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Selective aortic arch perfusion with fresh whole blood or HBOC-201 reverses hemorrhage-induced traumatic cardiac arrest in a lethal model of noncompressible torso hemorrhage

Hoops, Heather E. MD; Manning, James E. MD; Graham, Todd L. BS; McCully, Belinda H. PhD; McCurdy, Shane L. BS; Ross, James D. PhD

Journal of Trauma and Acute Care Surgery: August 2019 - Volume 87 - Issue 2 - p 263–273
doi: 10.1097/TA.0000000000002315
AAST 2018 PODIUM
Free
SDC
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BACKGROUND Hemorrhage-induced traumatic cardiac arrest (HiTCA) has a dismal survival rate. Previous studies demonstrated selective aortic arch perfusion (SAAP) with fresh whole blood (FWB) improved the rate of return of spontaneous circulation (ROSC) after HiTCA, compared with resuscitative endovascular balloon occlusion of the aorta and cardiopulmonary resuscitation (CPR). Hemoglobin-based oxygen carriers, such as hemoglobin-based oxygen carrier (HBOC)-201, may alleviate the logistical constraints of using FWB in a prehospital setting. It is unknown whether SAAP with HBOC-201 is equivalent in efficacy to FWB, whether conversion from SAAP to extracorporeal life support (ECLS) is feasible, and whether physiologic derangement post-SAAP therapy is reversible.

METHODS Twenty-six swine (79 ± 4 kg) were anesthetized and underwent HiTCA which was induced via liver injury and controlled hemorrhage. Following arrest, swine were randomly allocated to resuscitation using SAAP with FWB (n = 12) or HBOC-201 (n = 14). After SAAP was initiated, animals were monitored for a 20-minute prehospital period prior to a 40-minute damage control surgery and resuscitation phase, followed by 260 minutes of critical care. Primary outcomes included rate of ROSC, survival, conversion to ECLS, and correction of physiology.

RESULTS Baseline physiologic measurements were similar between groups. ROSC was achieved in 100% of the FWB animals and 86% of the HBOC-201 animals (p = 0.483). Survival (t = 320 minutes) was 92% (11/12) in the FWB group and 67% (8/12) in the HBOC-201 group (p = 0.120). Conversion to ECLS was successful in 100% of both groups. Lactate peaked at 80 minutes in both groups, and significantly improved by the end of the experiment in the HBOC-201 group (p = 0.001) but not in the FWB group (p = 0.104). There was no significant difference in peak or end lactate between groups.

CONCLUSION Selective aortic arch perfusion is effective in eliciting ROSC after HiTCA in a swine model, using either FWB or HBOC-201. Transition from SAAP to ECLS after definitive hemorrhage control is feasible, resulting in high overall survival and improvement in lactic acidosis over the study period.

From the Department of Surgery (H.E.H.), Oregon Health and Science University, Portland, Oregon; Department of Emergency Medicine (J.E.M., S.L.M.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Division of Trauma, Critical Care and Acute Care Surgery (T.L.G., B.H.M., J.D.R.), Oregon Health and Science University, Portland, Oregon.

Submitted: August 1, 2018, Revised: February 27, 2019, Accepted: March 16, 2019, Published online: April 18, 2019.

Presented at the 77th Annual Meeting at American Association for the Surgery of Trauma, September 26–29, 2018, in San Diego, CA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.jtrauma.com).

Address for reprints: James D. Ross, PhD, Division of Trauma, Critical Care and Acute Care Surgery, Department of Surgery, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Rd, Portland, OR 97239; email: rosja@ohsu.edu.

Online date: April 24, 2019

Hemorrhage is the leading cause of preventable traumatic death in both military and civilian settings, with most deaths occurring prior to medical treatment facility arrival.1–4 Hemorrhage-induced traumatic cardiac arrest (HiTCA) represents the most severe state of hemorrhagic shock, with a dismal survival rate of 0% to 20% despite current treatment methods (closed-chest compressions, resuscitative thoracotomy, and concurrent blood product resuscitation).5–7 Using resuscitative endovascular balloon occlusion of the aorta (REBOA) to achieve aortic hemostasis has not improved survival rates in HiTCA8 and may increase mortality.9 More efficacious treatment options for HiTCA are needed.

Selective aortic arch perfusion (SAAP) is a novel endovascular aortic occlusion technique that provides the same hemostatic effects as REBOA, but can additionally provide intra-aortic perfusion of the brain and coronary arteries for treatment of HiTCA.10 While REBOA is effective at treating severe hemorrhagic shock in both a swine model and in clinical settings,8,11–16 its efficacy in HiTCA is limited.8,17 Previous studies demonstrated that SAAP using oxygen-carrying perfusates are more effective than SAAP with Lactated Ringer's,17,18 REBOA17 and closed-chest compressions (unpublished data) with whole blood resuscitation for reversing HiTCA in a swine model.

