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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.
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Hipotensão , Pressão Intracraniana , Animais , Encéfalo , Circulação Cerebrovascular/fisiologia , Impedância Elétrica , Homeostase/fisiologia , Pressão Intracraniana/fisiologia , SuínosRESUMO
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.
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Lesões Encefálicas Traumáticas , Pressão Intracraniana , Animais , Pressão Arterial , Encéfalo , Circulação Cerebrovascular , Impedância Elétrica , Homeostase , SuínosRESUMO
BACKGROUND: A novel arterial everter device was engineered to simplify microvascular coupling of arteries by reliably securing the stiff, muscular wall of arteries over coupler pins. We compare microvascular coupling with the everter device to manual suturing for arterial anastomoses in a live large animal model. MATERIALS AND METHODS: In this preliminary study, bilateral external femoral arteries of five male swine were exposed and sharply divided. Arteries were anastomosed using either interrupted sutures (n = 5) or the everter device and Synovis Coupler (n = 5). The efficiency in engaging coupler pins, the time taken to perform the anastomosis, and vessel patency immediately post-op and at 1-week postanastomosis were evaluated. Vessel wall injury and luminal stenosis were compared between groups using histomorphometric analyses. RESULTS: On an average, 80% of coupler pins engaged the vessel walls after a single pass of the everter. The average time to perform the anastomosis was significantly less when using the everter/coupler compared with manual suturing (6:35 minutes versus 25:09 minutes, p < 0.001). Immediately post-op, 100% patency was observed in both groups. At 1 week post-op, four of five (80%) of coupled arteries and all five (100%) of hand-sewn arteries were patent. The degree of arterial wall injury, neointimal formation, and luminal stenosis for patent arteries were similar between groups. CONCLUSIONS: Successful arterial anastomoses using the everter device with the Synovis Coupler was easier and significantly more efficient when compared with a standard hand-sewn technique. Both techniques had acceptable patency rates and similar effects on the vessel wall and intima.
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Anastomose Cirúrgica/métodos , Artérias/fisiopatologia , Microcirurgia , Grau de Desobstrução Vascular/fisiologia , Animais , Artérias/cirurgia , Masculino , Microcirurgia/métodos , Modelos Animais , SuínosRESUMO
BACKGROUND: Blood flow to the brain is a critical physiological function and is useful to monitor in critical care settings. Despite that, a surrogate is most likely measured instead of actual blood flow. Such surrogates include velocity measurements in the carotid artery and systemic blood pressure, even though true blood flow can actually be obtained using MRI and other modalities. Ultrasound is regularly used to measure blood flow and is, under certain conditions, able to provide quantitative volumetric blood flow in milliliters per minute. Unfortunately, most times the resulting flow data is not valid due to unmet assumptions (such as flow profile and angle correction). Color flow, acquired in three dimensions, has been shown to yield quantitative blood flow without any assumptions (3DVF). METHODS: Here we are testing whether color flow can perform during physiological conditions common to severe injury. Specifically, we are simulating severe traumatic brain injury (epidural hematoma) as well as hemorrhagic shock with 50% blood loss. Blood flow was measured in the carotid artery of a cohort of 7 Yorkshire mix pigs (40-60 kg) using 3DVF (4D16L, LOGIQ 9, GE HealthCare, Milwaukee, WI, USA) and compared to an invasive flow meter (TS420, Transonic Systems Inc., Ithaca, NY, USA). RESULTS: Six distinct physiological conditions were achieved: baseline, hematoma, baseline 2, hemorrhagic shock, hemorrhagic shock plus hematoma, and post-hemorrhage resuscitation. Mean cerebral oxygen extraction ratio varied from 40.6% ± 13.0% of baseline to a peak of 68.4% ± 15.6% during hemorrhagic shock. On average 3DVF estimated blood flow with a bias of -9.6% (-14.3% root mean squared error) relative to the invasive flow meter. No significant flow estimation error was detected during phases of flow reversal, that was seen in the carotid artery during traumatic conditions. The invasive flow meter showed a median error of -11.5% to 39.7%. CONCLUSIONS: Results suggest that absolute volumetric carotid blood flow to the brain can be obtained and potentially become a more specific biomarker related to cerebral hemodynamics than current surrogate markers.
