There was no difference in the time taken to perform the splenectomy across the three groups with an overall mean time of 29 ± 14 min (Table 1). Splenic weight was also consistent among the groups, with a mean weight of 535 ± 150 g. There was no difference in postsplenectomy hemodynamic or laboratory parameters (Supplementary Table 1, http://links.lww.com/SHK/A193).
The liver injury was accomplished within 2 min in all animals, resecting a consistent segment of the left lobe across the groups, with a mean overall weight of 286 ± 71 g and percentage resection of 75.0% ± 7.5% (Table 1).
Following liver injury, all animals underwent a precipitous cardiovascular collapse during the 10-min free-bleed period (Fig. 3). Systolic blood pressure (in mmHg) at the end of free-bleed period for the cREBOA, iREBOA, and nREBOA groups was 31 ± 14, 48 ± 28, and 28 ± 17, respectively; P = 0.125 (Fig. 3A).
The initiation of balloon occlusion in the cREBOA and iREBOA groups during the intervention phase resulted in restoration of SBP to values significantly higher than BL (79 ± 12 vs. 107 ± 19 [P = 0.015] and 85 ± 9 vs. 117 ± 20 [P = 0.023], respectively). However, the SBP in the nREBOA control group continued to decrease with all animals progressing to asystolic cardiac arrest by 25 min of the intervention phase (35 min after injury) (Fig. 3A).
A similar trend was observed for pulmonary SBP, SVO2, and carotid flow among the groups (Fig. 3, B, D, and E). Following a significant decrease in each parameter during the free-bleed period, the deployment of REBOA resulted in the restoration of supranormal values; this was not observed in the nREBOA group.
Throughout the 60-min intervention phase, the cREBOA and iREBOA groups both maintained SBP following the initial elevation after injury. This is in contrast to CO, which decreased during the injury phase in the cREBOA and iREBOA groups to 3.2 ± 1.3 and 5.1 ± 1.2, respectively (Fig. 3C). Cardiac output made little recovery during the intervention phase decreasing to the lowest value of 2.5 ± 0.5 at 30 min in the cREBOA group and 4.6 ± 1.6 at 10 min in the iREBOA group. Following resuscitation during the damage control surgery phase, CO increased to levels higher than BL, with a peak of 7.6 ± 2.5 at 110 min in the cREBOA group and 7.7 ± 1.3 at 150 min in the iREBOA group. All indices of hemodynamic performance were maintained through to the EOS.
Throughout the free bleed and intervention phase, there was an increase in lactate and a commensurate decrease in pH (Fig. 4). In the nREBOA group, the lactate peaked at 14.4 mmol/L before the demise of the last animal in the group at 35 min after injury. The lactate trend was similar for both the cREBOA and iREBOA groups with peaks of 13.7 ± 2.2 at 90 min and 13.5 ± 3.3 at 105 min, respectively. Similarly, the lowest pH occurred at 105 min for both the cREBOA and iREBOA groups with measurements of 7.17 ± 0.09 and 7.17 ± 0.10.
Lactate measurements continued to decline from their peak measurement during the critical care phase to a lowest measurement at 4.5 h of 7.7 ± 2.4 and 6.6 ± 2.9 for the cREBOA and iREBOA groups. The pH peaked at this time point with values 7.39 ± 0.83 and 7.31 ± 0.13, respectively. The EOS values saw a small increase in lactate to 9.0 ± 4.5 and 7.8 ± 4.5 and a decrease in pH of 7.22 ± 1.45 and 7.28 ± 0.18 for the cREBOA and iREBOA groups.
A comparison of BL and EOS laboratory parameters for the cREBOA and iREBOA groups is presented in Table 2. Measures of hemoglobin, clotting time (prothrombin and partial thromboplastin time) and fibrinogen did not differ between BL and EOS. There was a significant decrease in platelet count observed between BL and EOS samples in the iREBOA group (292 ± 119 vs. 152 ± 98; P = 0.027).
An increase was observed in laboratory measures of end organ damage including renal, hepatic, and cardiac parameters. Blood urea nitrogen increased significantly in the cREBOA and iREBOA groups to 12.0 ± 1.6 and 11 ± 3.2, respectively. A similar trend was observed in creatinine. There was a nonsignificant increase in alanine aminotransferase across both groups and a significant rise in aspartate aminotransferase in the cREBOA group (20 ± 9 vs. 403 ± 133; P = 0.001). Significant cTnI increases were also observed, greatest in the cREBOA group (0 vs. 2.9 ± 1.5; P = 0.005) but also in the iREBOA group (0 vs. 1.8 ± 1.5; P = 0.033).
