Following the 60-minute shock period, pREBOA deployment resulted in a significantly higher average proximal MAP for HS-TBI-pREBOA (64.4 ± 11.1 mm Hg; p = 0.002) and HS-pREBOA (66.6 ± 14.7 mm Hg; p = 0.003) groups compared with the HS-TBI group (33.4 ± 2.2 mm Hg) (Fig. 4 A and B). There was a trend towards a lower proximal MAP for the HS-TBI-pREBOA group compared with the HS-pREBOA group, although not statistically significant. As expected, pREBOA deployment resulted in a significantly lower average distal MAP for HS-TBI-pREBOA (22.1 ± 3.1 mm Hg; p = 0.001) and HS-pREBOA (23.1 ± 2.1 mm Hg; p = 0.001) groups compared with the HS-TBI group (33.4 ± 2.2 mm Hg) (Fig. 4 C and D). Following pREBOA deflation, aortic pressure gradients quickly dissipated, returning to baseline MAP with fluid resuscitation and vasopressors (Fig. 4 A and C).
Following resuscitation, no significant differences were noted in intraoperative hemodynamics and physiologic responses between the groups, although several trends were noted (Fig. 5). Heart rate was elevated in the HS-TBI-pREBOA group compared with other groups during the critical care phase. CVP was elevated in the HS-pREBOA group following fluid resuscitation, while CVP was decreased in the HS-TBI-pREBOA group during the early critical care phase. Cardiac output was elevated in the HS-TBI-pREBOA group during the early hours of the critical care phase compared with other groups. Lastly, the ICP values were higher in the two TBI groups, but the difference between the three groups did not reach statistical significance.
Severity of shock was greatest in the HS-TBI-pREBOA group (Fig. 6). At the end of the critical care phase, lactate level was significantly higher in the HS-TBI-pREBOA group (lactate level, mmol/L: HS-TBI-pREBOA, 15 ± 2 mmol/L; HS-pREBOA, 2 ± 1 mmol/L; HS-TBI, 3 ± 2 mmol/L; p = 0.001) (Fig. 6 A). The pH nadir was also significantly lower for the HS-TBI-pREBOA (pH, mmol/L: HS-TBI-pREBOA, 7.16 ± 0.04; HS-TBI, 7.26 ± 0.04; HS-pREBOA, 7.31 ± 0.03; p = 0.007) (Fig. 6 B).
Resuscitation and Vasopressor Requirements
Total fluid requirement during the critical care phase was significantly higher in the HS-TBI-pREBOA group (3,360 ± 706 mL) compared with the HS-TBI (300 ± 0 mL; p = 0.001) and HS-pREBOA (660 ± 371 mL; p = 0.004) groups (Fig. 7 A). Norepinephrine requirement was also significantly higher in the HS-TBI-pREBOA group compared with the other groups (norepinephrine, mg/kg per hour: HS-TBI-pREBOA, 0.14 ± 0.02 mg/kg per hour; HS-pREBOA, 0.014 ± 0.001 mg/kg per hour; HS-TBI, 0 ± 0 mg/kg per hour; p < 0.01) (Fig. 7 B).
Brain Hemispheric Swelling and Lesion Size
Compared with the HS-pREBOA group, ipsilateral hemispheric swelling was significantly increased in the HS-TBI and HS-TBI-pREBOA groups (ipsilateral hemispheric swelling, %: HS-TBI = 32.5 ± 6.5; HS-TBI-pREBOA = 26.5 ± 8.5; HS-pREBOA, 1.1 ± 2.1; p = 0.001) (Fig. 8 A); however, no significant differences were noted between the HS-TBI and HS-TBI-pREBOA groups. No significant differences were noted between brain lesion sizes in the HS-TBI and HS-TBI-pREBOA groups (mean lesion size, mm3: HS-TBI = 3,107 ± 999; HS-TBI-pREBOA: 3,084 ± 619.7, p = 0.99) (Fig. 8 B).
Although REBOA use has gained wide attention for NCTH, its deployment in the setting of TBI has not been well studied. With an increasing use of pREBOA, a better understanding of pREBOA deployment in multiple injuries and rigorous patient selection guidelines are required. In this study, we found that prolonged application of pREBOA does not contribute to early worsening of brain lesion size or swelling. However, the degree of circulatory shock is significantly increased when pREBOA is deployed in the presence of severe TBI. As such, providers should be aware of the potential physiologic sequelae induced by TBI in the setting of pREBOA deployment.
