Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a technique to control noncompressible torso hemorrhage in adults. However, the use of REBOA has not expanded to pediatric patients, and there is a paucity of data on the use of this technology in children. Pediatric mortality from hemorrhagic injuries both during recent armed conflicts and in the United States' civilian population suggests an opportunity for potential REBOA use. In the most recent wars in Iraq and Afghanistan, a vascular injury within the torso was the cause of death in 71.4% of the pediatric patients with a vascular injury. Furthermore, 43% of the deaths occurred on the operating room table because the hemorrhage could not be controlled before exsanguination.1 In the United States, a pediatric trauma patient requiring greater than 20 mL/kg of blood products has a strikingly high 24-hour mortality rate of 23.1%.2 Resuscitative endovascular balloon occlusion of the aorta should be evaluated as a hemorrhage control adjunct to potentially reduce mortality due to hemorrhage in pediatric trauma patients.
We have previously shown that complete zone 1 (supraceliac) aortic occlusion was feasible and improved hemorrhage control with a trend toward improved survival time when compared with no REBOA in a pediatric swine liver injury model.3 However, the tolerable duration of aortic occlusion in a pediatric population is unknown. In adults, less than 60 minutes of zone 1 aortic occlusion is recommended based on translational evidence of an irreversible ischemia reperfusion injury with occlusion times longer than 60 minutes.4,5 Children have a different tolerance for and physiologic response to trauma than adults, so the guidelines for adults cannot be directly translated to the pediatric population.6
We developed a pediatric swine controlled hemorrhage model to evaluate the physiologic effects of increasing durations of zone 1 REBOA. Our objective was to determine the duration of zone 1 REBOA that pediatric swine would tolerate without inducing an irreversible physiologic insult defined as a failure to return to physiologic baseline with critical care. We hypothesized that pediatric swine could undergo at least 60 minutes of zone 1 REBOA and return to physiologic baseline with critical care. Sixty minutes was selected given the pediatric patient's robust response to trauma and improved ability to recover when compared with adults.6
This study was approved by the Institutional Animal Care and Use Committee at David Grant USAF Medical Center, Travis Air Force Base, California under protocol FDG20180028A. The care and use of all animals were in strict compliance with the Guide for the Care and Use of Laboratory Animals in a facility accredited by the Association for the Assessment and Accreditation of the Laboratory Animal Care International. Twelve juvenile male Yorkshire cross swine (S & S Farms, Ramona, CA) arrived together and were acclimated in conventional indoor group housing for at least 10 days prior to use. The housing structure maintained a consistent temperature and humidity with a 12–12-h light-dark cycle that was controlled by a system engineered and maintained to meet Institute of Laboratory Animal Resources Guide recommendations. The animals were provided visual, olfactory and tactile contact with conspecifics, social interaction, and enrichment. They were fed twice daily with daily monitoring of their health status.
Twelve child-sized juvenile Yorkshire cross swine (pediatric swine), approximately 2 months to 3 months of age, weighing 20 kg to 30 kg, the mean weight of a 5- to 10-year-old human child, were utilized in the study.7,8 Sample size was calculated using the resource equation method with 12 animals and two treatment groups yielding an error term of 10.9 All swine underwent a controlled hemorrhage. Six pediatric swine first underwent 60 minutes of zone 1 REBOA because this is the upper limit of the recommended duration of complete zone 1 occlusion in adults.4,10 All swine then underwent critical care for 4 hours or until death, whichever came first. Based on the high mortality rate and poor physiologic status of these pediatric swine, the next six pediatric swine underwent 30 minutes of REBOA, as opposed to a longer occlusion time of 90 minutes. The study schema is depicted in Figure 1.
