Gastroesophageal resuscitative occlusion of the aorta prolongs survival in a lethal liver laceration model.

BACKGROUND: Noncompressible torso hemorrhage management remains a challenge especially in the prehospital setting. We evaluated a device designed to occlude the aorta from the stomach (gastroesophageal resuscitative occlusion of the aorta [GROA]) for its ability to stop hemorrhage and improve survival in a swine model of lethal liver laceration and compared its performance to resuscitative endovascular balloon occlusion of the aorta (REBOA) and controls. METHODS: Swine (n = 24) were surgically instrumented and a 30% controlled arterial hemorrhage over 20 minutes was followed by liver laceration. Animals received either GROA, REBOA, or control (no treatment) for 60 minutes. Following intervention, devices were deactivated, and animals received whole blood and crystalloid resuscitation. Animals were monitored for an additional 4 hours. RESULTS: The liver laceration resulted in the onset of class IV shock. Mean arterial blood pressure (MAP) (standard deviation) decreased from 84.5 mm Hg (11.69 mm Hg) to 27.1 mm Hg (5.65 mm Hg) at the start of the intervention. Seven of eight control animals died from injury prior to the end of the intervention period with a median survival (interquartile) time of 10.5 minutes (12 minutes). All GROA and REBOA animals survived the duration of the intervention period (60 minutes) with median survival times of 86 minutes (232 minutes) and 79 minutes (199 minutes) after resuscitation, respectively. The GROA and REBOA animals experienced a significant improvement in survival compared with controls (p = 0.01). Resuscitative endovascular balloon occlusion of the aorta resulted in higher MAP at the end of intervention 114.6 mm Hg (22.9 mm Hg) compared with GROA 88.2 mm Hg (18.72 mm Hg) (p = 0.024), as well as increased lactate compared with GROA 13.2 meq·L-1 (1.56 meq·L-1) versus 10.5 meq·L-1 (1.89 meq·L-1) (p = 0.028). Histological examination of the gastric mucosa in surviving animals revealed mild ischemic injury from both GROA and REBOA. CONCLUSION: The GROA and REBOA devices were both effective at temporarily stanching lethal noncompressible torso hemorrhage of the abdomen and prolonging survival.

Trans-Ocular Brain Impedance Indices Predict Pressure Reactivity Index Changes in a Porcine Model of Hypotension and Cerebral Autoregulation Perturbation.

BACKGROUND: Cerebrovascular autoregulation (CA) is a protective mechanism that enables the cerebral vasculature to automodulate tone in response to changes in cerebral perfusion pressure to ensure constant levels of cerebral blood flow (CBF) and oxygen delivery. CA can be impaired after neurological injury and contributes to secondary brain injury. In this study, we report novel impedance indices using trans-ocular brain impedance (TOBI) during controlled systemic hemorrhage and hypotension to assess CA in comparison with pressure reactivity index (PRx). METHODS: Yorkshire swine were instrumented to record intracranial pressure (ICP), mean arterial pressure (MAP), and CBF. TOBI was recorded using electrocardiographic electrodes placed on the closed eyelids. Impedance changes (dz) were recorded in response to introducing an alternating current (0.4 mA) through the electrodes. MAP, ICP, and CBF were also measured. Animals were subjected to a controlled hemorrhage to remove 30-40% of each animal's total blood volume over 25-35 min. Hemorrhage was titrated to reach an MAP of approximately 35 mm Hg and end-tidal carbon dioxide above 28 mm Hg. PRx was calculated as a moving Pearson correlation between MAP and ICP. TOBI indices were calculated as the amplitude of the respiratory-induced changes in dz. DZx was calculated as a moving Pearson correlation between dz and MAP. TOBI indices (dz and DZx) were compared with hemodynamic indicators and PRx. RESULTS: dz was shown to be highly correlated with MAP, ICP, cerebral perfusion pressure, and CBF (r = - 0.823, - 0.723, - 0.813, and - 0.726), respectively (p < 0.0001). During hemorrhage, cerebral perfusion pressure and CBF had a mean percent decrease (standard deviation) from baseline of - 54.2% (12.5%) and - 28.3% (14.7%), respectively, whereas dz increased by 277% (268%). Receiver operator characteristics and precision-recall curves demonstrated high predictive performance of DZx when compared with PRx with an area under the curve above 0.82 and 0.89 for receiver operator characteristic and precision-recall curves, respectively, with high sensitivity and positive predictive power. CONCLUSIONS: TOBI indices appear to track changes in PRx and hemodynamics that affect CA during hemorrhage-induced hypotension. TOBI may offer a suitable, less invasive surrogate to PRx for monitoring and assessing CA.