Only data from the cREBOA and iREBOA groups are presented as no animal in the nREBOA group survived to the EOS (Table 2). There was no difference in BL measurements between the cREBOA and iREBOA groups for IL-6, TNF-α, or IL-8. A significant increase from BL to EOS was noted in IL-6 measurements in both the cREBOA (32 ± 14 vs. 1,188 ± 279; P = 0.001) and iREBOA (36 ± 26 vs. 227 ± 296; P = 0.003) groups.
While an increase in EOS compared with BL TNF-α and IL-8 was observed, it was not significant in either group (Table 2). In terms of EOS values between the groups, cREBOA had incurred a greater IL-6 (1,187 ± 279 vs. 834 ± 287; P = 0.084), TNF-α (205 ± 92 vs. 110 ± 36; P = 0.063), and IL-8 (329 ± 505 vs. 227 ± 296; P = 0.708) release than the nREBOA group, although again, none achieved statistical significance.
Operative intervention and resuscitation
Damage control surgery was performed in the cREBOA and iREBOA groups as no animal in the nREBOA group survived beyond the intervention phase (Table 2). Total Pringle time was similar between the cREBOA and iREBOA groups (18 ± 5 vs. 12 ± 3; P = 0.095) as was the intraoperative REBOA time (in minutes) (20 ± 9 vs. 15 ± 8; P = 0.293). Emergent reinflation was required for two animals in the cREBOA and four in the iREBOA groups, predominantly for control of hypotension. All laparotomies were performed within the allocated 60 min with an overall mean time of 35 ± 10 min.
Both groups received similar volumes of WB and crystalloid. Insulin and 50% dextrose were used in five animals to treat a K+ greater than 5.5 mmol/L, two required 50% dextrose for hypoglycemia, and inotropic support was necessary in five cases. One animal developed a tension pneumothorax, which was treated with tube thoracostomy.
There were two unplanned relaparotomies. One animal in the cREBOA group had a rising lactate despite resuscitation, and re-exploration identified global small bowel ischemia, which improved following withdrawal of the REBOA catheter from the thoracic aorta. The second relaparotomy occurred in an iREBOA animal, in response to hemodynamic instability and falling hemoglobin suggestive of ongoing bleeding. There was evidence of gross coagulopathy with no surgically remedial solution; despite exhaustion of WB reserves, the animal survived to the EOS.
There were 11 early deaths from exsanguination that occurred during the intervention phase. All of the nREBOA animals died within 35 min of injury. Deployment of REBOA was unable to salvage two animals in the iREBOA group (11 and 15 min after injury) and one animal in the cREBOA group (12 min after injury).
There was one intraoperative death in the iREBOA group (80 min after injury). This animal tolerated balloon deflation during the intervention phase poorly, requiring emergent reocclusion during both attempts. The animal displayed gross hemodynamic instability 10 min before damage control laparotomy, deteriorating into cardiac arrest with pulseless electrical activity 3 min before damage control surgery. Despite aggressive resuscitation attempts, including internal cardiac massage and rapid WB infusion, there was no return of spontaneous circulation. One death was observed during the critical care phase in the cREBOA group (5 h after injury). This animal developed cardiogenic shock refractory to inotropic support.
The overall survival rates for the cREBOA, iREBOA, and nREBOA groups to EOS were 75.0%, 62.5%, and 0.0% respectively (Fig. 5). A pairwise log-rank (Mantel-Cox) comparison between the groups demonstrated a significant difference in survival when comparing nREBOA to cREBOA (P = 0.001) and nREBOA to iREBOA (P = 0.007). There was no difference comparing cREBOA to iREBOA (P = 0.572).
The current study examines the effectiveness of REBOA as a hemorrhage control adjunct in a highly lethal porcine model of noncompressible torso hemorrhage. It is the first study to evaluate this adjunct in conjunction with modern DCR. Resuscitative endovascular balloon occlusion of the aorta was used to successfully salvage 13 (81.3%) of 16 animals from imminent circulatory arrest and to sustain the circulation of 12 (75.0%) of 16 animals until definitive hemorrhage control. This is in contrast to the control animals, all of whom died of rapid exsanguination. Furthermore, the current study also examined outcomes between intermittent and continuous occlusion, in an effort to assess whether transient reperfusion reduced the metabolic or inflammatory burden. No difference was detected in these outcomes between the continuous and iREBOA groups.
This study confirms and extends previous work characterizing the hemodynamic and metabolic sequelae of balloon occlusion in hemorrhagic shock. White et al. (19) used a porcine model of controlled hemorrhage to demonstrated that REBOA had a comparably favorable hemodynamic profile to open clamp occlusion of the thoracic aorta, but resulted in less of a metabolic burden than RT. Markov et al. (20) used a similar model to evaluate the physiologic tolerance of 30 and 90 min of occlusion. A lactic acidosis was incurred with both occlusion times, greatest in the 90-min group, but ultimately survivable with the restoration of normal physiology following balloon deflation.