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Encéfalo , Circulação Cerebrovascular , Hemodinâmica , Circulação Cerebrovascular/fisiologia , Animais , Suínos , Hemodinâmica/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Velocidade do Fluxo Sanguíneo/fisiologia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/fisiopatologia , Lesões Encefálicas Traumáticas/metabolismoRESUMO
BACKGROUND: Gastroesophageal resuscitative occlusion of the aorta (GROA) has been shown effective in creating zone II aortic occlusion capable of temporarily improving survival in animal models of lethal noncompressible torso hemorrhage. In this study, tandem application of GROA transitioning to resuscitative endovascular balloon occlusion of the aorta (REBOA) is explored to demonstrate feasibility as a potential point-of-injury bridge to more advanced care, using a swine model of lethal abdominal hemorrhage. METHODS: Swine (n = 19) were anesthetized, instrumented, and subjected to a combination of controlled and uncontrolled hemorrhage from a grade-V liver laceration. Animals were designated as intervention (n = 9; GROA to REBOA) or control (n = 10), for 60 minutes. Following intervention, devices were deactivated, and animals received blood and crystalloid resuscitation. Animals were monitored for 4 hours. RESULTS: Injury resulted in onset of class IV shock in all animals with a mean arterial pressure (SD) of 24.5 (4.11) mm Hg at the start of intervention. Nine of 10 controls died during the intervention period with a median (interquartile) survival time of 8.5 (9.25) minutes. All animals receiving the intervention survived both the 60-minute intervention period demonstrating a significant survival improvement ( p = 0.0007). Transition from GROA to REBOA was successful in all animals with a transition time ranging from 30 to 90 seconds. Mean arterial pressure significantly improved in animals receiving GROA to REBOA for the duration of intervention, regardless of the method of aortic occlusion, with a range of 70.9 (16.04) mm Hg to 101.1 (15.3) mm Hg. Additional hemodynamics, metrics of shock, and oxygenation remained stable during intervention. CONCLUSION: Less invasive technologies such as GROA may present an opportunity to control noncompressible torso hemorrhage more rapidly, with a subsequent transition to more advanced care such as REBOA.
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Oclusão com Balão , Procedimentos Endovasculares , Lacerações , Choque Hemorrágico , Suínos , Animais , Modelos Animais de Doenças , Aorta/lesões , Hemorragia/terapia , Fígado/lesões , Oclusão com Balão/métodos , Ressuscitação/métodos , Procedimentos Endovasculares/métodos , Choque Hemorrágico/terapiaRESUMO
AIM: To investigate the effect of tandem use of transient balloon occlusion of the descending aorta (AO) and percutaneous left ventricular assist device (pl-VAD) during cardiopulmonary resuscitation in a large animal model of prolonged cardiac arrest. METHODS: Ventricular fibrillation was induced and left untreated for 8 minutes followed by 16 minutes of mechanical CPR (mCPR) in 24 swine, under general anesthesia. Animals were randomized to 3 treatment groups (n = 8 per group): A) pL-VAD (Impella CP®) B) pL-VAD+AO, and C) AO. Impella CP® and the aortic balloon catheter were inserted via the femoral arteries. mCPR was continued during treatment. Defibrillation was attempted 3 times starting at minute 28 and then every 4 minutes. Haemodynamic, cardiac function and blood gas measurements were recorded for up to 4 hours. RESULTS: Coronary perfusion pressure (CoPP) in the pL-VAD+AO Group increased by a mean (SD) of 29.2(13.94) mmHg compared to an increase of 7.1(12.08) and 7.1(5.95) mmHg for groups pL-VAD and AO respectively (p = 0.02). Similarly, cerebral perfusion pressure (CePP) in pL-VAD+AO increased by a mean (SD) of 23.6 (6.11), mmHg compared with 0.97 (9.07) and 6.9 (7.98) mmHg for the other two groups (p < 0.001). The rate of return of spontaneous heartbeat (ROSHB) was 87.5%, 75%, and 100% for pL-VAD+AO, pL-VAD, and AO. CONCLUSION: Combined AO and pL-VAD improved CPR hemodynamics compared to either intervention alone in this swine model of prolonged cardiac arrest.