Traumatic brain injury remains a leading cause of death and disability worldwide.24,25 In both civilian and military traumatic settings, TBI is frequently associated with other traumatic insults, including vascular injury and HS, which are the leading cause of preventable death in trauma.26 Because hypotension or hypertension can affect clinical outcomes of TBI, providers must be well-versed in the management of concurrent injuries.
Concerns exist regarding REBOA deployment in patients with TBI. Supraphysiologic blood pressure and flow in the proximal aorta may exacerbate intracranial hemorrhage and increase cerebral edema by destabilizing intracerebral clots, ultimately worsening TBI.14,27,28 Several studies have demonstrated that patients with TBI and a low GCS were more likely to die following REBOA deployment compared to patients without TBI.29 Furthermore, several reports demonstrate that REBOA deployment may lead to death secondary to exacerbation of TBI progression.15 However, these studies have had several limitations regarding patient selection and lack of cerebral flow monitoring. Also, these studies used the traditional REBOA with complete aortic occlusion, and it remains unclear whether pREBOA would have the same impact on TBI progression.
Studies assessing the effects of REBOA in clinically realistic, large animal models of TBI are lacking. A previous preclinical study used a mild model of concurrent HS and TBI, involving 25% total blood volume hemorrhage and a 1,200 mm3 CCI-induced brain lesion.16 That particular study involved an early deployment of cREBOA and pREBOA immediately following hemorrhage and external automated devices to ensure optimal proximal perfusion. These circumstances may not reflect clinical scenarios and current practices. Our study decided to use a model of severe HS (40% total blood volume hemorrhage) and TBI (2,400 mm3 CCI-induced brain lesion). We also simulated a delay in pREBOA deployment and had a resuscitation schedule designed to represent a clinically realistic timeline with limited resuscitation to mimic prehospital settings. Furthermore, we elected to test the concept of partial aortic occlusion, as there has been an increasing use of pREBOA clinically and in preclinical large animal studies.12,13,16,30–33 The pREBOA-PRO catheter, which facilitates ease of transition from complete to partial to no aortic occlusion, is currently being evaluated in numerous studies.30
The optimal duration of aortic balloon occlusion remains a matter of investigation. Well-described porcine models have demonstrated that cREBOA deployment in zone 1 is tolerated for approximately 30 minutes.13,34,35 In an attempt to maintain distal perfusion and prolong aortic occlusion, several strategies have been devised, including the development of pREBOA that involves partially occluding aortic flow.12,13 In this study, we used pREBOA to target a distal MAP goal of 20 to 25 mm Hg, which achieved a 60% to 73% systolic-to-diastolic pressure gradient, similar to other studies.12,16,30,32,36 This was well tolerated, as all animals subjected to pREBOA following HS recovered toward baseline physiology with minimal fluid resuscitation and vasopressor requirements. Furthermore, pREBOA was successfully deployed for twice as long (60 minutes) in isolated HS compared to cREBOA.13,34,35 Several other preclinical large animal studies using pREBOA have demonstrated successful deployment for up to 60 and 90 minutes; however, these have mainly involved nonsurvival studies with milder insults (25% total blood volume hemorrhage) and immediate pREBOA deployment following hemorrhage.12,16 The upper limit of pREBOA deployment time remains unknown but is likely much longer (four- to sixfold) compared with cREBOA based on our and others' preliminary studies.
In this study, we observed severe cardiovascular dysfunction and an increased degree of shock following pREBOA deployment in the setting of TBI. During pREBOA deployment, animals subjected to HS and TBI were unable to sustain an elevated proximal MAP, which decreased during the last 30 minutes of the balloon inflation period compared with animals without TBI. This is consistent with prior studies demonstrating a degree of cardiac dysfunction and endotheliopathy with REBOA deployment.16 Furthermore, animals with TBI subjected to pREBOA required significantly more fluid resuscitation and had higher vasopressor requirements, lactate levels, and acidosis.