A novel swine model of the acute respiratory distress syndrome using clinically relevant injury exposures.

To date, existing animal models of the acute respiratory distress syndrome (ARDS) have failed to translate preclinical discoveries into effective pharmacotherapy or diagnostic biomarkers. To address this translational gap, we developed a high-fidelity swine model of ARDS utilizing clinically relevant lung injury exposures. Fourteen male swine were anesthetized, mechanically ventilated, and surgically instrumented for hemodynamic monitoring, blood, and tissue sampling. Animals were allocated to one of three groups: (1) Indirect lung injury only: animals were inoculated by direct injection of Escherichia coli into the kidney parenchyma, provoking systemic inflammation and distributive shock physiology; (2) Direct lung injury only: animals received volutrauma, hyperoxia, and bronchoscope-delivered gastric particles; (3) Combined indirect and direct lung injury: animals were administered both above-described indirect and direct lung injury exposures. Animals were monitored for up to 12 h, with serial collection of physiologic data, blood samples, and radiographic imaging. Lung tissue was acquired postmortem for pathological examination. In contrast to indirect lung injury only and direct lung injury only groups, animals in the combined indirect and direct lung injury group exhibited all of the physiological, radiographic, and histopathologic hallmarks of human ARDS: impaired gas exchange (mean PaO2 /FiO2 ratio 124.8 ± 63.8), diffuse bilateral opacities on chest radiographs, and extensive pathologic evidence of diffuse alveolar damage. Our novel porcine model of ARDS, built on clinically relevant lung injury exposures, faithfully recapitulates the physiologic, radiographic, and histopathologic features of human ARDS and fills a crucial gap in the translational study of human lung injury.

Novel intraperitoneal hemostasis device prolongs survival in a swine model of noncompressible abdominal hemorrhage.

BACKGROUND: Noncompressible torso hemorrhage (NCTH) of the abdomen is a challenge to rapidly control and treat in the prehospital and emergency department settings. In this pilot study, we developed a novel intraperitoneal hemostasis device (IPHD) prototype and evaluated its ability for slowing NCTH and prolonging survival in a porcine model of lethal abdominal multiorgan hemorrhage. METHODS: Yorkshire male swine (N = 8) were instrumented under general anesthesia for monitoring of hemodynamics and blood sampling. Animals were subjected to a 30% controlled arterial hemorrhage followed by lacerating combinations of the liver, spleen, and kidney. The abdomen was closed and after 2 minutes of NCTH, and the IPHD was inserted into the peritoneal cavity via an introducer (n = 5). The balloon was inflated and maintained for 60 minutes. At 60 minutes postdeployment, the balloon was deflated and removed, and blood resuscitation was initiated followed by gauze packing for hemostasis. The remaining animals (n = 3) were used as controls and subjected to the same injury without intervention. RESULTS: All animals managed with IPHD intervention (5 of 5 swine) survived the duration of the intervention period (60 minutes), while all control animals (3 of 3 swine) died at a time range of 15 to 43 minutes following organ injury (p = 0.0042). Animals receiving IPHD remained hemodynamically stable with a mean arterial pressure range of 44.86 to 55.10 mm Hg and experienced increased cardiac output and decreased shock index after treatment. Controls experienced hemodynamic decline in all parameters until endpoints were met. Upon IPHD deflation and removal, all treated animals began to hemorrhage again and expired within 2 to 132 minutes despite packing. CONCLUSION: Our data show that the IPHD concept is capable of prolonging survival by temporarily stanching lethal NCTH of the abdomen. This device may be an effective temporary countermeasure to NCTH of the abdomen that could be deployed in the prehospital environment or as a bridge to more advanced therapy.

Trans-ocular brain impedance index for assessment of cerebral autoregulation in a porcine model of cerebral hemodynamic perturbation.

