SHOCK, Vol. 44, Supplement 1, pp. 123Y128, 2015

AN EVOLVING UNCONTROLLED HEMORRHAGE MODEL USING CYNOMOLGUS MACAQUES Benjamin A. Bograd,*† Jason S. Radowsky,*†‡ Diego A. Vicente,*† Earl H. Lee,*† Thomas A. Davis,†‡ and Eric A. Elster*†‡ *Department of Surgery, Walter Reed National Military Medical Center, Bethesda; and † Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring; ‡ Department of Surgery, Uniformed Services, University of the Health Sciences, Bethesda, Maryland Received 1 Oct 2014; first review completed 28 Oct 2014; accepted in final form 17 Dec 2014 ABSTRACT—Background: Trauma-induced hemorrhagic shock produces hemodynamic changes that often result in a systemic inflammatory response that can lead to multiple organ failure and death. In this prospective study, the pathophysiology of a nonhuman primate uncontrolled hemorrhagic shock model is evaluated with the goal of creating an acute systemic inflammatory syndrome response and a reproducible hemorrhage. Methods: Nonhuman primates were divided into 2 groups. A laparoscopic left hepatectomy was performed in groups A and B, 60% and 80%, respectively, resulting in uncontrolled hemorrhage. Resuscitation during the prehospital phase lasted 120 min and included a 0.9% saline bolus at 20 mL/kg. The hospital phase involved active warming, laparotomy, hepatorrhaphy for hemostasis, and transfusion of packed red blood cells (10 mL/kg). The animals were recovered and observed over a 14-day survival period with subsequent necropsy for histopathology. Results: Baseline demographics and clinical parameters of the two groups were similar. Group A (n = 7) underwent a 57.7% T 2.4% left hepatectomy with a 33.9% T 4.0% blood loss and 57% survival. Group B (n = 4) underwent an 80.0% T 6.0% left hepatectomy with 56.0% T 3.2% blood loss and 75% survival. Group B had significantly lower hematocrit (P G 0.05) for all postinjury time points. Group A had significantly elevated creatinine on postoperative day 1. Nonsurvivors succumbed to an early death, averaging 36 h from the injury. Histopathologic evaluation of nonsurvivors demonstrated kidney tubular degeneration. Conclusions: Nonhuman primates displayed the expected physiologic response to hemorrhagic shock due to liver trauma as well as systemic inflammatory response syndrome with resultant multiple organ dysfunction syndrome and either early death or subsequent recovery. Our next step is to establish a clinically applicable nonhuman primate polytrauma model, which reproduces the prolonged maladaptive immunologic reactivity and end-organ dysfunction consistent with multiple organ failure found in the critically injured patient. KEYWORDS—Trauma, hemorrhagic shock, nonhuman primate, systemic inflammatory response, syndrome, multiple organ failure

INTRODUCTION

(6). These models have inherent limitations, given the variable physiologic and immunologic reaction to injury exhibited by the different animal species (7). Notably, the rodent response to trauma as well as the pharmycodynamic effects of drugs varies significantly from humans (8,9). While a closer physiologic match, swine demonstrate significant immunologic differences including an altered cytokine profile following traumatic insult (10Y12). These differences may influence the identification of targets for therapeutic intervention as well as the response to immune-altering pharmacologic therapies. Nonhuman primates (NHPs), however, develop a SIRS response that closely mimics both the physiologic and immunologic response observed in severely injured trauma patients (13Y15). Nonhuman primate studies provide an essential translational model for biomedical research serving as a fundamental bridge between the mechanistic understanding gained through rodents and swine and the application of those insights to patient care, immune reactivity, human disease, and pharmacokinetics. Importantly, NHPs share with humans significant genetic homology, immunologic reactivity, physiologic responsiveness, and behavioral characteristics than do rodents and swine (16). Studies investigating the pathophysiology of trauma-induced hemorrhagic shock, ischemic reperfusion injury, SIRS, and MOF are of considerable importance with potential lifesaving applications. Numerous trauma models have been described using different animal species and varying techniques. Current hemorrhage models entail either a controlled bleed from a cannulated vessel