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Oclusão com Balão , Reanimação Cardiopulmonar , Parada Cardíaca , Coração Auxiliar , Animais , Modelos Animais de Doenças , Parada Cardíaca/terapia , Hemodinâmica , Suínos , Fibrilação Ventricular/terapiaRESUMO
Aim: To evaluate coagulofibrinolytic abnormalities and the effects of ART-123 (recombinant human thrombomodulin alpha) in a porcine model of cardiac arrest and prolonged cardiopulmonary resuscitation (CA/CPR). Methods: Fifteen pigs (n = 5 per group) underwent 8 minutes of no-flow CA followed by 50 minutes of mechanical CPR, while 2 pigs underwent sham arrest. CA/CPR animals were randomized to receive saline or 1 mg/kg ART-123 pre-arrest (5 minutes prior to ventricular fibrillation) or post-arrest (2 minutes after initiation of CPR). Arterial and venous blood samples were drawn at multiple time points for blood gas analysis and measurement of plasma and whole blood markers of coagulation and fibrinolysis. Results: In saline-treated CA/CPR, but not sham animals, robust and persistent activation of coagulation and fibrinolysis was observed throughout resuscitation. After 50 minutes of CPR, plasma tests and thromboelastography indicated a mix of hypercoagulability and consumptive coagulopathy. ART-123 had a robust anticoagulant effect, reducing both thrombin-antithrombin (TAT) complexes and d-dimer (p < 0.05 for each). The duration of anticoagulant effect varied depending on the timing of ART-123 administration. Similarly, ART-123 when given prior to cardiac arrest was found to have pro-fibrinolytic effects, increasing free tissue plasminogen activator (tPA, p = 0.02) and decreasing free plasminogen activator inhibitor-1 (PAI-1, p = 0.04). Conclusion: A porcine model of prolonged CA/CPR reproduces many of the coagulofibrinolytic abnormalities observed in human cardiac arrest patients. ART-123 demonstrates a combination of anticoagulant and profibrinolytic effects, depending on the timing of its administration relative to cardiac arrest.
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BACKGROUND: It remains unclear if percutaneous left ventricular assist device (pLVAD) reduces post-cardiac arrest myocardial dysfunction. METHODS: This is a prespecified analysis of a subset of swine that achieved return of spontaneous circulation (ROSC) in a study comparing pLVAD, transient aortic occlusion (AO), or both during cardiopulmonary resuscitation (CPR). Devices were initiated after 24 minutes of ventricular fibrillation cardiac arrest (8 min no-flow and 16 min mechanical CPR). AO was discontinued post-ROSC, and pLVAD support or standard care were continued. Beginning 60 minutes post-ROSC, pLVAD support was weaned to < 1.0 L/min and subsequently removed at 240 minutes. The primary outcome was cardiac index (CI), stroke volume index (SVI), and left ventricular ejection fraction (LVEF) at 240 minutes post-ROSC. Data are shown as mean (standard error). RESULTS: Seventeen swine achieved ROSC without complication and were included in this analysis (pLVAD group, n = 11 and standard care group, n = 6). For the primary outcomes, the pLVAD group had significantly higher CI of 4.2(0.3) vs. 3.1(0.4) L/min/m2 (p = 0.043) and LVEF 60(3) vs. 49(4) % (p = 0.029) at 240 minutes after ROSC when compared with the standard care group, while SVI was not statistically significantly different (32[3] vs. 23[4] mL/min/m2, p = 0.054). During the first 60 minutes post-ROSC, the pLVAD group had significantly higher coronary perfusion pressure, lower LV stroke work index, and total pulmonary resistance index. CONCLUSION: These results suggest that early pLVAD support after ROSC is associated with better recovery myocardial function compared to standard care after prolonged cardiac arrest.