Blind placement of intra-arterial catheters in patients with cardiac arrest in a prehospital setting has been shown to be feasible.8,19–21 However, the logistics of using SAAP with fresh whole blood (FWB) presents a challenge in the prehospital environment due to storage considerations and citrate-related calcium sequestration, requiring coadministration of exogenous calcium.22

While controversial in use associated with elective surgery,23–25 and presently not FDA-approved, the benefits of hemoglobin-based oxygen carrier (HBOC)-201 (HbO2 Therapeutics, Souderton, PA) and other hemoglobin-based oxygen carriers may outweigh risks in settings where blood products are unavailable or unacceptable due to austere medical environments or religious preferences.26,27

Selective aortic arch perfusion using HBOC-201 has been shown to effectively achieve return of spontaneous circulation (ROSC) after HiTCA in a swine model.18 HBOC-201 may provide additional benefit in the treatment of HiTCA in austere environments or emergent settings as it does not require calcium co-administration. However, there have been no previous randomized trials comparing the efficacy of SAAP with FWB to HBOC-201 in the treatment of HiTCA.

After ROSC, ongoing cardiovascular support may be needed due to severe cardiac dysfunction and systemic physiologic derangements from ischemia-reperfusion injury. Venoarterial extracorporeal life support (ECLS) has been successfully used in trauma patients with prehospital or in-hospital HiTCA,28,29 with a published survival rate of 42% to 63% in a recent systematic review.30

We hypothesized that there will be similar rates of ROSC and short-term survival after HiTCA treated with SAAP therapy using either FWB or HBOC-201. Secondarily, we assessed the feasibility of conversion from SAAP to ECLS to provide additional ongoing hemodynamic support. We hypothesized that SAAP followed by conversion to ECLS would be feasible and promote reversal of lactic acidosis over the study period.

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METHODS

Study Design and Overview

This study was approved by the Oregon Health and Science University Institutional Animal Care and Use Committee. Twenty-six fasting male Yorkshire swine (Sus scrofa, 78.8 [3.9] kg) were obtained from a single source animal vendor (Oakhill Genetics, Ewing, IL). Swine were randomly allocated into two groups (FWB and HBOC-201). Investigators were blinded to randomization during preparatory phases. The study protocol was divided into five phases: preparation, injury, intervention, damage control surgery (DCS) with concurrent FWB resuscitation, and critical care (Fig. 1).

Figure 1

Figure 1

After sedation, induction of anesthesia, preparation, and 10-minute stabilization, a liver injury was performed followed by controlled hemorrhage to induce HiTCA. Animals were then randomized and resuscitated in accordance with their intervention group. The prehospital phase consisted of 20 minutes from SAAP intervention, followed by a 40-minute DCS and DCR phase, then a subsequent 260-minute critical care phase for a total study period of 320 minutes.

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Experimental Preparation

Sedation and analgesia were achieved with intramuscular Telazol (8 mg/kg; Zoetis Services, Parsippany, NJ) and intramuscular buprenorphine (0.025 mg/kg). Animals were intubated and general anesthesia was maintained using continuous inhaled isoflurane (1–3%) until HiTCA was achieved. Tidal volumes were set at 6 mL/kg to 8 mL/kg, and end-tidal CO2 (EtCO2) was maintained in a range of 38 mm Hg to 42 mm Hg until initiation of injury. The inspired fraction of oxygen (FIO2) was weaned to atmospheric level. After injury initiation, ventilator settings were not altered, allowing EtCO2 to be a surrogate for the effectiveness of resuscitation during the prehospital period.

Following induction, electrocardiographic monitoring was established. The left carotid artery, right femoral artery, right external jugular vein (EJV), left EJV (x2), and right femoral vein were cannulated using ultrasound-guided percutaneous Seldinger technique, with percutaneous catheters placed for blood sampling, physiologic monitoring, and subsequent resuscitation. A pulmonary artery thermodilution catheter (Edwards Lifesciences, Irvine, CA) was inserted through the right EJV sheath. A 14-Fr sheath was inserted into the left femoral artery to facilitate deployment of the SAAP catheter. A right carotid artery cut down was performed to place an ultrasonic flow probe (Transonic Systems Inc, Ithaca, NY). A transesophageal defibrillation probe was fashioned by rolling the posterior external defibrillator pad (Zoll, Chelmsford, MA) around a 20-Fr plastic tube stiffened by a flexible metal stylet. The anterior defibrillation pad was placed on the anterior left chest, and the posterior pad was lubricated using electrically conductive gel and inserted into the esophagus so that the pad was situated posterior to the heart.

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Surgical Preparation

In accordance with the established swine model of Non-Compressible Torso Hemorrhage (NCTH), a midline laparotomy and splenectomy were performed, four abdominal wall laparoscopic ports were placed, then the abdomen was closed.27 Based on surface measurements, the SAAP catheter was inserted into the left femoral sheath with the deflated aortic balloon advanced to the thoracic aorta. A 10-minute stabilization period was observed prior to obtaining baseline blood samples and physiologic measurements.