General anesthesia was induced, the pediatric swine were intubated and maintenance crystalloid fluids were administered. An open splenectomy was performed to eliminate the robust autotransfusion capability of the spleen in swine.11,12 A cystostomy was performed to accurately measure urine output. Vascular access was obtained through bilateral external jugular veins, the right carotid artery and bilateral femoral arteries (4-Fr and 6-Fr sheaths). A target proximal mean arterial pressure (pMAP) of at least 60 mm Hg was achieved with the use of up to three 20-mL/kg boluses of crystalloid followed by a norepinephrine infusion starting at 0.01 mcg/kg/min and titrated every 3 minutes to 5 minutes, if needed, to ensure pre-hemorrhage euvolemia and to counteract the vasodilatory effects of anesthesia. A deflated 5.5-Fr Fogarty catheter (Edwards Lifesciences, Irvine, CA) was placed in zone 1 of the aorta through the 6-Fr common femoral arterial sheath to serve as the aortic occluding device (Fig. 1).
Swine were hemorrhaged 60% of their total blood volume (TBV). Total blood volume was estimated as 67.3 mL/kg.12 The controlled hemorrhage was performed over 30 minutes at a variable rate to simulate the nonlinear rate of hemorrhage from a traumatic injury and to induce a physiologic response more similar to that from trauma.13 Sixty percent hemorrhage was selected because it reliably produced a mean pMAP of 20 mm Hg to 30 mm Hg during model development experiments, representing severe hemorrhagic shock where REBOA could be considered for immediate hemorrhage control. The start of hemorrhage marked time 0 of the experiment (Fig. 1).
The 5.5-Fr Fogarty catheter (Edwards Lifesciences, Irvine, CA) was completely inflated in zone 1 to obtain complete aortic occlusion for either 30 minutes or 60 minutes after the completion of hemorrhage (Fig. 1). Complete aortic occlusion was clinically achieved when distal mean arterial pressure (dMAP) was less than 15 mm Hg without a pulsatile waveform. Occlusion was confirmed with angiography immediately after occlusion and again halfway through the occlusion period. The balloon was then deflated over 10 minutes. A longer deflation time was selected, as opposed to the typical 5-minute deflation period used in adult swine experiments, because it resulted in improved postdeflation hemodynamic stability during our model development experiments.14–16
All pediatric swine underwent 240 minutes of critical care after REBOA balloon deflation (Fig. 1). The full volume of shed blood (autologous whole blood) was transfused starting 10 minutes before balloon deflation and ending 5 minutes after balloon deflation. This simulated a patient with REBOA undergoing resuscitation prior to balloon deflation in preparation for the physiologic effects of reperfusion. The goal pMAP during critical care was 60 mm Hg. If pMAP was less than 60 mm Hg, up to two 20 mL/kg boluses of crystalloid were given. If pMAP remained below 60 mm Hg and the animal was fluid-responsive, boluses were continued. Otherwise, norepinephrine was administered and titrated to a pMAP of 60 mm Hg with a maximum rate of 0.2 mcg/kg/min. If the pediatric swine were not responsive to norepinephrine, a crystalloid bolus was trialed again and every 60 minutes thereafter. Hypoglycemia, hyperkalemia and hypocalcemia were treated per standardized protocols. The study concluded at the end of critical care or death, whichever came first. Criteria for death were asystole, pMAP less than 10 mm Hg for 5 minutes or end-tidal carbon dioxide less than 10 mm Hg for 5 minutes. Necropsy was performed on all swine. Tissues were fixed in 10% buffered formalin solution, routinely processed, embedded in paraffin, and stained with hematoxylin and eosin. Heart, kidney, lung, liver, spinal cord, and muscle injury were scored from 0 to 4 (0, no gross injury; 1, focal injury; 2, multifocal injury; 3, locally extensive injury; and 4, generalized injury). Duodenal injury was scored from 0 to 3 (0, no gross injury; 1, less than 25%; 2, 25% to 50%; and 3, greater than 50% mucosal necrosis).
Continuous recorded physiologic data included: pMAP, dMAP, heart rate (HR), and central venous pressure (CVP). Blood was obtained for complete blood count, comprehensive metabolic panel, and serum metanephrine and catecholamine assays at baseline, time 0 and at the end of critical care in all surviving pediatric swine (Fig. 1). Arterial blood gases (ABGs) analyses were performed at baseline, time 0 and every 30 minutes until the end of the study or death.