Trauma is the leading cause of preventable death for civilians as well as military service members (1Y3). Both blunt and penetrating trauma may result in hemorrhage and concomitant shock physiology. Even with expedient control of bleeding, hemorrhagic shock can induce a maladaptive systemic inflammatory response syndrome (SIRS) leading to significant morbidity and mortality independent of the traumatic injuries. This overexuberant response may result in secondary end-organ injury, multiple organ failure (MOF), and death (4,5). To study the physiologic response to hemorrhagic insult, we have traditionally turned to lower mammalian species such as rats and swine Address reprint requests to Eric A. Elster, MD, FACS, Norman M. Rich Department of Surgery, Uniformed Services, University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814. E-mail: [email protected]. Support: BUMED 6.5 604771 N.C210.001.A0812 and DMRDP-Intra-ATTD BUMED GDF 602115HP.4130.001.A1105. The authors declare no conflicts of interest. The authors_ team is composed of military service members and employees of the US Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that BCopyright protection under this title is not available for any work of the US Government.[ Title 17 U.S.C. 101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, the Department of the Navy, the Department of Defense, or the US Government. DOI: 10.1097/SHK.0000000000000322 Copyright Ó 2015 by the Shock Society

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or uncontrolled blood loss secondary to reproducible injuries. These methods result in different physiologic responses, dissimilar hemodynamic profiles, and an altered immunologic response to divergent wound profiles (17). Many studies have utilized severe liver injury to facilitate uncontrolled hemorrhage that allows for both the sequelae of trauma along with global ischemia from blood loss (18, 19). Predominantly, these use open-abdominal injuries, which may alter the immunophysiologic pathology experienced during trauma and influence the local inflammatory milieu postinjury (20). An open abdominal wound fails to reproduce the general injury pattern of civilian trauma as well as that of the combat wounded by removing the hemostatic activity of an intact peritoneum and abdominal wall (21). In addition, an altered local immune response has been demonstrated following laparotomy, potentially influencing the inflammatory response as well as immunologic targets (22). As our understanding and ability to manipulate the molecular and cellular components involved in this maladaptive immune response develop, there grows a need for a clinically relevant animal model that mimics this immunophysiology in order to enhance the care of the most severely injured. This has necessitated preclinical studies in a more closely related model system, the NHP (23). Unfortunately, there is a paucity of data regarding the NHP response to trauma and hemorrhage. As such, this prospective study was conducted to evaluate the pathophysiologic response of the NHP using a laparoscopic, uncontrolled hemorrhage model with the goal of creating an acute SIRS response and reproducible hemorrhagic shock. METHODS Animal surgical preparation and overview The experiments reported herein were conducted in compliance with the Animal Welfare Act and in accordance to the principles set forth in the BGuide for the Care and Use of Laboratory Animals,[ Institute of Laboratory Animals Resources, National Research Council, National Academy Press, 1996. The study was approved by the National Medical Research Center Institutional Animal Care and Use Committee (protocol KO07-10), and all procedures were performed in animal facilities approved by the Association for Assessment and Accreditation for Laboratory Animal Care International. Eleven male Mauritian cynomolgus macaques (Macaca fascicularis) were included in the protocol. The protocol timeline is outlined in Figure 1.

Anesthesia, monitoring, and liver injury The animals were sedated and transported to the surgery suite and intubated with a 4F to 5F endotracheal tube to allow for mechanical ventilation and general anesthesia. The abdomen and bilateral groins were prepared and draped in sterile fashion. The NHPs heart rate and oxygen saturations were continuously monitored. A cut-down technique was performed to place a 22-gauge angiocatheter into the right femoral artery for blood pressure recording and laboratory test draws. A 20-gauge angiocatheter was introduced into the right femoral vein for infusions. The cephalad-caudad length of the left lobe of the liver was then measured using a sterile plastic ruler. Sixty percent or 80% of the left lobe of the liver was marked with electrocautery in group A and group B, respectively. This demarcated liver was then resected with curved endoshears, resulting in uncontrolled hemorrhage (Fig. 2). At this time, all laparoscopic instruments were removed, and the abdomen was allowed to desufflate.

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FIG. 2. Laparoscopic nonanatomic left hepatectomy.