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Injury: Creation of NCTH and HiTCA

The abdomen was insufflated to a pressure of 15 mm Hg. The left lateral lobe of the liver was visualized then transected 3 cm to 4 cm away from the hilum using laparoscopic scissors, creating a lethal grade IV liver injury. The abdomen was then rapidly desufflated, all ports were removed, and the incisions were approximated using staples. After 5 minutes, a controlled hemorrhage was initiated at 1 mL·kg−1·min−1 to 2 mL·kg−1·min−1 until cardiac arrest was achieved. Cardiac arrest was defined as no pulsatile waveforms on the carotid arterial pressure tracing. At that time, isoflurane was stopped.

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Intervention

At t = 0, 3 minutes after onset of HiTCA, animals were randomly allocated to one of two groups: (1) SAAP with up to 6 L of oxygenated FWB, or (2) SAAP with up to 6 L of oxygenated HBOC-201. In both groups the intra-aortic balloon catheter (11.5-Fr outer diameter, 7.5-Fr inner diameter, 80 cm long with a 17-mL aortic occlusion balloon (Vention Medical Inc., Denver, CO) was deployed so that the inflation of the balloon occluded Zone 1 of the aorta as defined by Morrison et al.11 Immediately following balloon inflation, a 50-mL bolus of lactated Ringer's solution was rapidly infused through the SAAP catheter to close the aortic valve, optimizing coronary artery perfusion and reducing left ventricular distension.14

  • a) FWB group: Resuscitation with oxygenated, room-temperature FWB infused in conjunction with a 1% calcium chloride (CaCl2) at a ratio of 8:1 to achieve a total infusion rate of 10 mL·kg−1·min−1.14 CaCl2 was required to chelate citrate in stored FWB and prevent ionized hypocalcemia, which was combined with FWB immediately prior to infusion.
  • b) HBOC-201 group: HBOC-201 solution was prepared by dilution in lactated Ringer's solution to achieve an Hemoglobin (Hgb) of 8.5 g/dL. Resuscitation with oxygenated, room-temperature HBOC-201 was initiated at a rate of 10 mL·kg−1·min−1.14
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Selective Aortic Arch Perfusion Circuit

Bespoke SAAP circuits were constructed, consisting of a 3-L reservoir (Belmont Instrument Corp., Billerica, MA), a Cardiohelp system and HLS-7 circuit (Maquet Inc., Wayne, NJ), and MASTERFLEX peristaltic pumps (Cole-Parmer, Vernon Hills, IL). This apparatus included recirculation pathways and ports to convert the SAAP resuscitation into arteriovenous ECLS (Supplemental Digital Content 1, Figure 1, http://links.lww.com/TA/B380).

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Prehospital Resuscitation Protocol and Endpoints

Selective aortic arch perfusion resuscitation with either oxygenated FWB or HBOC-201 was maintained until ROSC was achieved. Return of spontaneous circulation was defined as Systolic Blood Pressure (SBP) greater than 50 mm Hg with pulsatile carotid waveforms. If ROSC was not achieved by 2 minutes, or ventricular fibrillation developed, intra-aortic epinephrine (0.5 mg) was administered every 30 seconds (up to 2 mg maximum), as needed, until ROSC. If ventricular fibrillation occurred, biphasic defibrillation (200 J) was performed and repeated as necessary to achieve an organized electrocardiographic rhythm. Once ROSC was achieved, continuous inhaled isoflurane was restarted.

If following ROSC, the SBP dropped below 90 mm Hg or the MAP decreased below 50 mm Hg, a 250-mL bolus of oxygenated FWB or HBOC-201 was administered via the SAAP catheter up to 2 L. Boluses of FWB were given in conjunction with 1% CaCl2, as previously described. No other interventions were performed during the prehospital phase.

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DCS Phase

After the 20-minute prehospital phase, animals underwent simultaneous exploratory laparotomy and resuscitation with up to 3 L of warmed intravenous FWB with concurrent 1% CaCl2. The FIO2 was increased to 1.0. Resuscitation was titrated to SBP greater than 90 mm Hg and MAP greater than 60 mm Hg. Low ionized calcium (iCa) < 0.9 g/dL was treated with 1 g 10% intravenous CaCl2. Profound acidosis (pH < 7.10) was treated with 50 mL of 8.4% sodium bicarbonate solution. Hyperkalemia (K+ > 5.5 mEq/L) was treated with 10 U of regular insulin and 50 mL of 50% dextrose solution. Hypoglycemia (serum glucose, <3 mmol/L) was treated with 50 mL of 50% dextrose solution.