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Reanimação Cardiopulmonar , Parada Cardíaca , Coração Auxiliar , Animais , Suínos , Volume Sistólico , Função Ventricular Esquerda , Parada Cardíaca/complicações , Perfusão/efeitos adversos , Reanimação Cardiopulmonar/métodos , Fibrilação Ventricular/complicações , Modelos Animais de DoençasRESUMO
Background: Recent studies describe an emerging role for percutaneous left ventricular assist devices such as Impella CP® as rescue therapy for refractory cardiac arrest. We hypothesized that the addition of mechanical chest compressions to percutaneous left ventricular assist device assisted CPR would improve hemodynamics by compressing the right ventricle and augmenting pulmonary blood flow and left ventricular filling. We performed a pilot study to test this hypothesis using a swine model of prolonged cardiac arrest. Methods: Eight Yorkshire swine were anesthetized, intubated, and instrumented for hemodynamic monitoring. They were subjected to untreated ventricular fibrillation for 5.75 (SD 2.90) minutes followed by mechanical chest compressions for a mean of 20.0 (SD 5.0) minutes before initiation of percutaneous left ventricular assist device. After percutaneous left ventricular assist device initiation, mechanical chest compressions was stopped (n = 4) or continued (n = 4). Defibrillation was attempted 4, 8 and 12 minutes after initiating percutaneous left ventricular assist device circulatory support. Results: The percutaneous left ventricular assist device + mechanical chest compressions group had significantly higher percutaneous left ventricular assist device flow prior to return of spontaneous heartbeat at four- and twelve-minutes after percutaneous left ventricular assist device initiation, and significantly higher end tidal CO2 at 4-minutes after percutaneous left ventricular assist device initiation, when compared with the percutaneous left ventricular assist device alone group. Carotid artery flow was not significantly different between the two groups. Conclusion: The addition of mechanical chest compressions to percutaneous left ventricular assist device support during cardiac arrest may generate higher percutaneous left ventricular assist device and carotid artery flow prior to return of spontaneous heartbeat compared to percutaneous left ventricular assist device alone. Further studies are needed to determine if this approach improves other hemodynamic parameters or outcomes after prolonged cardiac arrest.
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Prolonged cardiac arrest (CA) causes microvascular thrombosis which is a potential barrier to organ reperfusion during extracorporeal cardiopulmonary resuscitation (ECPR). The aim of this study was to test the hypothesis that early intra-arrest anticoagulation during cardiopulmonary resuscitation (CPR) and thrombolytic therapy during ECPR improve recovery of brain and heart function in a porcine model of prolonged out-of-hospital CA. DESIGN: Randomized interventional trial. SETTING: University laboratory. SUBJECTS: Swine. INTERVENTIONS: In a blinded study, 48 swine were subjected to 8 minutes of ventricular fibrillation CA followed by 30 minutes of goal-directed CPR and 8 hours of ECPR. Animals were randomized into four groups (n = 12) and given either placebo (P) or argatroban (ARG; 350 mg/kg) at minute 12 of CA and either placebo (P) or streptokinase (STK, 1.5 MU) at the onset of ECPR. MEASUREMENTS AND MAIN RESULTS: Primary outcomes included recovery of cardiac function measured by cardiac resuscitability score (CRS: range 0-6) and recovery of brain function measured by the recovery of somatosensory-evoked potential (SSEP) cortical response amplitude. There were no significant differences in recovery of cardiac function as measured by CRS between groups (p = 0.16): P + P 2.3 (1.0); ARG + P = 3.4 (2.1); P + STK = 1.6 (2.0); ARG + STK = 2.9 (2.1). There were no significant differences in the maximum recovery of SSEP cortical response relative to baseline between groups (p = 0.73): P + P = 23% (13%); ARG + P = 20% (13%); P + STK = 25% (14%); ARG + STK = 26% (13%). Histologic analysis demonstrated reduced myocardial necrosis and neurodegeneration in the ARG + STK group relative to the P + P group. CONCLUSIONS: In this swine model of prolonged CA treated with ECPR, early intra-arrest anticoagulation during goal-directed CPR and thrombolytic therapy during ECPR did not improve initial recovery of heart and brain function but did reduce histologic evidence of ischemic injury. The impact of this therapeutic strategy on the long-term recovery of cardiovascular and neurological function requires further investigation.
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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.
