ability to achieve hemodynamic stability (78% of patients compared to 51%, p = 0.007) as well as ability for longer occlusion times at 58 minutes in the partial occlusion group compared with 33 minutes (p = 0.04).32 However, partial occlusion is not well defined in these studies, making it difficult to identify specific advantages to develop more standardized methods for prescription and wider implementation. Further, the ability to achieve reproducible and reliable partial occlusion with the noncompliant balloons that are currently available is unproven, and tight control of partial flow is not possible with existing devices. Achieving true “partial REBOA” with the ability to accurately and reliably dial-in the amount of desired flow will require redesign of both the balloon-occlusion system and the inflation/deflation system. There are currently several experimental prototype devices aiming to achieve this goal, but until these are available and validated, we must optimize strategies to minimize ischemia-reperfusion and increase the tolerable duration of zone 1 aortic occlusion.
Our laboratory has recently published the results of using our intermittent system in a 120-minute survival study for a rapidly fatal major abdominal combined arteriovenous vascular injury.14 In that study, we were able to show the feasibility of using simple deflation and inflation schedules to effectively control NCTH while preventing fatal reperfusion injury. Using identical intermittent REBOA schedules, 120-minute survival was seen in all animals which was significantly superior to the continuous REBOA at 63 minutes of survival (average, 3 minutes after deflation, p < 0.001). This improvement in survival was also accompanied by improved hemodynamic profiles as 60 minutes in intermittent groups as well as lower lactate levels. There was significantly larger blood loss in the intermittent groups (>1 L compared with 250 mL in continuous REBOA animals, p < 0.001) which was reflected in a heavier intra-abdominal clot weight and need for larger-volume blood resuscitation. Comparison in that study between the time-based intermittent group and the pressure-based group found that the total ischemia time was significantly longer in the time-based group (90 minutes vs. 48 minutes, p < 0.001) which resulted in worsened lactic acidosis in the time-based group.
The data presented here support some of the findings from our previous study. We were able to redemonstrate that our simple intermittent schedules are easily reproducible, feasible, and successful for controlling NCTH utilizing proximal MAPs for intervention monitoring and guidance. For this rapidly fatal liver injury, a time-based schedule was clearly beneficial in terms of survival to 120 minutes when compared with iRP and cR groups. For animals who were able to survive iRP, presumably early clot formation led to minimal need for proximal occlusion which in turn resulted in a more normal physiology with minimal ongoing hemorrhage over the subsequent 120 minutes. Furthermore, although not significant, there was a trend toward larger specimen weight in our iRP group (Table 1) when compared with the cR and iRT groups which may have contributed to the two early deaths seen in the iRP group. Interestingly, we found increased rate of hemorrhage as well as total hemorrhage in our cR group when compared with our iREBOA groups. We believe this may be attributed to the fact that there is some continuous venous and portal bleeding from hepatic injury even after REBOA inflation over the course of the experiment. Mean arterial pressure continues to rise in the cR group, causing significant heart strain and ultimately increases in CVP. A phenomenon not seen with intermittent strategies that may contribute to an increase in venous blood loss in the cR groups. Finally, we were able to appreciate marked differences in distal organ necrosis and ischemic changes with less damage seen in the intermittent arms when compared to continuous REBOA animals. This is remarkable given that the overall balloon inflation time was approximately 90 minutes in most intermittent animals while it was only 60 minutes in the continuous animals. If it were possible to harvest tissue at the same time point in both groups, it would have been likely even more evident. Clinically, it is recognized that the effects of end organ ischemia are progressive over time and that the relatively short survival period may even underestimate any true differences.
The findings presented here are limited by the preclinical nature of the study in an animal model and as such may not be directly applicable for human implementation. The injury and hemorrhage were standardized and do not accurately represent the largely variable nature of NCTH that occurs from traumatic injury. Further liver injury that was developed is extreme, rapidly fatal, is rare, and represents a small subset of patients; however, such model was meant to evaluate a “worst case scenario” in terms of solid organ injury for NCTH. Animals were never awakened from anesthesia, and thus, we were unable to evaluate or comment on more long-term outcomes or survival. Although early changes were seen with small bowel and kidney histology in terms of ischemic necrosis, it is difficult to comment on eventual clinical manifestations because we did not see any other physiologic differences at the 30 minutes and 60 minutes time points between the groups. Finally, given that a prolonged need for REBOA is most likely to be needed in a combat-associated, prolonged field care scenario, the resuscitation and timelines used were made to mimic such circumstances and are less applicable to centralized civilian trauma centers with early access to operating rooms or interventional angiography.
Resuscitative endovascular balloon occlusion of the aorta has recently emerged as one of the only currently available modalities to intervene in cases of NCTH outside of the operating room or angiography-suite environment. Overwhelming ischemia-reperfusion injury continues to limit prolonged REBOA use prior to definitive interventions, particularly for zone I deployment. Previously studied partial inflation schedules of REBOA for fatal solid organ injuries have not adequately provided a simple standard approach that would be applicable in a limited resource setting. Prolonged tolerance of zone 1 REBOA for NCTH due to severe solid organ injury appears feasible with both time-based and pressure-based schedules. A simple, reproducible time-based schedule had improved overall survival while a pressure-based schedule had lower survival but resulted in less physiologic injury for animals surviving to 120 minutes. Ideally, this will be further evaluated in a prospective nature in patients with NCTH in a clinical setting.
All authors conducted and contributed to the literature search. All authors contributed to study design. J.K., M.B., D.M., C.P., T.L. and J.K. collected the data. J.K., M.D., C.P., M.E., and M.M. interpreted the data. J.K., M.B., D.M., SM., and M.M. wrote the article. All authors critically revised the final article.
This work was supported by a Department of Defense Medical Research and Development Program (DMRDP), DHP 6.7 research grant.
The authors declare no conflicts of interest.
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Kuckleman and colleagues present here their well-designed examination of the impact of different approaches to REBOA implementation in a porcine hemorrhage model. The use of this adjunct continues to grow in modern trauma care and is now expanding to use in other clinical arenas plagued by the challenge of hemorrhage from non-compressible sources – including post-partum hemorrhage. In the context of this expanded use, attention has rightly turned to the mitigation of the dangers of prolonged ischemic time and re-perfusion injury. The authors here examine two approaches that are increasingly being utilized – partial balloon occlusion (p-REBOA) and intermittent REBOA.
The investigators demonstrate that both of these modalities have the potential to improve outcomes among patients for whom REBOA is employed. It is important to note, however, that each has potential challenges. Intermittent approaches, with full balloon deflation, represents the less controlled of the two modalities with regards to distal flow re-establishment. As a consequence, the theoretic risk for the dislodgement of distal clot and acute decompensation may be greater compared to p-REBOA.
By comparison, p-REBOA represents a more controlled re-introduction of distal flow and can be titrated to achieve the desired hemodynamic states above and below the level of occlusion. In this fashion, an ideal response would facilitate normotension above the balloon – to optimally perfuse both the brain and the heart – while facilitating a hypotensive resuscitative state for the tissues below the balloon – mitigating the risk for clot disruption until definitive hemorrhage control can be achieve. P-REBOA is, however, a more task intensive intervention at present – and may prove exceptionally challenging in the task saturated conditions common to emergent hemorrhage control.
Additional investigation of the optimal utilization of REBOA is required – but the authors here provide the first stones of a foundation upon which those practices can be built. I salute their very important work and look forward to their continued investigations in this arena. Their work – combined with further technological innovation that may provide assistance in achieving greater fine control of balloon titration, promise to improve outcomes among those patients for which REBOA is employed.
Joseph DuBose, MD