Damage control surgery laparotomy was performed, with rapid evacuation of intra-abdominal shed blood and hemostasis of the liver injury using manual pressure and hemostatic clamps. Hemoperitoneum was collected and weighed. After clamping, the liver was packed with laparotomy sponges. The SAAP catheter balloon was deflated after a minimum of 40 minutes of abdominal organ ischemia. Balloon deflation time was 20 minutes to 30 minutes after SAAP initiation and adjusted within this range based on variable pre-SAAP injury time. This adjustment standardized total time of hypotension and abdominal ischemic burden. Balloon deflation was only initiated after blood pressure resuscitation targets were met. Hypotension was treated with epinephrine injection or norepinephrine infusion for concurrent Systemic Vascular Resistance (SVR) less than 80% of baseline and dobutamine infusion for cardiac output (CO) less than 80% of baseline despite fluid resuscitation.

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Conversion to ECLS

A 15-Fr venous ECLS catheter was placed in the right femoral vein and advanced to the inferior vena cava. Animals were heparinized to achieve an activated clotting time of twice the baseline level. Extracorporeal life support was initiated at a flow rate of 500 mL/min, which was the maximum flow rate achievable at 400 mm Hg given the resistance from the SAAP catheter and the intrinsic aortic pressure post-ROSC.

A urinary catheter was inserted via cystotomy to track urine output. A temporary abdominal closure was performed using a sterile clear plastic cover secured over the bowel to minimize insensible fluid losses.40

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Critical Care Phase

After DCS and DCR, experimental treatment was continued using simulated critical care algorithms. Packed red blood cells (up to 6 units) were administered for Hgb less than 7 g/dL. Fresh frozen plasma (FFP) (up to 6 units) was given for SBP less than 90 mm Hg with Hgb ≥ 7 g/dL. Norepinephrine, up to 0.4 μg·kg−1·min−1, was infused to maintain SBP greater than 90 mm Hg if animals were not fluid responsive and SVR less than 80% of baseline. Dobutamine, up to 20 μg·kg−1·min−1, was infused for inotropic support if the animal was not fluid responsive and CO less than 80% of baseline. FIO2 was titrated to maintain a normal PO2 based on Arterial Blood Gas (ABG)s. Interventions for profound acidemia, hyperkalemia, hypocalcemia, and hypoglycemia were continued as described in the DCS Phase. Active warming was achieved using a heated water-circulating blanket system. End of study was defined as 320 minutes post-SAAP intervention at which point animals were euthanized using sodium pentobarbital per institutional protocol. Following euthanasia, the liver was removed and weighed to quantify the liver transection.

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Data Acquisition

A data acquisition system was used to record high-frequency (500 Hz) data for arterial blood pressure, EKG tracing, and carotid blood flow (BIOPAC Goleta, CA). Other variables were recorded at 60-second intervals including heart rate (HR), ETCO2, central venous pressure, CO, SVR, stroke volume, central venous oxygen saturation (SvO2), and core temperature.

Arterial blood gas (pH, PO2, K+, iCa, lactate, base deficit) samples were obtained at baseline after a 10-minute stabilization period, 5 minutes after SAAP intervention (t = 5 minutes), at arrival to hospital (t = 20 minutes), and every 30 minutes afterward until the end of the protocol.

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Study Outcomes

Primary outcomes were rate of ROSC and end of experiment survival. Secondary outcomes included correction of hemodynamic derangements (HR, SBP, MAP, CO, SVR, carotid flow, SvO2, amount of vasopressor medications) and metabolic derangements (pH, lactate, base deficit, iCa, K+, glucose) as well as resuscitation volumes (total volume of resuscitation during prehospital, DCS, and critical care phases of the experiment).

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Statistical Analysis

Data were analyzed using SigmaPlot 12.0 (Systat Software, Inc, San Jose, CA). An a priori power analysis was performed (Fisher's exact test) to detect a 40% difference in survival. Survival was analyzed with a log-rank test in conjunction with a Kaplan Meier survival plot. Categorical and continuous variables were analyzed using Fisher's exact test and two-tailed Student's t tests, respectively. Significance was defined as alpha less than 0.05.

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RESULTS

Baseline and Injury Characteristics

Baseline and injury characteristics are presented in Table 1. Physiologic and laboratory baseline values were similar between groups. There were no significant differences in liver injury parameters, or total blood loss per kg of body weight.

TABLE 1

TABLE 1

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Induction of HiTCA

Cardiac arrest and resuscitation characteristics are presented in Table 2. Following injury, time to cardiac arrest was similar. During the 3-minute period of cardiac arrest, cardiac dysrhythmias were common; asystole occurred in 25% of the FWB group versus 21% of the HBOC-201 group (p = 1.000) and ventricular fibrillation occurred in 33% of the FWB group and 7% of the HBOC-201 group prior to intervention (p = 0.148).