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Lacerações , Choque Hemorrágico , Animais , Aorta/lesões , Modelos Animais de Doenças , Hemorragia/etiologia , Hemorragia/terapia , Lacerações/terapia , Fígado/lesões , SuínosRESUMO
INTRODUCTION: Oxidation-reduction (redox) reactions, and the redox potential (RP) that must be maintained for proper cell function, lie at the heart of physiologic processes in critical illness. Imbalance in RP reflects systemic oxidative stress, and whole blood RP measures have been shown to correlate with oxygen debt level over time in swine traumatic shock. We hypothesize that RP measures reflect changing concentrations of metabolites involved in oxidative stress. To test this hypothesis, we compared blood and urine RP with concentrations of multiple metabolites in a swine traumatic shock model to identify meaningful RP-metabolite relationships. METHODS: Seven swine were subjected to traumatic shock. Mixed venous (MV) RP, urine RP, and concurrent MV and urine metabolite concentrations were assessed at baseline, max O 2 Debt (80âmL/kg), end resuscitation, and 2 h post-resuscitation. RP was measured at collection via open circuit potential using nanoporous gold electrodes with Ag/AgCl reference and a ParstatMC potentiostat. Metabolite concentrations were measured by quantitative 1 H-NMR spectroscopy. MV and urine RP were compared with time-matched metabolites across all swine. LASSO regression with leave-one-out cross validation was used to determine meaningful RP/metabolite relationships. Metabolites had to maintain magnitude and direction of coefficients across 6 or more swine to be considered as having a meaningful relationship. KEGG IDs of these metabolites were uploaded into Metscape for pathway identification and evaluation for physiologic function. RESULTS: Meaningful metabolite relationships (and mean coefficients across cross-validation folds) with MV RP included: choline (-6.27), ATP (-4.39), glycine (5.93), ADP (1.84), glucose (15.96), formate (-13.09), pyruvate (6.18), and taurine (-7.18). Relationships with urine RP were: betaine (4.81), urea (4.14), glycine (-2.97), taurine (10.32), 3-hydroxyisobutyrate (-7.67), N-phenylacetylglycine, PAG (-14.52), hippurate (12.89), and formate (-5.89). These meaningful metabolites were found to scavenge extracellular peroxide (pyruvate), inhibit ROS and activate cellular antioxidant defense (taurine), act as indicators of antioxidant mobilization against oxidative stress (glycineâ+âPAG), and reflect renal hydroxyl radical trapping (hippurate), among other activities. CONCLUSIONS: Real-time RP measures demonstrate significant relationships with metabolites attributable to metabolic pathways involved in systemic responses to oxidative stress, as well as those involved in these processes. These data support RP measures as a feasible, biologically relevant marker of oxidative stress. As a direct measure of redox state, RP may be a useful biomarker and clinical tool in guiding diagnosis and therapy in states of increased oxidative stress and may offer value as a marker for organ injury in these states as well.
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Antioxidantes , Choque Traumático , Animais , Biomarcadores , Formiatos , Glicina , Hipuratos , Oxirredução , Estresse Oxidativo , Ácido Pirúvico , Suínos , TaurinaRESUMO
Despite the enormous impact on human health, acute respiratory distress syndrome (ARDS) is poorly defined, and its timely diagnosis is difficult, as is tracking the course of the syndrome. The objective of this pilot study was to explore the utility of breath collection and analysis methodologies to detect ARDS through changes in the volatile organic compound (VOC) profiles present in breath. Five male Yorkshire mix swine were studied and ARDS was induced using both direct and indirect lung injury. An automated portable gas chromatography device developed in-house was used for point of care breath analysis and to monitor swine breath hourly, starting from initiation of the experiment until the development of ARDS, which was adjudicated based on the Berlin criteria at the breath sampling points and confirmed by lung biopsy at the end of the experiment. A total of 67 breath samples (chromatograms) were collected and analysed. Through machine learning, principal component analysis and linear discrimination analysis, seven VOC biomarkers were identified that distinguished ARDS. These represent seven of the nine biomarkers found in our breath analysis study of human ARDS, corroborating our findings. We also demonstrated that breath analysis detects changes 1-6â h earlier than the clinical adjudication based on the Berlin criteria. The findings provide proof of concept that breath analysis can be used to identify early changes associated with ARDS pathogenesis in swine. Its clinical application could provide intensive care clinicians with a noninvasive diagnostic tool for early detection and continuous monitoring of ARDS.