Cardiovascular complications are common following severe TBI and are linked to increased morbidity and mortality.37,38 Immediately following TBI, a systemic catecholamine storm can massively increase sympathetic outflow, inducing severe systemic vasoconstriction.39 This can increase cardiac afterload, inducing myocardial ischemia, impairment of ventricular function, and even systemic hypotension in severe cases.39 As the catecholamine surge diminishes, the early hyperdynamic response is blunted and significant hypotension can ensue secondary to unopposed peripheral vasodilation and ventricular dysfunction.39 In this study, high-dose norepinephrine was required to improve systemic vasodilation; however, we suspect that the increased β1 adrenergic activity may have also worsened existing cardiac dysfunction, promoting ventricular dysfunction and cardiogenic shock. However, we did not use intraoperative echocardiography to confirm this.
We suspect that several additional reasons played a role in the development of cardiovascular shock following TBI. Neurogenic stunned myocardium, which results from an excessive norepinephrine release from cardiac sympathetic nerve terminals, may lead to prolonged β1 activity and cardiac mitochondrial dysfunction, resulting in hypotension.39 We suspect that animals subjected to TBI exhibited a degree of ventricular dysfunction and neurogenic stunned myocardium. In addition, TBI can activate a massive neuroinflammatory response leading to widespread release of cytokines into systemic circulation.38,39 The presence of TBI may have worsened the inflammatory cytokine release causing circulatory shock and organ dysfunction in the setting of pREBOA deployment. Overall, these reasons may have led to high-dose norepinephrine requirements, causing significant systemic vasoconstriction contributing to intestinal ischemia with worsening acidosis, increased lactate levels, and even death. Mechanistic studies are currently underway to elucidate the impact of TBI on the cardiovascular system and how it contributes to an increase in mortality.
In addition, pREBOA deployment did not appear to worsen early brain lesion size and swelling following TBI. Comparisons between HS-TBI and HS-TBI-pREBOA groups revealed similar hemispheric brain swelling and lesion sizes, suggesting that there was no further extension of the TBI following pREBOA deployment. This is consistent with prior studies where no change in brain lesion size was observed using serial computed tomography imaging following cREBOA and pREBOA deployment compared with controls.16 Furthermore, no significant increase in ICP was observed with pREBOA deployment in the setting of TBI compared to the HS-TBI group.
Several reasons may explain why pREBOA deployment did not worsen brain lesion size and swelling. First, supraphysiologic proximal MAP during pREBOA deployment may not be as extreme as that observed with cREBOA; furthermore, the proximal MAP may be higher in milder HS models due to decreased hemorrhage volumes. In this study, however, we focused on the effects of pREBOA deployment in a severe HS model. Second, the increase in proximal MAP following pREBOA deployment may help maintain an appropriate cerebral perfusion pressure despite an increase in ICP; this may have minimized any exacerbation of TBI. Third, only a subset of patients demonstrate TBI progression during the first 24 hours following injury; therefore, detection of TBI progression is difficult early following injury as was the case in this experiment.40,41 Despite the absence of early worsening in brain lesion size and swelling following pREBOA deployment seen in this study, survival studies are required to further assess the effects of pREBOA deployment on neurologic outcomes and mortality following TBI and HS.
Although the presence of TBI is not a contraindication for pREBOA in HS, it is crucial for providers to be aware of the potential physiologic sequelae induced by TBI. The presence of TBI may significantly affect patient physiology, hemodynamics, and clinical outcomes following pREBOA deployment. For example, patients may require more fluid resuscitation, vasopressors, and pharmacologic therapies. Ultimately, this may translate into more utilization of resources, which is especially relevant for far-forward and other austere settings.