TABLE 2

TABLE 2

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Aortic Hemostasis and Resuscitation Using SAAP

Data collected in the SAAP intervention phase of the experiment are shown in Table 2. Time to initiation of SAAP therapy was similar between groups. Return of spontaneous circulation was achieved in 100% of FWB animals versus 86% of HBOC-201 animals (p = 0.483). The rate of ventricular fibrillation either before or immediately after initiation of SAAP was similar between groups (42% in FWB, 50% in HBOC-201). Two animals in the HBOC-201 group went into refractory ventricular fibrillation despite repeated defibrillation attempts and intra-aortic epinephrine. The time required to achieve ROSC was similar between groups. Fresh whole blood animals required significantly more volume during initial SAAP resuscitation to achieve ROSC as compared with HBOC-201 (p = 0.034), however, required fewer additional post-ROSC bolus resuscitation during the remainder of the prehospital period (p = 0.306) resulting in similar prehospital total fluid volumes administered between groups. We observed a rapid improvement in carotid blood pressure, HR, and carotid flow in both groups after initiating SAAP therapy (Fig. 2). Carotid flow and HR in the FWB group were lower than the HBOC-201 group during the prehospital period. Carotid systolic and diastolic pressures were similar between groups. Prehospital survival was similar in both groups, with 100% survival for FWB and 86% with HBOC-201 (p = 0.483). Both prehospital deaths in the HBOC-201 group occurred due to refractory ventricular fibrillation.

Figure 2

Figure 2

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DCS and Resuscitation

Damage control surgery was performed in all animals that achieved ROSC. Two animals in the HBOC-201 group with initial successful ROSC were excluded during DCS due to equipment failure (one due to calcium pump failure, one due to ECLS circuit failure). The single death in the FWB group was caused by vena caval thrombosis and pulmonary embolism; the two deaths in the HBOC-201 group occurred during DCS and were both secondary to profound hypotension refractory to fluid resuscitation and vasopressors. Time to definitive hemorrhage control and total volume of FWB resuscitation during DCS was similar between groups. All animals surviving DCS in both groups were successfully transitioned to ECLS after placement of a femoral venous catheter.

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Critical Care Phase

Figure 3 depicts a Kaplan-Meier survival curve for both experimental groups. Overall survival was not significantly different between groups, with 92% survival in the FWB group versus 67% in the HBOC-201 group (p = 0.119). Two FWB animals surviving to 320 minutes were decompensating with very high lactates. Eight animals in each group were stable or improving at critical care phase end.

Figure 3

Figure 3

Trends of serum lactate and pH over time are demonstrated in Figure 4. Serum lactate was significantly higher than baseline values at the end of the prehospital period in both groups, peaked at 80 minutes, then decreased over the critical care phase of the experiment. Serum lactate was similar between groups at baseline, 80 minutes (peak), and end of experiment. In both groups, end of experiment lactate was significantly higher than the baseline level (10.1 [8.2] mmol/L vs. 2.2 [0.7] mmol/L, p = 0.008 FWB and 7.5 [3.5] mmol/L vs. 1.9 [0.5] mmol/L, p = 0.002 HBOC-201]. Compared with 80 minutes (peak), lactate levels significantly improved by end of experiment in the HBOC-201 group (p = 0.001) but not in the FWB group (p = 0.104), influenced by the two unstable FWB animals.

Figure 4

Figure 4

Serum pH significantly decreased after HiTCA and subsequent SAAP therapy, nadiring at 50 minutes. In both groups, pH significantly increased from 50 minutes to end of experiment. However, end of experiment pH in both groups was significantly lower than baseline (7.31 [0.16] vs. 7.46 [0.03], p = 0.007 FWB and 7.31 [0.09] vs. 7.46 [0.03], p = 0.003 HBOC-201). There were no significant differences in pH between groups at baseline, 50 minutes, or 320 minutes. Similar amounts of 8.4% sodium bicarbonate were given in each group.

The amounts of FFP, norepinephrine, dobutamine, epinephrine, 50% dextrose, and insulin were similar between groups. Total urine output between groups was also similar between groups.

When comparing end of experiment physiologic and laboratory parameters between groups, there was a significant elevation in pulmonary artery pressure and carotid flow in the HBOC-201 group, compared with FWB (Table 1). In the HBOC-201 group, pulmonary artery pressures were significantly higher than baseline (41 [6] mm Hg vs. 30 [5] mm Hg; p = 0.021) and carotid flow was similar to baseline level (178 [68] mL/min vs. 184 [44] mL/min; p = 0.305). There were no other significant differences in end of experiment physiologic parameters between groups.

When comparing end of experiment parameters to baseline values within groups, there were significant differences in both the FWB and HBOC-201 animals (Table 1). Heart rate was significantly increased in both groups and carotid SBP was significantly lower in both groups. Carotid blood flow was significantly lower in the FWB group but not the HBOC-201 group. Cardiac output was significantly decreased in the HBOC-201 group, but not the FWB group. SVR was significantly lower in both groups. There were no significant differences in temperature, hemoglobin, or iCa in either group.