Normally distributed data are presented as mean ± standard deviation and compared with a t-test. Survival time was analyzed with a log-rank test. Laboratory values and vital signs over time were compared with a mixed-effect model and post hoc Fisher's least significant difference test. Histology results are presented as median (interquartile range), and analyzed with a Mann-Whitney U tests. All analyses were performed using GraphPad Prism version 8.0.0 (GraphPad Software, San Diego, CA). Significance was set at p less than 0.05.
One pediatric swine in the 60-minute REBOA group (60R) and three in the 30-minute REBOA group (30R) were excluded from analysis because we were not able to maintain complete aortic occlusion for the duration of intervention due to either the Fogarty balloon flipping or the aortic diameter exceeding the maximum inflation diameter of the balloon due to compensatory aortic dilation after initial inflation. Therefore, complete data analysis was performed on five 60R and three 30R pediatric swine. There were no statistically significant differences in baseline characteristics, laboratory values, vital signs or percent of TBV hemorrhaged between the two groups, except for an elevated blood urea nitrogen in the 30R compared with the 60R pediatric swine by chance (10.0 ± 1.0 vs. 7.8 ± 0.8, p = 0.02).
There was no difference in survival time between the two groups (p = 0.99, Fig. 2). All swine survived the hemorrhage and REBOA phases, but not all survived the critical care phase. Two 60R pediatric swine died 23 minutes and 50 minutes after balloon deflation, whereas one 30R pediatric swine died 16 minutes after balloon deflation.
Compared with baseline complete blood count and comprehensive metabolic panel values, both the 60R and 30R pediatric swine had elevated end white blood cell count (17.1 ± 3.7 vs. 25.2 ± 3.4 × 1010/L, p = 0.02 and 14.2 ± 2.3 vs. 21.4 ± 1.2 × 1010/L, p = 0.03, respectively), aspartate transaminase (8.6 ± 0.7 U/L vs. 403.0 ± 245.2 U/L, p = 0.01 and 17.0 ± 7.8 U/L vs. 116.0 ± 36.8 U/L, p = 0.02, respectively) and alkaline phosphatase (310.4 ± 124.4 U/L vs. 266.7 ± 114.6 U/L, p = 0.03 and 114.0 ± 7.8 U/L vs. 158.5 ± 17.7 U/L, p = 0.03, respectively). Compared with baseline, only 60R pediatric swine had a decreased end carbon dioxide (30.7 ± 3.2 mEq/L vs. 22.5 ± 4.1 mEq/L, p = 0.02), and increased end creatinine (1.0 ± 0.1 mg/dL vs. 1.7 ± 0.3 mg/dL, p = 0.002) and creatinine kinase (335.4 ± 56.4 U/L vs. 961.0 ± 170.7 U/L, p = 0.0002). This is in contrast to the 30R pediatric swine who, compared with baseline, did not have a difference in end carbon dioxide (29.7 ± 5.0 mEq/L vs. 31.6 ± 0.1 mEq/L, p = 0.65), creatinine (0.9 ± 0.1 mg/dL vs. 1.2 ± 0.2 mg/dL, p = 0.06) or creatinine kinase (432.7 ± 201.5 U/L vs. 769.5 ± 178.9 U/L, p = 0.15).
There were no differences between time 0 and end values of 60R and 30R groups' metanephrine (4.7 ± 0.8 ng/mL vs. 4.7 ± 1.0 ng/mL, p = 0.98 and 4.3 ± 2.6 ng/mL vs. 3.6 ± 2.4 ng/mL, p = 0.81 respectively) or catecholamine levels (116.1 ± 23.7 ng/mL vs. 175.0 ± 77.3 ng/mL, p = 0.15 and 82.7 ± 20.2 ng/mL vs. 95.0 ± 20.8 ng/mL, p = 0.56).