There are several limitations to this study. First, sample size in this study was limited by ethical considerations and costs, and therefore, the results may be prone to a type II error. Furthermore, there were unbalanced groups at the completion of the study given the increased mortality observed in the HS-TBI-pREBOA group; this finding may also affect the statistical analyses. Second, although swine are commonly used for human translation, they serve as an imperfect surrogate for human subjects. Studies of pREBOA application in patients with TBI are needed to confirm the results of this study. Third, we used a controlled-hemorrhage model for proof-of-concept testing of pREBOA in the setting of TBI and to minimize variability; however, uncontrolled hemorrhage models (from vascular injuries in the abdomen and pelvis) are more clinically realistic and optimal for testing pREBOA deployment. Fourth, objective thresholds were used to guide fluid resuscitation and vasopressor requirements even though resuscitation is often guided by fluid responsiveness in the clinical setting. Fluid responsiveness as a benchmark for resuscitation is highly subjective and operator dependent. Therefore, we used predefined thresholds to minimize investigator bias. Fifth, animals were not transfused blood during the study. We realize that this may not reflect clinical practice in urban centers; however, we sought to attain a worst case scenario with limited resuscitation and vasopressors, reflecting military or austere settings with delayed evacuation where blood products may not be available. Lastly, this study involved a short-term nonsurvival model. In the future, the effects of pREBOA deployment on long-term TBI progression and neurologic outcomes should be tested. Our team is planning follow-up studies to address many of these issues.
In conclusion, this study demonstrates that prolonged application of pREBOA in the setting of TBI does not contribute to early worsening of brain lesion size and swelling. However, the addition of TBI to HS-pREBOA may worsen the severity of shock and create a situation that is difficult to reverse with resuscitation. Although the presence of TBI is not a contraindication for pREBOA in HS, it is crucial for providers to be aware of the potential physiologic sequelae induced by TBI. Overall, the findings of this study support continued evaluation of pREBOA deployment in preclinical models of polytraumatic injuries, including HS, TBI, and multiorgan injuries.
A.M.W., J.E., and H.B.A. contributed in the conception and design. A.M.W., U.F.B., I.S.D., N.J.G., V.C.N., K.C., P.C., J.Z., and B.E.B. contributed in the data acquisition. A.M.W., U.F.B., I.S.D., N.J.G., V.C.N., K.C., P.C., J.Z., B.E.B., J.E., and H.B.A. contributed in the data interpretation. A.M.W., U.F.B., I.S.D., N.J.G., V.C.N., K.C., P.C., J.Z., B.E.B., J.E., and H.B.A. contributed in the article preparation. All authors contributed in the critical revision of the article.
We thank Dr. Patrick Georgoff, Dr. Yongqing Li, Rachael O'Connell, and Jessica Lee for their assistance with animal experiments. We would also like to acknowledge Prytime Medical (Lakewood, CO) who provided the pREBOA catheters for testing.
A.M.W. and H.B.A. received grant funding. For all other authors, no conflicts are declared. This work was funded by the US Army Materiel and Research Command (contract W81XWH-09-1-0520), National Institutes of Health grant 2 R01 GM084127, and the Frederick A. Coller Surgical Society Research Grant.
1. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, Pons PT. Epidemiology of trauma deaths: a reassessment. J Trauma
2. Acosta JA, Yang JC, Winchell RJ, Simons RK, Fortlage DA, Hollingsworth-Fridlund P, Hoyt DB. Lethal injuries and time to death in a level I trauma center. J Am Coll Surg
3. Kauvar DS, Wade CE. The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care
. 2005;9 Suppl 5:S1–S9.
4. Meislin H, Criss EA, Judkins D, Berger R, Conroy C, Parks B, Spaite DW, Valenzuela TD. Fatal trauma: the modal distribution of time to death is a function of patient demographics and regional resources. J Trauma
5. Martin M, Oh J, Currier H, Tai N, Beekley A, Eckert M, Holcomb J. An analysis of in-hospital deaths at a modern combat support hospital. J Trauma
. 2009;66(4 Suppl):S51–S60; discussion S-1.
6. Eastridge BJ, Jenkins D, Flaherty S, Schiller H, Holcomb JB. Trauma system development in a theater of war: Experiences from Operation Iraqi Freedom and Operation Enduring Freedom. J Trauma
. 2006;61(6):1366–72; discussion 1372–73.