Resuscitation Postinjury resuscitation was modeled on the current combat casualty paradigm where the wounded are initially treated by a prehospital provider, such as a corpsman or medic, with limited resources for intervention. During the prehospital phase (time 0 min), resuscitation was initiated with crystalloid at 20 mL/kg, which continued for the remainder of the case (225 min). After 120 min, the hospital phase began with the initiation of continuous monitoring, continued resuscitation, oxygen therapy, blood-type matched and leukocytereduced blood transfusion at 10 mL/kg, active rewarming, and laparotomy for surgical control of the hemorrhage. After entering the abdomen through a midline laparotomy, the injured liver edge was oversewn with chromic suture. The cut liver edge was cauterized and covered with a piece of Surgicel (Ethicon, Somerville, NJ). All free blood and clot in the abdomen were collected in preweighed laparotomy pads for calculation of shed blood. Total blood volume was estimated as 6% of total body weight in accordance with a previously published report that estimated the total blood volume in cynomolgus macaques (35). The abdomen was then closed, and after the last blood draw, the arterial and venous catheters were removed. At this time anesthesia was weaned, and the NHP was extubated, with approximate duration of anesthesia time roughly 5 h.

Postoperative care Following extubation, the animals were taken to an BICU[ setting, where they recovered under direct observation by research and veterinary medical staff. Animals were allowed fluids and returned to a regular diet as deemed appropriate by the research team and veterinary medical staff. Buprenorphine (0.1Y0.3 mg/kg) was administered intramuscularly every 4 to 8 h as needed for pain. On postoperative days 1 and 3, animals received an infusion of normal saline (20 mL/kg) via saphenous vein cannulation or subcutaneous infusion. In addition, if the animal displayed evidence of anemia to include hemoglobin less than 9.0 g/dL on laboratory evaluation as well as clinical signs of anemia to include lethargy, decreased urine output, and pale mucus membranes, then a blood transfusion (10 mL/kg) was initiated. Once recovered and tolerating an oral diet, the animals were returned to their single-caged group housing rooms. Evaluation for euthanasia was performed in conjunction with veterinary medical staff and based on the animal_s clinical states, response to resuscitation, and laboratory parameters to include indices of fulminant renal failure. Animals deemed nonsurvivable were killed with pentobarbital (Fatal-Plus; Vortech Pharmaceuticals, Dearborn, Mich).

Laboratory analysis FIG. 1. Schematic that outlines the experimental timeline with the various postinjury phases.

Baseline values where obtained for each animal with laboratory tests drawn at 4 and 2 weeks preoperatively. Hemodynamic variables were recorded and laboratory tests drawn at the time of injury, time 0, as well as time 15, 30, 60, 120, 180, and 240 min after injury. In addition, hemodynamic values were

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TABLE 1. Baseline characteristics and operative values for group A (60% hepatectomy group) and group B (80% hepatectomy group) Group A (n = 7) Group B (n = 4)

P

Baseline Weight, kg

8.1 T 0.3

8.0 T 0.6

0.83

HR, beats/min

91 T 6

112 T 6

0.06

MAP, mmHg

45 T 4

52 T 8

0.54

Hematocrit, %

45 T 2

42 T 1

0.11

Blood urea nitrogen, mg/dL

18 T 2

16 T 1

0.37

Creatinine, mg/dL

1.4 T 0.1

1.3 T 0.1

0.41

% Left hepatectomy

57.7 T 2.4

80.0 T 6.0

G0.05

% Blood loss

33.9 T 4.0

56.0 T 3.2

G0.05

Operative

Survival Surviving animals

4

3

0.51

obtained and laboratory test results collected via femoral stick on the mornings of postoperative days 1, 3, 5, 7, 10, and 14. Complete blood count (IDEXX ProCyte DxR Hematology Analyzer, Westbrook, Me), arterial blood gas (Gem 4000 Premier, Bedford, Mass), and blood chemistry panel (Catalyst DxR Chemistry Analyzer) were measured at each time point.

Statistical analysis Repeated-measures analysis of variance was conducted within each experimental group (one-way repeated measures) as well as between groups (two-way repeated measures) over time. Independent-samples t test was used to evaluate individual time points. Log-rank test was used to compare survival. Results are expressed as mean T SD. Significance was defined as P G 0.05

RESULTS Baseline data did not differ between the two treatment groups. Group A included seven cynomolgus macaques that underwent a 57.7% T 2.4% left hepatectomy with a 33.9% T 4.0% blood loss and 57% survival. Group B included four cynomolgus macaques that underwent an 80.0% T 6.0% left hepatectomy with associated 56.0% T 3.2% blood loss and 75% survival (Table 1). The difference in survival was not statistically significant between the 2 groups (P = 0.51) with euthanasia on postoperative day 1 (n = 2) and postoperative day 2 (n = 1) in group A and postoperative day 3 (n = 1) in group B. These animals were killed because of progressing laboratory evidence of renal failure, along with clinical evidence