The 30R pediatric swine had ABG values that deviated less from baseline during the experiment and returned to baseline sooner than the 60R pediatric swine. Over the course of the experiment, compared with 60R pediatric swine, 30R pediatric swine had a higher bicarbonate (HCO3) (p = 0.01), and lower base excess (p = 0.02) and lactate (p = 0.02). There was no difference in pH between the 30R and 60R groups (p = 0.08). On post hoc analysis, the differences between the groups mostly occurred during critical care (Fig. 3). Furthermore, 30R pediatric swine's HCO3, base excess, lactate and pH returned to baseline during critical care. This is in contrast to the 60R pediatric swine where HCO3, base excess, lactate and pH persistently differed from baseline, with worsening values at the end of critical care (Fig. 3).
Overall, the groups differed in pMAP (p = 0.03), dMAP (p = 0.007) and HR (p = 0.02), but not CVP (p = 0.29). The 30R group had a higher pMAP and HR than the 60R group at the end of REBOA and during critical care (Fig. 4). The 30R group also had a higher dMAP than the 60R group during critical care (Fig. 4). When compared with baseline, the 30R group's pMAP and dMAP no longer differed from baseline during critical care, but HR was persistently higher than baseline throughout the experiment (Fig. 4). In contrast, the 60R group's pMAP and dMAP were persistently lower than baseline, and HR was persistently higher than baseline (Fig. 4). Central venous pressure did not differ from baseline in both groups during critical care (Fig. 4).
Critical Care Needs, Urine Output and Histology
Surviving pediatric swine in the 60R group required more norepinephrine than animals in the 30R group (47.7 ± 4.5 mL vs. 0.0 ± 0.0 mL, p = 0.007). All of the 60R pediatric swine required norepinephrine at the end of critical care while none of the 30R pediatric swine required norepinephrine during critical care. Throughout the experiment, there were no differences between the 30R and 60R groups in the required number of boluses (p = 0.97), glucose (p = 0.44), insulin for hyperkalemia (p = 0.55) or calcium (p = 0.74).
There was no difference in the urine output of the surviving pediatric swine in the 60R and 30R groups over the course of the experiment when controlled for time (p = 0.27).
There were no differences in histologic injury scores between the 60R and 30R groups in heart (1 [0.25–1.75] vs. 0 [0–2], p = 0.37), lung (0 [0–3] vs. 0 [0–0], p = 0.57), liver (4 [3.25–4] vs. 4 [0–4], p = 0.43), kidney (3.5 [2–4] vs. 3 [3–4], p = 0.45), duodenum (0 [0–0.75] vs. 0 [0–0], p = 0.57), ileum (1 [0–2.75] vs. 0 [0–1], p = 0.29), colon (2 [0.25–3] vs. 1 [0–2], p = 0.31), skeletal muscle (0 [0–1.5] vs. 0 [0–1], p = 0.50), and spinal cord (0 [0–0] vs. 0 [0–0], p = 0.57) tissues.
In a controlled hemorrhage model, pediatric swine had near complete recovery of hemodynamic and laboratory values to baseline after a 60% TBV hemorrhage and 30 minutes of zone 1 REBOA, while the pediatric swine that underwent 60 minutes of REBOA did not. After 4 hours of critical care following balloon deflation, pediatric swine who underwent 60 minutes of REBOA had a persistent and worsening metabolic acidosis, a persistently elevated lactate, and required vasopressors. In contrast, swine that underwent 30 minutes of REBOA had a resolved metabolic acidosis, a lactate that was no different than baseline, and did not require vasopressors. Pediatric swine were able to physiologically recover after 30 minutes of REBOA, whereas 60 minutes of REBOA resulted in significant and persistent laboratory and hemodynamic derangements, suggesting an irreversible physiologic insult.