7. Napolitano LM. Resuscitative endovascular balloon occlusion of the aorta: indications, outcomes, and training. Crit Care Clin
8. DuBose JJ, Scalea TM, Brenner M, Skiada D, Inaba K, Cannon J, Moore L, Holcomb J, Turay D, Arbabi CN, et al. The AAST prospective Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA) registry: data on contemporary utilization and outcomes of aortic occlusion and resuscitative balloon occlusion of the aorta (REBOA). J Trauma Acute Care Surg
9. Biffl WL, Fox CJ, Moore EE. The role of REBOA in the control of exsanguinating torso hemorrhage. J Trauma Acute Care Surg
10. Gupta BK, Khaneja SC, Flores L, Eastlick L, Longmore W, Shaftan GW. The role of intra-aortic balloon occlusion in penetrating abdominal trauma. J Trauma
11. Inoue J, Shiraishi A, Yoshiyuki A, Haruta K, Matsui H, Otomo Y. Resuscitative endovascular balloon occlusion of the aorta might be dangerous in patients with severe torso trauma: a propensity score analysis. J Trauma Acute Care Surg
. 2016;80(4):559–566. discussion 66–67.
12. Russo RM, Williams TK, Grayson JK, Lamb CM, Cannon JW, Clement NF, Galante JM, Neff LP. Extending the golden hour: partial resuscitative endovascular balloon occlusion of the aorta in a highly lethal swine
liver injury model. J Trauma Acute Care Surg
. 2016;80(3):372–8; discussion 378–80.
13. Russo RM, Neff LP, Lamb CM, Cannon JW, Galante JM, Clement NF, Grayson JK, Williams TK. Partial resuscitative endovascular balloon occlusion of the aorta in swine
model of hemorrhagic shock
. J Am Coll Surg
14. Sellmann T, Miersch D, Kienbaum P, Flohe S, Schneppendahl J, Lefering R. The impact of arterial hypertension on polytrauma and traumatic brain injury
. Dtsch Arztebl Int
15. Uchino H, Tamura N, Echigoya R, Ikegami T, Fukuoka T. “REBOA” — is it really safe? A case with massive intracranial hemorrhage possibly due to endovascular balloon occlusion of the aorta (REBOA)
. Am J Case Rep
16. Johnson MA, Williams TK, Ferencz SE, Davidson AJ, Russo RM, O'Brien WT Sr., Galante JM, Grayson JK, Neff LP. The effect of resuscitative endovascular balloon occlusion of the aorta, partial aortic occlusion
and aggressive blood transfusion on traumatic brain injury
in a swine
multiple injuries model. J Trauma Acute Care Surg
17. Jin G, DeMoya MA, Duggan M, Knightly T, Mejaddam AY, Hwabejire J, Lu J, Smith WM, Kasotakis G, Velmahos GC, et al. Traumatic brain injury
and hemorrhagic shock
: evaluation of different resuscitation strategies in a large animal model of combined insults. Shock
18. Imam AM, Jin G, Duggan M, Sillesen M, Hwabejire JO, Jepsen CH, DePeralta D, Liu B, Lu J, deMoya MA, et al. Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury
and hemorrhagic shock
19. Halaweish I, Bambakidis T, Chang Z, Wei H, Liu B, Li Y, Bonthrone T, Srinivasan A, Bonham T, Chtraklin K, et al. Addition of low-dose valproic acid to saline resuscitation provides neuroprotection and improves long-term outcomes in a large animal model of combined traumatic brain injury
and hemorrhagic shock
. J Trauma Acute Care Surg
. 2015;79(6):911–919. discussion 919.
20. Williams AM, Dennahy IS, Bhatti UF, Halaweish I, Xiong Y, Chang P, Nikolian VC, Chtraklin K, Brown J, Zhang Y, et al. Mesenchymal stem cell-derived exosomes provide neuroprotection and improve long-term neurologic outcomes in a swine
model of traumatic brain injury
and hemorrhagic shock
. J Neurotrauma
. 2018; Jul 30. doi: 10.1089/neu.2018.5711.
21. Nikolian VC, Georgoff PE, Pai MP, Dehaney IS, Chtraklin K, Eidy H, Ghandour M, Han Y, Srinivasan A, Li Y, et al. Valproic acid decreases brain lesion size and improves neurologic recovery in swine
subjected to traumatic brain injury
, hemorrhagic shock
, and polytrauma. J Trauma Acute Care Surg
. 2017. 83(6):1066–73.
22. Rhee P, Talon E, Eifert S, Anderson D, Stanton K, Koustova E, Ling G, Burris D, Kaufmann C, Mongan P, et al. Induced hypothermia during emergency department thoracotomy: an animal model. J Trauma
. 2000;48(3):439–47; discussion 447–50.