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Complications

There were two bleeding complications in the FWB group, both occurring after heparinization: one animal developed a retroperitoneal hematoma discovered on necropsy and a second had bleeding from the liver edge requiring relaparotomy for hemorrhage control. There were three bleeding complications in the HBOC-201 group, all occurring after heparinization: one had rebleeding from the liver edge requiring relaparotomy for hemorrhage control, and two animals had abdominal wall bleeding requiring relaparotomy. There was one thrombotic event in the FWB group prior to heparinization and conversion to ECLS with formation of fatal pulmonary embolism and thrombosis of the vena cava, which was confirmed on necropsy.

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DISCUSSION

Selective aortic arch perfusion is efficacious using either FWB or HBOC-201 in the reversal of HiTCA in the setting of NCTH in this experimental animal model. Selective aortic arch perfusion using both FWB and HBOC-201 achieved excellent rates of ROSC (100% vs. 86%) and short-term survival during a 320-minute study period (92% vs. 67%). However, there were significant physiologic derangements from the ischemia-reperfusion injury that were still detectable after 5 hours.

Treatment for the range of hemorrhagic shock to HiTCA should also be managed by consideration of a continuum of support options for hemostasis and resuscitation (Supplemental Digital Content 2, Figure 2, http://links.lww.com/TA/B381). After the balloon is inflated but without administration of fluids through the distal lumen, SAAP functions similarly to REBOA, which has been shown to be effective in the treatment of severe shock with less morbidity than resuscitative thoracotomy with aortic cross clamping.31

In addition to passive aortic occlusion, SAAP provides active intra-aortic resuscitation during cardiac arrest and is highly effective at achieving ROSC and 60 minutes survival after HiTCA in swine models.17,18 The rates of ROSC and survival after 5 hours using SAAP in this study are significantly higher than published rates of ROSC and survival after HiTCA in both swine and clinical studies using CPR,6 resuscitative thoracotomy,5,7 or REBOA in conjunction with a balanced blood product resuscitation.8,9,17 We also have demonstrated consistent efficacy of achieving ROSC using SAAP in animals with electrocardiographic asystole, which has been previously considered an unsalvageable condition.32

Selective aortic arch perfusion is a promising new therapy in achieving ROSC and improving survival after HiTCA, but physiologic derangements caused by ischemia-reperfusion injury cannot be overlooked. The consequences of ischemia-reperfusion injury after balloon occlusion of the aorta are well documented,33–36 and have led to development of strategies using partial8,34,42 or intermittent aortic occlusion.11 However, partial occlusion of the aorta may decrease survival in the prehospital setting due to inadequate hemorrhage control.33 Further work is needed to determine the optimum balance between hemostasis and ischemic sequelae in HiTCA, as previous studies have used less severe models of hemorrhagic shock.

In this study, we also demonstrated the ability to transition from aortic occlusion and resuscitation to ongoing cardiopulmonary support with partial venoarterial ECLS using the SAAP catheter functioning as the arterial cannula, which provided 500 mL/min of support. A higher level of venoarterial ECLS support may be helpful in the setting of severe physiologic derangements secondary to HiTCA and ischemia-reperfusion injury.29

Additionally, the complexity of prehospital administration of intra-aortic oxygenated FWB must be considered as SAAP is transitioned from laboratory to clinical settings. Citrate-anticoagulated blood has very low (nondetectable) iCa, yet normal iCa is important to avoid potential refractory ventricular fibrillation.22 Thus, calcium must be added to blood immediately before infusion. Although not presently FDA-approved, HBOC-201 is isocalcemic and room temperature stable for 3 years.37 These properties provide significant advantages for SAAP implementation, particularly prehospital.

In this study, HBOC-201 appears to have similar rates of ROSC and short-term survival as FWB, similar physiologic derangements and logistically is much simpler to administer. The only significant variance in physiologic parameters between groups was pulmonary hypertension, which is a known side effect of HBOC-201, due to vasoconstriction and nitric oxide scavenging.38 Previous studies have demonstrated that sodium nitrate may help counteract this pulmonary vasoconstriction in the setting of hemorrhagic shock.38 HBOC-201 is currently only approved for clinical use in South Africa. However, it has been used in the United States for compassionate use in patients with severe anemia who refused blood products due to religious beliefs, showing an improvement in survival compared to conventional therapy.26 Further work is needed to determine the efficacy of HBOC-201 versus standard therapy in prehospital settings where blood products are not available.

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Complications

Ventricular fibrillation was a significant confounding factor in this study. Overall, ventricular fibrillation occurred in 67% of animals, including two episodes refractory to repeated defibrillation. Swine have a lower fibrillation threshold as compared to humans.39 However, ventricular fibrillation in our model was more common than in previous studies utilizing SAAP therapy in a swine model.17,18 This could be swine model-related or reflect a reperfusion dysrhythmia event. Further studies are needed to determine the effect of SAAP therapy on ventricular fibrillation in this model of NCTH.