The physiologic changes observed with REBOA in this study were consistent with previous animal and human studies.5,16–18 Resuscitative endovascular balloon occlusion of the aorta produces an ischemic injury distal to the balloon and hemodynamic instability following reperfusion.17 Both groups in this study developed laboratory evidence of liver and kidney injury, lactic acidosis, and abnormal vital signs during critical care. The severity of the physiologic injury increased with the increased duration of aortic occlusion.
The pediatric swine were able to withstand a much greater percent hemorrhage than adult swine. In adult swine models, the typical percent of TBV hemorrhaged is 25% to 35%, which produces MAPs less than 40 mm Hg.15,16,19–21 Though we were aiming for a slightly lower MAP range of 20 mm Hg to 30 mm Hg to simulate a situation where REBOA could be immediately indicated, the pediatric swine required a 60% TBV hemorrhage to reach this level of hypotension. This further supports the general belief the pediatric patients have a more robust hemodynamic response to hemorrhage than adults.6
Though the pediatric patients are able to withstand and recover from hemorrhage better than adults, it does not appear that pediatric swine can tolerate longer durations of REBOA than an adult population.4,6,22 We hypothesized that pediatric swine could undergo at least 60 minutes of zone 1 REBOA, a longer duration of REBOA than the adult population, without inducing an unrecoverable physiologic insult because of their robust response to trauma and improved ability to recover.6 However, 40% of the swine in the 60R group died during critical care. They had a persistent and worsening metabolic acidosis with a final mean arterial carbon dioxide concentration of 18.4 mmol/L and final mean lactate concentration of 5.6 mmol/L. They also had a persistent and worsening base deficit despite a normal CVP. Finally, MAP remained decreased despite fluid resuscitation and vasopressor use. The pediatric swine were not able to physiologically recover from 60 minutes of REBOA within the 4 hours of critical care in this study.
Differing from the ER-REBOA catheter (Prytime Medical, Boerne, TX) commonly used in adult patients, which often does not require full inflation of the balloon to obtain complete zone 1 aortic occlusion, the 5.5-Fr Fogarty catheter (Edwards Lifesciences, Irvine, CA) required complete inflation to obtain aortic occlusion. While this initially occluded the aortic lumen in our experiment, compensatory vasodilation widened the aortic diameter beyond the maximum diameter of the 5.5-Fr Fogarty balloon in some pediatric swine, leading to loss of complete occlusion. When this occurs in adults with the ER-REBOA catheter in place, additional volume can be added to the balloon. This was not possible with the 5.5-Fr Fogarty catheter because it was already maximally inflated. A larger balloon would have required a larger sheath, which is too large for the femoral vessels in the younger patient population. An alternative is the NuMed balloon catheter (NuMed Inc., Hopkinton, NY) which allows a larger balloon through a 6-Fr sheath, however the balloon occludes 25% of aortic flow while deflated, which was unacceptably high for this study. The Fogarty catheter itself was also not stiff enough to withstand the force of aortic blood flow. Without a wire, the balloon contorted into a knot, migrated distally, or flipped (Fig. 5). Therefore, it is not feasible with the current technology to safely perform REBOA and maintain aortic occlusion without a wire-based balloon catheter in pediatric patients that are too small to accommodate the ER-REBOA catheter. Though there may be fewer opportunities to use pediatric REBOA than in the adult population, there are still many benefits of developing a smaller REBOA device. There has already been a trend toward downsizing the access sheath required to place the REBOA catheter, which has decreased vascular complications in adults.5,23 An even smaller access sheath may further decrease this risk. It could also potentially allow use of the device in smaller vessels, such as the subclavian artery via access of the brachial artery, for immediate hemorrhage control in other anatomic regions. Thus, developing a smaller REBOA catheter might have a board use.