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BACKGROUND: Large animal studies are an important step in the translation pathway, but single laboratory experiments do not replicate the variability in patient populations. Our objective was to demonstrate the feasibility of performing a multicenter, preclinical, randomized, double-blinded, placebo-controlled cardiac arrest trial. We evaluated the effect of epinephrine on coronary perfusion pressure (CPP) as previous single laboratory studies have reported mixed results. METHODS: Forty-five swine from 5 different laboratories (Ann Arbor, MI; Baltimore, MD; Los Angeles, CA; Pittsburgh, PA; Toronto, ON) using a standard treatment protocol. Ventricular fibrillation was induced and left untreated for 6 min before starting continuous cardiopulmonary resuscitation (CPR). After 2 min of CPR, 9 animals from each lab were randomized to 1 of 3 interventions given over 12 minutes: (1) Continuous IV epinephrine infusion (0.00375 mg/kg/min) with placebo IV normal saline (NS) boluses every 4 min, (2) Continuous placebo IV NS infusion with IV epinephrine boluses (0.015 mg/kg) every 4 min or (3) Placebo IV NS for both infusion and boluses. The primary outcome was mean CPP during the 12 mins of drug therapy. RESULTS: There were no significant differences in mean CPP between the three groups: 14.4 ± 6.8 mmHg (epinephrine Infusion), 16.9 ± 5.9 mmHg (epinephrine bolus), and 14.4 ± 5.5 mmHg (placebo) (p = NS). Sensitivity analysis demonstrated inter-laboratory variability in the magnitude of the treatment effect (p = 0.004). CONCLUSION: This study demonstrated the feasibility of performing a multicenter, preclinical, randomized, double-blinded cardiac arrest trials. Standard dose epinephrine by bolus or continuous infusion did not increase coronary perfusion pressure during CPR when compared to placebo.
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Reanimação Cardiopulmonar , Parada Cardíaca , Animais , Reanimação Cardiopulmonar/métodos , Epinefrina , Parada Cardíaca/tratamento farmacológico , Perfusão , Suínos , Fibrilação Ventricular/terapiaRESUMO
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.
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Traumatismos Abdominais/terapia , Oclusão com Balão/instrumentação , Hemorragia/terapia , Traumatismos Abdominais/fisiopatologia , Animais , Modelos Animais de Doenças , Hemodinâmica , Hemorragia/fisiopatologia , Hemostasia , Masculino , Projetos Piloto , Pressão , Ressuscitação/métodos , Taxa de Sobrevida , SuínosRESUMO
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 4â¯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⯵m) 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¯41.6â¯×â¯104 vs 12.3⯱â¯8.3â¯×â¯104 vs 10.5⯱â¯11.2â¯×â¯104; pâ¯<â¯0.05), with a shift in particle size toward larger aerosols. Two consecutive human coughs generated 54.7⯱â¯33.9â¯×â¯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.
Assuntos
Aerossóis/análise , COVID-19/transmissão , Reanimação Cardiopulmonar/efeitos adversos , Massagem Cardíaca/efeitos adversos , Parada Cardíaca Extra-Hospitalar/terapia , Animais , Feminino , Humanos , Projetos Piloto , SARS-CoV-2 , SuínosRESUMO
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.
Assuntos
Modelos Animais de Doenças , Síndrome do Desconforto Respiratório/patologia , Animais , Escherichia coli/patogenicidade , Pulmão/microbiologia , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Troca Gasosa Pulmonar , Síndrome do Desconforto Respiratório/microbiologia , Síndrome do Desconforto Respiratório/fisiopatologia , SuínosRESUMO
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.
Assuntos
Oclusão com Balão/métodos , Procedimentos Endovasculares/instrumentação , Traumatismo por Reperfusão/terapia , Choque Hemorrágico/terapia , Animais , Aorta/patologia , Oclusão com Balão/efeitos adversos , Modelos Animais de Doenças , Hemodinâmica/fisiologia , Hemorragia/prevenção & controle , Hemorragia/terapia , Masculino , Reperfusão , Ressuscitação/métodos , SuínosRESUMO
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.