Most recently, Scott et al. (21) used an occlusion time of 60 min with which to assess the performance of a newly developed, self-centering, low-profile, prototype REBOA catheter. Results from that study demonstrated the reproducibility of blind or fluoroscopy-free placement, with physiological results that complemented the work of Markov et al. Although this body of literature demonstrates the hemodynamic advantages of REBOA and the survivability following balloon deflation, more clinically relevant models of uncontrolled hemorrhage have been required to assess the practical application of REBOA.
Avaro et al. (22) used a porcine model of open splenic trauma, resuscitated with saline, to evaluate a control group with 40 or 60 min of REBOA followed by splenectomy. The control group all exsanguinated within 80 min of injury, and 9 (75.0%) of 12 of the 60-min group died upon balloon deflation due to metabolic derangement. All animals in the 40-min group in the study of Avaro et al. survived, suggesting that 40 min constitutes an optimum physiologic threshold for resuscitative aortic occlusion.
The current study builds on the work of Avaro et al. (22), by incorporating DCR (including WB administration) that successfully extends this physiological threshold to 60 min. This approach results in a greater overall survival (68.8%), despite a longer occlusion time and a more lethal model. The combination of WB resuscitation, prompt correction of electrolyte derangement, active warming, and hemodynamic support can successfully ameliorate the metabolic consequences of balloon deflation and reperfusion.
However, it is important to acknowledge that the current study’s resuscitation was by no means comprehensive. Whole blood reserves were limited, and adjuncts such as tranexamic acid (23) or specialized blood products such as cryoprecipitate (24) were not used. This was reflected by the ongoing acidosis during the critical care phase, which is frequently corrected intraoperatively using contemporary DCR (25).
There are further limitations that are important to discuss. The use of iREBOA was an attempt to permit a degree of ischemic preconditioning that would enhance resilience to the reperfusion injury. The time of 1 min was used, as during the model development phase, it was clear that animals would not tolerate prolonged deflation without resuscitation. It is likely that the period of minute is too brief, and therefore conclusions relating to the iREBOA group should be cautious. Further work examining techniques to ameliorate reperfusion injury should be explored.
The use of REBOA has not been limited to animal studies, with the earliest reported human use during the Korean War in 1953 by Lt. Col. Hughes (26). He described two casualties with exsanguinating truncal injuries, both of whom responded to balloon occlusion, but ultimately died of their wounds. Despite its attractions, balloon occlusion was surpassed by the experience of open clamp occlusion, which became the standard of care (27).
Resuscitative aortic balloon occlusion was explored again in the 1980s; however, success was limited by patient selection and insertion technique (28, 29). The majority of patients were either in established cardiac arrest or moribund, and the method of arterial access was generally by cut-down, frequently unsuccessful. Resuscitative endovascular balloon occlusion of the aorta may be most successful as a proactive intervention (i.e., aortic pressure monitoring with capacity to inflate a balloon) in patients with a spontaneous circulation, at risk of circulatory arrest.
Following the refinement of both catheter technology and Seldinger insertion techniques during the 2000s (30,31), along with the developments in trauma resuscitation, the reevaluation of this technology is a logical step (16). Brenner and colleagues (32) recently report a series of six trauma patients, injured by a mixture of blunt and penetrating trauma treated using REBOA as an adjunct to DCR. The mean admission SBP was 59 ± 27 mmHg, which was increased to 114 ± 20 mmHg following the deployment of REBOA. While one patient died of traumatic brain injury and another of multiorgan failure, there were no REBOA-related complications. Ultimately, this adjunct was used as a hemostatic and resuscitative bridge to definitive hemorrhage control, incurring no hemorrhage-related mortality.
Resuscitative endovascular balloon occlusion of the aorta can temporize exsanguinating hemorrhage and restore life-sustaining perfusion, bridging critical physiology to definitive hemorrhage control (i.e., surgical hemostasis). In the current study, iREBOA compared with cREBOA offered no additional benefit, although different schedules of occlusion should be explored in future studies. Importantly, the physiologic penalty incurred by 60 min of occlusion could be ameliorated with aggressive DCR. Prospective observational studies of REBOA as a hemorrhage control adjunct should be undertaken in appropriate groups of human trauma patients.
The authors thank the laboratory and veterinary staff at the 59th Medical Wing, Clinical Research Division, Lackland Air Force Base, for their work supporting the experiments and laboratory assays performed during this study.
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