There are multiple limitations of this study. The pediatric swine were not randomized. This was done because we could only evaluate two durations of aortic occlusion. Based on our initial results following 60 minutes of occlusion, we evaluated a second shorter duration, as opposed to a longer duration. Unfortunately, the number of animals in the final data analysis in each group was further reduced due to incomplete occlusion of the aorta. The physiologic effects were assessed up to 4 hours after balloon deflation which might be too early to show the full extent of injury or ability to ultimately recover. This was also a controlled hemorrhage model, which does not incorporate the additional effects due to tissue injury. However, this model was selected to obtain a precise, consistent and standardized hemorrhage in all pediatric swine.24,25 To make the model more closely approximate a traumatic hemorrhage model, a variable rate of hemorrhage was used with hemorrhage occurring at a faster rate initially then tapering off.13 This could have contributed to the incomplete occlusion with the 5.5-Fr Fogarty catheter (Edwards Lifesciences, Irvine, CA), as the arterial vasoconstriction may not have been as drastic as it would have been in an uncontrolled injury model. Additionally, the common femoral artery sheath was placed prior to the hemorrhage, removing the rate limiting step of cannulating a vasoconstricted pediatric common femoral artery. This was done to standardize the time of intervention.
In a controlled hemorrhage model, pediatric swine were able to recover to baseline after a 60% TBV hemorrhage and 30 minutes of complete zone 1 REBOA. If a pediatric patient presents with a massive noncompressible torso hemorrhage and immediate hemorrhage control is needed, complete zone 1 REBOA for 30 minutes or less may be a bridge to operative hemorrhage control. Complete zone 1 occlusion times longer than 30 minutes should be done with extreme caution.
Further research is needed to develop a pediatric specific REBOA catheter. Ideally, a pediatric REBOA catheter could be placed through a 4-Fr sheath, would be stiff enough to withstand the pressure of aortic flow, minimally occlude aortic flow while deflated and have a large enough maximum balloon diameter to prevent the partial occlusion we experience in this experiment. Additionally, future studies should be done to evaluate the efficacy and tolerable duration of partial aortic occlusion versus complete aortic occlusion in the pediatric patient population.
In conclusion, pediatric swine were able to recover from the physiologic insult of a 60% TBV hemorrhage and 30 minutes of zone 1 REBOA. However, the physiologic insult after a longer REBOA occlusion time of 60 minutes persisted and was worsening after 4 hours of critical care. Sixty minutes of complete zone 1 aortic occlusion may lead to an irreversible physiologic insult in the pediatric patient population, whereas 30 minutes may be acceptable. If a Fogarty catheter is used as the REBOA device, it should not be utilized without a wire.
K.J.Y. participated in the literature search. K.J.Y., L.A.G., J.K.G., M.A.J., C.A.B., A.M.W., J.T.S. participated in the study design. K.J.Y., L.A.G., J.K.G., M.A.J., C.A.B., M.W.S., C.M.C., A.F.T., J.T.S. participated in the data collection. K.J.Y., M.A.J., J.T.S. participated in the data analysis and interpretation. K.J.Y. participated in the drafting of the article. All authors critically revised the article and approved the final version for publication.
We would like to thank the staff at the Clinical Investigation Facility, David Grant Medical Center for their outstanding technical assistance and support.
Funding for this study was provided by The Clinical Investigation Facility, David Grant USAF Medical Center, Travis Air Force Base, Fairfield, CA. Author LG was supported by the National Center for Advancing Translation Sciences, National Institutes of Health, through grant number UL1TR001860. The content is solely the responsibility of the authors and does not represent the official views of the NIH.
Disclosure of funding from the NIH: L.G. was supported by the National Center for Advancing Translation Sciences, National Institutes of Health, through grant number UL1TR001860. The content is solely the responsibility of the authors and does not represent the official views of the NIH.
The authors declare no conflicts of interest.
M.A.J. is a founder and shareholder of Certus Critical Care Inc.
The views expressed in this material are those of the authors and do not reflect the official policy or position of the U.S. Government, the Department of Defense, or the Department of the Air Force. The animals involved in this study were procured, maintained, and used in accordance with the Laboratory Animal Welfare Act of 1966, as amended, and the Guide for the Care and Use of Laboratory Animals, National Research Council. The work reported herein was performed under United States Air Force Surgeon General-approved Clinical Investigation Number FDG20180028A.
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