There were five bleeding complications, all occurring after full anticoagulation with heparin. While rate of bleeding events was similar between groups, further work is needed to determine the effects of HBOC-201 on the coagulation profile in the setting of hemorrhagic shock.

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Limitations

Limitations of this study include its translational nature and the use of a swine model of NCTH though the choice of swine as a model was deliberate as swine cardiopulmonary and swine cardiovascular anatomy and physiology are similar to that of humans in response to traumatic injury. Physiologic monitoring used to guide clinical decisions may not be available in clinical settings, especially prior to arrival at a medical treatment facility. However, despite these limitations, this study builds on the existing evidence for the effectiveness of SAAP in HiTCA and future human trials.

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CONCLUSION

Selective aortic arch perfusion utilizing either FWB or HBOC-201 is a promising therapy for reversal of HiTCA, with potentially significant survival advantages over existing therapies. This animal study demonstrates HiTCA reversed by SAAP, but not without significant physiologic derangements associated with the subsequent ischemia-reperfusion. Further work is needed to determine the therapeutic window for aortic balloon occlusion in the setting of HiTCA, assess neurologic consequences, and streamline the steps needed to initiate SAAP therapy to improve safety and potential efficacy as human clinical trials are pursued.

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AUTHORSHIP

J.R., J.M., H.H., T.G. participated in the study design. H.H., J.M., T.G., B.M., S.M., J.R. participated in the data collection. H.H., T.G., J.M., J.R. participated in the data analysis and interpretation. H.H. participated in the drafting of the article. H.H., J.M., T.G., B.M., S.M., J.R. participated in the critical revisions.

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ACKNOWLEDGMENTS

We would like to acknowledge Lauren Wilson and Brianne Madtson for their superb technical contribution to the experiments presented here.

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FUNDING

This body of work was funded by the Defense Medical Research and Development Program. Award number: W81XWH-16-2-0012.

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DISCLOSURE

J.E.M. declares intellectual property interests in SAAP technology. He is also the co-founder of Resusitech, Inc., a medical device company developing SAAP technologies. J.E.M. has also delivered approximately 30 invited lectures on SAAP for resuscitation in medical and traumatic cardiac arrest. For several lectures, travel costs were reimbursed by the inviting organization or the University of North Carolina.

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REFERENCES

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DISCUSSION

SAMUEL TISHERMAN, M.D. (Baltimore, Maryland): Drs. Agarwal and deMoya, ladies and gentlemen, I’d like to congratulate Dr. Hoops on completing a complex project and an excellent presentation.

We all recognize that patients who exsanguinate to the point of cardiac arrest have a dismal prognosis despite aggressive attempts at resuscitation with airway management, massive transfusions, and resuscitative thoracotomy. Little has changed in our approach to these patients over the last several decades. So what options do we have to save these patients who are currently dying in front of us?

One option is to take the resuscitative thoracotomy to the field, as Drs. Davies and Lockey have done in highly-selected patients in London. Although we generally believe that open chest cardiopulmonary resuscitation (CPR) is superior to closed-chest CPR in trauma patients, this may not be true for patients without obvious thoracic trauma. Is closed chest compressions with Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) a better option? Maybe.

Novel intra-aortic approaches to resuscitation, however, could be game changers. Standard extracorporeal life support (ECLS) could provide circulation but be limited by ongoing hemorrhage. Alternatively, extracorporeal technology could be utilized to perfuse the patient with cold fluid to achieve deep hypothermia to increase tolerance for ischemia, as in Emergency Preservation and Resuscitation for which we have an ongoing trial at Shock Trauma.

This brief discussion of intra-aortic approaches now brings us to another novel approach, Selective Aortic Arch Perfusion (SAAP), presented by Dr. Hoops. In the current study, she and her colleagues utilized a complex, clinically-relevant, large animal model of lethal liver injury, exsanguinating hemorrhage to the point of arrest, resuscitation using SAAP with oxygenated whole blood or Hemoglobin-Based Oxygen Carrier-201 (HBOC-201), followed by damage control laparotomy and conversion to ECLS. They suggest that SAAP with either whole blood or HBOC-201 shows promise and the conversion to at least low-flow ECLS is feasible.

I have several questions for Dr. Hoops.

Number 1. Calcium chloride infusion was used routinely, though it’s not needed for humans or even swine in other studies receiving massive transfusion. Is this a unique issue with swine or with SAAP or with both?

Number 2. You discussed the importance of ischemia reperfusion injury in this model, looking at lactate levels, in particular. How can you differentiate between global ischemia from shock and cardiac arrest versus the ischemia from aortic occlusion?

Number 3. Proving equivalence of two therapies is difficult as large numbers of subjects are needed, making this even more difficult with expensive, complex animal models. I am concerned that there is a trend for worse survival in your HBOC group and changing the outcome of one animal could have led to a statistically significant difference favoring whole blood. In addition, the HBOC group required less volume to achieve restoration of spontaneous circulation and, in your manuscript, had higher pulmonary artery pressures, consistent with the known vasoconstrictive effects of HBOCs. Given the questionable outcome equivalence, potential deleterious vasoconstriction, and lack of approval in the U.S., what are your thoughts about the future of HBOC-201?