23. Jin G, Duggan M, Imam A, Demoya MA, Sillesen M, Hwabejire J, Jepsen CH, Liu B, Mejaddam AY, Lu J, et al. Pharmacologic resuscitation for hemorrhagic shock
combined with traumatic brain injury
. J Trauma Acute Care Surg
24. Chauhan NB. Chronic neurodegenerative consequences of traumatic brain injury
. Restor Neurol Neurosci
25. Menon DK, Schwab K, Wright DW, Maas AI. Position statement: definition of traumatic brain injury
. Arch Phys Med Rehabil
26. Alam HB. Trauma care: Finding a better way. PLoS Med
27. Freeman WD, Aguilar MI. Intracranial hemorrhage: diagnosis and management. Neurol Clin
. 2012;30(1):211–240. ix.
28. Mori T, Katayama Y, Kawamata T. Acute hemispheric swelling associated with thin subdural hematomas: pathophysiology of repetitive head injury in sports. Acta Neruochir Suppl
29. Norii T, Crandall C, Terasaka Y. Survival of severe blunt trauma patients treated with resuscitative endovascular balloon occlusion of the aorta compared with propensity score-adjusted untreated patients. J Trauma Acute Care Surg
30. Madurska MJ, Jansen JO, Reva VA, Mirghani M, Morrison JJ. The compatibility of computed tomography scanning and partial REBOA: a large animal pilot study. J Trauma Acute Care Surg
31. Matsumura Y, Matsumoto J, Kondo H, Idoguchi K, Ishida T, Kon Y, Tomita K, Ishida K, Hirose T, Umakoshi K, et al. Fewer REBOA complications with smaller devices and partial occlusion: evidence from a multicentre registry in Japan. Emerg Med J
32. DuBose JJ. How I do it: partial resuscitative endovascular balloon occlusion of the aorta (P-REBOA). J Trauma Acute Care Surg
33. Johnson MA, Neff LP, Williams TK, DuBose JJ. Partial resuscitative balloon occlusion of the aorta (P-REBOA): clinical technique and rationale. J Trauma Acute Care Surg
. 2016;81(5 Suppl 2 Proceedings of the 2015 Military Health System Research Symposium):S133–s7.
34. Causey MW, Miller S, Hoffer Z, Hempel J, Stallings JD, Jin G, Alam H, Martin M. Beneficial effects of histone deacetylase inhibition with severe hemorrhage and ischemia-reperfusion injury. J Surg Res
35. Sokol KK, Black GE, Shawhan R, Marko ST, Eckert MJ, Tran NT, Starnes BW, Martin MJ. Efficacy of a novel fluoroscopy-free endovascular balloon device with pressure release capabilities in the setting of uncontrolled junctional hemorrhage. J Trauma Acute Care Surg
36. Williams TK, Neff LP, Johnson MA, Ferencz SA, Davidson AJ, Russo RM, Rasmussen TE. Extending resuscitative endovascular balloon occlusion of the aorta: endovascular variable aortic control in a lethal model of hemorrhagic shock
. J Trauma Acute Care Surg
37. Krishnamoorthy V, Mackensen GB, Gibbons EF, Vavilala MS. Cardiac dysfunction after neurologic injury: what do we know and where are we going? Chest
38. Lim HB, Smith M. Systemic complications after head injury: a clinical review. Anaesthesia
39. Nguyen H, Zaroff JG. Neurogenic stunned myocardium. Curr Neurol Neurosci Rep
40. Juratli TA, Zang B, Litz RJ, Sitoci KH, Aschenbrenner U, Gottschlich B, Daubner D, Schackert G, Sobottka SB. Early hemorrhagic progression of traumatic brain contusions: frequency, correlation with coagulation disorders, and patient outcome: a prospective study. J Neurotrauma
41. Kurland D, Hong C, Aarabi B, Gerzanich V, Simard JM. Hemorrhagic progression of a contusion after traumatic brain injury
: a review. J Neurotrauma
Keywords:© 2019 Lippincott Williams & Wilkins, Inc.
Traumatic brain injury; hemorrhagic shock; partial aortic occlusion; noncompressible torso hemorrhage; swine