FIG. 3. Intraoperative isoflurane levels. Results expressed as mean T SD. *P G 0.05 comparing group A versus group B at the indicated time point.

of pitting edema, persistent hypothermia despite warming measures, dyspnea, lethargy, and decreased response to painful stimuli. Evaluation of intraoperative hemodynamic parameters and anesthesia revealed that group A had higher isoflurane levels (Fig. 3) and lower heart rate (Fig. 4) throughout the operation (P G 0.05). In addition, group A had lower mean arterial pressure (MAP) values, with significance (P G 0.05) achieved between groups at time point 30 min (Fig. 4). Intraoperative and postoperative laboratory evaluation revealed that group B had a significantly lower hematocrit (P G 0.05) throughout the experiment as seen in Figure 5. In addition, there was no statistically significant difference between lactate levels (P = 0.55) and base excess (P = 0.15) throughout the experiment as seen in Figure 4, respectively. Both groups A and B demonstrated significant leukocytosis from baseline with no difference noted between the groups (Fig. 5). Group A demonstrated higher creatinine levels which were significant (P G 0.05) on postoperative day 1 (Fig. 6). Histopathologic evaluation of the animals that survived to postoperative day 14 was unremarkable except for the expected postoperative fibrotic changes at the cut liver edge. In addition, histopathologic evaluation of the nonsurvivors at necropsy demonstrated evidence of renal tubular degeneration. DISCUSSION A large multicenter prospective study conducted by Minei and colleagues (24) effectively describes the physiologic response to polytrauma as well as the postinjury course of the severely injured human patient. During a 4-year period, more than 1,000 patients were evaluated following blunt trauma with a median injury severity score of 29. On presentation to the hospital, these trauma patients were hypotensive, with a peak lactate of 5.1 mmol/L and base deficit of 10 mmol/L (25). In

FIG. 4. Intraoperative hemodynamic profile (time 0 j 240 min). A, Heart rate (HR) and (B) MAP. Results expressed as mean T SD. *P G 0.05 comparing group A versus group B at the indicated time point.

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FIG. 5. Intraoperative and postoperative laboratory values. A, Hematocrit, (B) white blood cell count, (C) lactate, (D) base excess. Results expressed as mean T SD. *P G 0.05 comparing group A versus group B at the indicated time point.

addition, there was evidence of SIRS as well as an 8.6% early death rate reflective of the severe injury. The present study mimicked these findings with an injury severity score of 16 to 25 and depressed MAP throughout the prehospital phase. Clinically, a SIRS response was noted with tachycardia and a significant leukocytosis from baseline. The lactate peaked at 5.3 mmol/L and base deficit at 5.3 mmol/L. Moreover, the severity of the injury is demonstrated by an overall mortality rate of 36%, with death occurring early, a mean time of 36 h from injury. In a prospective study by Ciesla et al. (26), the clinical impact of severe trauma as ranging from mild SIRS to fulminate organ failure was investigated. Furthermore, they demonstrated organ dysfunction occurring within 48 h of trauma often represented a reversible physiologic response to injury with the potential to resolve once resuscitation was complete. In addition, Wohlauer and colleagues (27) discussed acute kidney injury as a consequence of trauma-induced global ischemia and found a 78% MOF rate and 27% mortality rate when present. While evaluating renal function in the current study, we note evidence of acute kidney injury with an elevated creatinine of approximately 200% from baseline (28). Within 48 h, recovery was noted in group A. Importantly, if these findings are placed in the context of the animal_s clinical course, benign recovery, and inflammatory data, the delayed recovery of group B appears indicative of underresuscitation from the increased hemorrhage within our

protocol and not MOF. This is supported by the minimal response in hematocrit to the whole-blood transfusion received during the hospital phase in group B. Likewise, group B demonstrated a smoldering lactate, representing possible underresuscitation in this group despite their clinical recovery. Anesthesia care can dramatically influence outcomes during surgical intervention. In a prospective study conducted by Monk and colleagues (29), they identified cumulative deep anesthesia time and intraoperative hypotension as significant independent predictors of mortality. In the current study, mortality approached

FIG. 6. Intraoperative and post operative creatinine values. Results expressed as mean T SD. *P G 0.05 comparing group A versus group B at the indicated time point.