Number 4. It’s not clear to me why the study included the addition of conversion to ECLS. You already know that the SAAP catheter with a maximum flow of about 500 mls per minute does not provide much hemodynamic support, which the animals in this study didn’t even seem to need. How do you see this interface between SAAP and ECLS moving forward? And what about SAAP and Emergency Preservation and Resuscitation?

Number 5. Finally, what is next for SAAP? Are you continuing this work in the lab? As it seems that all the technical aspects of SAAP are feasible with current technology, what is needed before starting a clinical trial?

I would again like to congratulate Dr. Hoops and her colleagues for pushing the field of resuscitation for exsanguinating trauma patients forward. We need this type of creative research. I look forward to more great work from this group.

I’d like to thank the Association for the privilege of the podium.

JEREMY W. CANNON, M.D. (Philadelphia, Pennsylvania): Very nicely presented. Just from a practical standpoint, you describe a reservoir where you have your whole blood or your HBOC. When it gets low how do you keep it from entraining air? Do you have any sort of safety mechanisms? It just seems like if you’re in an uncontrolled prehospital environment that could be a real issue. Thank you.

HEATHER E. HOOPS, M.D. (Portland, Oregon): I’d like to thank Dr. Tisherman for the excellent points in the discussion as well as the questions.For the intra-aortic calcium, the perfusate ionized calcium level of the perfuse used in SAAP therapy is 0.07. In contrast to administrating blood intravenously there is no time to equilibrate that calcium when you are perfusing it so close to the coronary arteries.

We found with previous studies with SAAP and swine animals that we needed the intra-aortic calcium to prevent ventricular fibrillation.

SAAP therapy has not been attempted in humans so I cannot comment on the necessity or whether the rates of calcium chloride administration would be the same.

As far as the dysfunction due to the traumatic cardiac arrest versus the ischemia rate perfusion injury of a balloon occlusion, I think this is difficult to determine.

A longer balloon occlusion time in our model development led to irreversible physiologic derangements so I think we still need to do further work to determine a therapeutic window associated with how long we can leave the intra-aortic balloon inflated in the setting of traumatic cardiac arrest.

As far as HBOC, I think our thought for the future of HBOC is to be able to be utilized in settings where fresh whole blood is not available so in austere medical environments where you need something that’s room temperature or in Jehovah’s Witness patients. It’s been using more and more commonly in the U.S. in patients who are refusing fresh whole blood as an alternative to simply crystalloid.

So we envision HBOC being used you know downrange in military settings or internationally or in patients who refuse fresh whole blood moving forward.

In the hospital setting we envision SAAP being used with fresh whole blood as that is the standard of care.

As far as conversion to ECLS, in this study we chose to convert to ECLS using the SAAP catheter. By switching out that catheter to an arterial ECLS cannula, we could provide much more support.

We did this for simplicity reasons but certainly something that could provide more support moving forward in animals or in patients with more physiologic derangements.

For future directions of this study, I think we need to determine the therapeutic window with a balloon occlusion of the aorta. Partial REBOA or partial occlusion versus intermittent occlusion maybe options to increase the therapeutic window associated with balloon occlusion.

I think further work is needed to determine the physiologic consequences of using HBOC versus fresh whole blood on the coagulation pathway as well as markers of tissue ischemia and also to evaluate neurologic outcomes as we try to move towards clinical trials, which there are ongoing efforts to get started.

As far as the niche or the SAAP therapy in the use for the treatment of traumatic cardiac arrest, cardiac arrest due to hemorrhage is a continuum where you have a low-flow state that eventually becomes a no-flow state.

And so adjuncts such as cross-clamping the aorta after resuscitative thoracotomy or endovascular balloon occlusion in the aorta do provide hemorrhage control but we envision SAAP being used when that low-flow state becomes a no-flow state. In other words, a way to achieve ROSC with oxygen delivery to the heart in addition to having hemorrhage control.

And we recognize one of the reasons why we included the ECLS in the study, we recognized that we need to convert that into more ongoing support that does not include ischemia of tissues below the aortic balloon.

Regarding the question regarding safety mechanism for entrapment of air, I think this highlights the complexity of this study as far as calcium co-administration as well as the Belmont blood transfuser (Belmont Medical Technologies, Billerica, MA). In this study, we had one person loading the Belmont with blood or HBOC-201 and we would stop before getting to that six liters.

And so I think as we are moving towards clinical trials more safety mechanisms need to be in place as far as determination of delivery of intra-aortic calcium as well as other safety mechanisms when refining this circuit to be used in clinical trials.

Thank you.

Keywords:

Resuscitation; traumatic cardiac arrest; Sus scrofa; selective aortic arch perfusion

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