Cerebrovascular autoregulation (CA) is often impaired following traumatic brain injury. Established technologies and metrics used to assess CA are invasive and conducive for measurement, but not for continuous monitoring. We developed a trans-ocular brain impedance (TOBI) method that may provide non-invasive and continuous indices to assess CA. In this study, we monitored impedance metrics such as respiratory-induced impedance amplitude changes (dz) as well as a novel impedance index (DZx), which is a moving Pearson correlation between mean arterial pressure (MAP) and dz. Yorkshire swine were instrumented to continuously record ICP, MAP, and cerebral blood flow (CBF). TOBI was recorded by placement of standard ECG electrodes on closed eyelids and connected to a data acquisition system. MAP, ICP and CBF were manipulated utilizing an intravenous vasopressor challenge. TOBI indices (dz and DZx) were compared to the hemodynamic indicators as well as pressure reactivity index (PRx). During the vasopressor challenge, dz was highly correlated with ICP, CPP, and CBF (r = < - 0.49, p < 0.0001). ICP, CPP, and CBF had a mean percent increase (standard deviation) from baseline of 29(23.2)%, 70(25)%, and 37(72.6)% respectively while dz decreased by 31(15.6)%. Receiver operator curve test showed high predictive performance of DZx when compared to PRx with area under the curve above 0.86, with high sensitivity and specificity. Impedance indices appear to track changes in PRx and hemodynamics that affect cerebral autoregulation. TOBI may be a suitable less invasive surrogate to PRx and capable of tracking cerebral autoregulation.

Aerosol generation during chest compression and defibrillation in a swine cardiac arrest model.

AIM: It remains unclear whether cardiac arrest (CA) resuscitation generates aerosols that can transmit respiratory pathogens. We hypothesize that chest compression and defibrillation generate aerosols that could contain the SARS-CoV-2 virus in a swine CA model. METHODS: To simulate witnessed CA with bystander-initiated cardiopulmonary resuscitation, 3 female non-intubated swine underwent 4 min of ventricular fibrillation without chest compression or defibrillation (no-flow) followed by ten 2-min cycles of mechanical chest compression and defibrillation without ventilation. The diameter (0.3-10 µm) and quantity of aerosols generated during 45-s intervals of no-flow and chest compression before and after defibrillation were analyzed by a particle analyzer. Aerosols generated from the coughs of 4 healthy human subjects were also compared to aerosols generated by swine. RESULTS: There was no significant difference between the total aerosols generated during chest compression before defibrillation compared to no-flow. In contrast, chest compression after defibrillation generated significantly more aerosols than chest compression before defibrillation or no-flow (72.4 ±â€¯41.6 × 104 vs 12.3 ±â€¯8.3 × 104 vs 10.5 ±â€¯11.2 × 104; p < 0.05), with a shift in particle size toward larger aerosols. Two consecutive human coughs generated 54.7 ±â€¯33.9 × 104 aerosols with a size distribution smaller than post-defibrillation chest compression. CONCLUSIONS: Chest compressions alone did not cause significant aerosol generation in this swine model. However, increased aerosol generation was detected during chest compression immediately following defibrillation. Additional research is needed to elucidate the clinical significance and mechanisms by which aerosol generation during chest compression is modified by defibrillation.

A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine.

BACKGROUND: The systemic responses to infection and its progression to sepsis remains poorly understood. Progress in the field has been stifled by the shortcomings of experimental models which include poor replication of the human condition. To address these challenges, we developed and piloted a novel large animal model of severe infection that is capable of generating multi-system clinically relevant data. METHODS: Male swine (n = 5) were anesthetized, mechanically ventilated, and surgically instrumented for continuous hemodynamic monitoring and serial blood sampling. Animals were inoculated with uropathogenic E. coli by direct injection into the renal parenchyma and were maintained until a priori endpoints were met. The natural history of the infection was studied. Animals were not resuscitated. Multi-system data were collected hourly to 6 hours; all animals were euthanized at predetermined physiologic endpoints. RESULTS: Core body temperature progressively increased from mean (SD) 37.9(0.8)°C at baseline to 43.0(1.2)°C at experiment termination (p = 0.006). Mean arterial pressure did not begin to decline until 6h post inoculation, dropping from 86(9) mmHg at baseline to 28(5) mmHg (p = 0.005) at termination. Blood glucose progressively declined but lactate levels did not elevate until the last hours of the experiment. There were also temporal changes in whole blood concentrations of a number of metabolites including increases in the catecholamine precursors, tyrosine (p = 0.005) and phenylalanine (p = 0.005). Lung, liver, and kidney function parameters worsened as infection progressed and at study termination there was histopathological evidence of injury in these end-organs. CONCLUSION: We demonstrate a versatile, multi-system, longitudinal, swine model of infection that could be used to further our understanding of the mechanisms that underlie infection-induced multi-organ dysfunction and failure, optimize resuscitation protocols and test therapeutic interventions. Such a model could improve translation of findings from the bench to the bedside, circumventing a significant obstacle in sepsis research.