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SHOCK AUGUST 2015 significance with a 43% mortality in group A and only 25% mortality in group B. A thorough review of the data was conducted to determine the reason for this unexpected finding. The intraoperative data proved intriguing as the amount of isoflurane, an inhalational anesthetic used during the experiment, was significantly different at all time points between groups. Veterinarian literature recommends 1.3 MAC (1.6%Y1.75%) of isoflurane for NHP undergoing invasive procedures (30). We noted levels of approximately 1.0% isoflurane resulted in significant hypotension in the injured NHP and may have played a role in the increased mortality of group A (31, 32). This is demonstrated by a significantly higher heart rate for the 80% hepatectomy group at all time points as well as a trend toward higher MAP despite a significantly larger hemorrhage. In response, we strived to maintain isoflurane levels less than 1.0%, usually between 0.6% and 0.8%, a level that still maintains an appropriate surgical plane in these wounded animals. These encouraging findings have important implications in the development of clinical therapeutic strategies targeting specific pathways involved in the immunologic reactivity following severe trauma. However, the findings of this study need to be interpreted with consideration and acknowledgement of the limitations. The principal limitation of this study is that the numbers of animals used is too small to determine which of the 2 approaches (60% or 80%) is superior in modeling the true clinical situations, which is complex. The nonsignificant results related to the outcome differences between the approaches are probably due to a type II error because of the small sample size. This standardized and reproducible model did not include further interventions attempting to restore physiologic homeostasis in animals exhibiting clinical or laboratory evidence of physiologic derangement. This includes administering further blood transfusions, crystalloid boluses, antibiotics, or reoperation. This is clearly incongruent with standard-of-care clinical practice. Also, unlike current Tactical Combat Casualty Care guidelines (http://www.health.mil/tccc) in which trauma patients received Hextend (Hospira, Lake Forest, Ill) colloid for signs of shock in prehospital resuscitation, in this model the NHPs underwent resuscitation with 20 mL/kg crystalloid per the Advanced Trauma Life Support guidelines. In addition, the administration of anesthesia may confound the physiologic response to injury. Blunting of the MAP through peripheral vasodilation secondary to isoflurane use may create a less significant hemorrhage than would otherwise be expected with the size of hepatectomy created in both the lesser and greater severity groups. Likewise, the use of narcotics preoperatively to lessen pain might have contributed to this effect. Furthermore, the hypotensive effect of these medications may contribute to the global ischemia and the physiologic derangement witnessed postoperatively (33,34). Another point, the use of NHPs in acute hemorrhage/traumatic injury research and number of reported studies in the literature are limited. These inherent challenges arise from the high cost and husbandry requirements in addition to postoperative course and perioperative and postoperative monitoring of the primate model. The aims of future studies include (1) development of a polytrauma model and (2) identifying potential biomarkers, outcome end points, the optimal window for protection, and interventions.

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In conclusion, the NHP displays the expected physiologic response to hemorrhagic shock due to liver trauma demonstrating SIRS with resultant multiple organ dysfunction syndrome and either early death or subsequent recovery. In addition, the laparoscopic left hepatectomy reproducibly created a class III to class IV hemorrhage based on the size of excision. The early death in the nonsurvivors was multifactorial. Necropsy results consistently demonstrated trauma-induced acute kidney injury. Contributing factors likely include anesthesia induced hypotension, as well as inadequate resuscitation and hypoperfusion in the immediate postinjury period. Our next step is to use the liver injury model of uncontrolled hemorrhage as a platform to establish a clinically applicable NHP polytrauma model, which reproducibly results in prolonged maladaptive immunologic reactivity and end-organ dysfunction consistent with MOF. This model will more closely replicate clinical practice with physiologic parameters and laboratory analysis used to guide resuscitation. With this model, we hope to evaluate pharmacologic interventions with the goal of mitigating the maladaptive immune response found in multiple organ dysfunction syndrome and MOF in order to enhance recovery, improve survivability, and decrease morbidity of the critically injured. ACKNOWLEDGMENTS The authors thank Mr Alexander Brown, Ms. Crystal Leonhardt, and Mr Darren Fryer, whose assistance was invaluable through development to the conclusion of this study. They also thank the veterinary medical and veterinary pathology departments and the Department of Regenerative Medicine laboratory research assistants for their work with animal care and sample analysis.

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An Evolving Uncontrolled Hemorrhage Model Using Cynomolgus Macaques.

Trauma-induced hemorrhagic shock produces hemodynamic changes that often result in a systemic inflammatory response that can lead to multiple organ fa...
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