Gastroesophageal resuscitative occlusion of the aorta: Physiologic tolerance in a swine model of hemorrhagic shock.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been shown to be effective for management of noncompressible torso hemorrhage. However, this technique requires arterial cannulation, which can be time-consuming and not amendable to placement in austere environments. We present a novel, less invasive aortic occlusion device and technique designated gastroesophageal resuscitative occlusion of the aorta (GROA). In this study, we aimed to characterize the physiological tolerance and hemodynamic effects of a prototype GROA device in a model of severe hemorrhagic shock and resuscitation and compare with REBOA. METHODS: Swine (N = 47) were surgically instrumented for data collection. A 35% controlled arterial hemorrhage was followed by randomizing animals to 30-minute, 60-minute, or 90-minute interventions of GROA, REBOA, or control. Following intervention, devices were deactivated, and animals received whole blood and crystalloid resuscitation. Animals were monitored for an additional 4 hours. RESULTS: All animals except one GROA 90-minute application survived the duration of their intervention periods. Survival through resuscitation phase in GROA, REBOA, and control groups was similar in the 30-minute and 60-minute groups. The 90-minute occlusion groups exhibited deleterious effects upon device deactivation and reperfusion with two GROA animals surviving and no REBOA animals surviving. Mean (SD) arterial pressure in GROA and REBOA animals increased across all groups to 98 (31.50) mm Hg and 122 (24.79) mm Hg, respectively, following intervention. Lactate was elevated across all GROA and REBOA groups relative to controls during intervention but cleared by 4 hours in the 30-minute and 60-minute groups. Postmortem histological examination of the gastric mucosa revealed mild to moderate inflammation across all GROA groups. CONCLUSION: In this study, the hemodynamic effects and physiological tolerance of GROA was similar to REBOA. The GROA device was capable of achieving high zone II full aortic occlusion and may be able to serve as an effective method of aortic impingement.

Dose optimization of early high-dose valproic acid for neuroprotection in a swine cardiac arrest model.

AIM: High-dose valproic acid (VPA) improves the survival and neurologic outcomes after asphyxial cardiac arrest (CA) in rats. We characterized the pharmacokinetics, pharmacodynamics, and safety of high-dose VPA in a swine CA model to advance clinical translation. METHODS: After 8 â€‹min of untreated ventricular fibrillation CA, 20 male Yorkshire swine were resuscitated until return of spontaneous circulation (ROSC). They were block randomized to receive placebo, 75 â€‹mg/kg, 150 â€‹mg/kg, or 300 â€‹mg/kg VPA as 90-min intravenous infusion (n â€‹= â€‹5/group) beginning at ROSC. Animals were monitored for 2 additional hours then euthanized. Experimental operators were blinded to treatments. RESULTS: The mean(SD) total CA duration was 14.8(1.2) minutes. 300 â€‹mg/kg VPA animals required more adrenaline to maintain mean arterial pressure ≥80 â€‹mmHg and had worse lactic acidosis. There was a strong linear correlation between plasma free VPA Cmax and brain total VPA (r2 â€‹= â€‹0.9494; p â€‹< â€‹0.0001). VPA induced dose-dependent increases in pan- and site-specific histone H3 and H4 acetylation in the brain. Plasma free VPA Cmax is a better predictor than peripheral blood mononuclear cell histone acetylation for brain H3 and H4 acetylation (r2 â€‹= â€‹0.7189 for H3K27ac, r2 â€‹= â€‹0.7189 for pan-H3ac, and r2 â€‹= â€‹0.7554 for pan-H4ac; p â€‹< â€‹0.0001). CONCLUSIONS: Up to 150 â€‹mg/kg VPA can be safely tolerated as 90-min intravenous infusion in a swine CA model. High-dose VPA induced dose-dependent increases in brain histone H3 and H4 acetylation, which can be predicted by plasma free VPA Cmax as the pharmacodynamics biomarker for VPA target engagement after CA.