Porcine Model Of Cardiac Arrest Research Articles

EFFECTS OF MESENCHYMAL STEM CELLS ON POSTRESUSCITATION RENAL AND INTESTINAL INJURIES IN A PORCINE CARDIAC ARREST MODEL.

Objectives: Systemic ischemia-reperfusion triggered by cardiac arrest (CA) and resuscitation often causes postresuscitation multiple organ injuries. Mesenchymal stem cells (MSCs) have been proven to be a promising treatment for regional renal and intestinal ischemia reperfusion injuries. This study aimed to investigate the effects of MSCs on renal and intestinal injuries after cardiopulmonary resuscitation (CPR) in a porcine CA model. Methods: Twenty-two male pigs were randomly assigned to the sham (n = 6), CA/CPR (n = 8), and CA/CPR + MSC (n = 8) groups. Mesenchymal stem cells were differentiated from human embryonic stem cells and then intravenously administered at a dose of 2.5 × 10 6 /kg at 1.5 and 3 d before the CA/CPR procedure. The experimental model was established by 8 min of untreated CA, followed by 8 min of CPR. Renal and intestinal injuries were evaluated based on the serum levels of creatinine, serum urea nitrogen, intestinal fatty acid-binding protein, and diamine oxidase at 1, 2, 4, and 24 h after resuscitation. At the end of the experiment, pathological damage was determined by cell apoptosis and ferroptosis in the renal and intestinal tissues. Results: During CPR, five pigs in the CA/CPR group and seven pigs in the CA/CPR + MSC group were successfully resuscitated. After resuscitation, the serum levels of creatinine, serum urea nitrogen, intestinal fatty acid-binding protein, and diamine oxidase were significantly increased in the CA/CPR and CA/CPR + MSC groups compared with those in the sham group. However, MSC administration significantly decreased the levels of renal and intestinal injury biomarkers compared with those in the CA/CPR group. Cell apoptosis and ferroptosis, which were indicated by the levels of apoptotic cells, iron deposition, lipid peroxidation, antioxidants, and ferroptosis-related proteins, were observed in renal and intestinal tissues after resuscitation in the CA/CPR and CA/CPR + MSC groups. Nevertheless, both were significantly milder in the CA/CPR + MSC group than in the CA/CPR group. Conclusions: MSC administration was effective in alleviating postresuscitation renal and intestinal injuries possibly through inhibition of cell apoptosis and ferroptosis in a porcine CA model.

High central venous pressure amplitude predicts successful defibrillation in a porcine model of cardiac arrest

AimIncreasing venous return during cardiopulmonary resuscitation (CPR) has been shown to improve hemodynamics during CPR and outcomes following cardiac arrest (CA). We hypothesized that a high central venous pressure amplitude (CVP-A), the difference between the maximum and minimum central venous pressure during chest compressions, could serve as a robust predictor of return of spontaneous circulation (ROSC) in addition to traditional measurements of coronary perfusion pressure (CPP) and end-tidal CO2 (etCO2) in a porcine model of CA. MethodsAfter 10 min of ventricular fibrillation, 9 anesthetized and intubated female pigs received mechanical chest compressions with active compression/decompression (ACD) and an impedance threshold device (ITD). CPP, CVP-A and etCO2 were measured continuously. All groups received biphasic defibrillation (200 J) at minute 4 of CPR and were classified into two groups (ROSC, NO ROSC). Mean values were analyzed over 3 min before defibrillation by repeated-measures Analysis of Variance and receiver operating characteristic (ROC). ResultsFive animals out of 9 experienced ROSC. CVP-A showed a statistically significant difference (p = 0.003) between the two groups during 3 min of CPR before defibrillation compared to CPP (p = 0.056) and etCO2 (p = 0.064). Areas-under-the-curve in ROC analysis for CVP-A, CPP and etCO2 were 0.94 (95% Confidence Interval 0.86, 1.00), 0.74 (0.54, 0.95) and 0.78 (0.50, 1.00), respectively. ConclusionIn our study, CVP-A was a potentially useful predictor of successful defibrillation and return of spontaneous circulation. Overall, CVP-A could serve as a marker for prediction of ROSC with increased venous return and thereby monitoring the beneficial effects of ACD and ITD.

Femoral artery collapse ratio as an indicator of chest compression quality during cardiopulmonary resuscitation in a porcine cardiac arrest model

Cardiopulmonary resuscitation (CPR) quality is crucial for improving patient survival rates after cardiac arrest. This study aimed to investigate the usefulness of femoral artery collapse ratio (systolic diameter/diastolic diameter ratio) measurement using M-mode ultrasound versus end-tidal carbon dioxide (ETCO2) for the assessment of high-quality CPR in a porcine cardiac arrest model. A total of 10 male mongrel pigs (age range, 16–20 weeks; weight, 45–50 kg) were used. After anesthesia, the carotid artery was dissected and exposed. The animals were instrumented with an arterial catheter in the exposed carotid artery to monitor arterial blood pressure. Cardiac arrest was induced by injecting potassium chloride (KCl, 40 equivalents of weight). The animals underwent chest compression using a mechanical device, and the chest compression depth and ETCO2 were measured using a defibrillator. To obtain hemodynamic information, two investigators performed an ultrasound examination on both femoral arteries. One examiner measured the femoral peak systolic velocity (PSV), while the other measured the diameters of the femoral artery (systolic diameter and diastolic diameter) in a transverse or longitudinal position using the M-mode of the linear ultrasound probe. As the compression depth increased, ETCO2, femoral artery diameter, collapse ratio (systolic diameter/diastolic diameter), and blood flow increased; however, PSV decreased. The ETCO2 and collapse ratio were positively correlated. The femoral artery collapse ratio, measured using the M-mode ultrasound, could be an alternative and simple method to evaluate high-quality CPR.

Effects of temperature control on hyperthermia-related cardiac dysfunction in a porcine model of cardiac arrest

The outcome of cardiac arrest is worse when there is fever after spontaneous circulation is restored (ROSC). The purpose of this study was to investigate the mechanism of post-ROSC cardiac dysfunction after hyperthermia treatment and the effects of temperature control. Twenty-four male Bama minipigs were randomized into 3 groups (8 per group): CPR + controlled normothermia (CN), CPR + hyperthermia (HT), and CPR + therapeutic mild hypothermia (TMH). Defibrillation was given to pigs with ventricular fibrillation after 8 min of untreated fibrillation. Subsequently, these animals received the post-ROSC treatments of hyperthermia (38 °C), controlled normothermia (37 °C) or hypothermia (33 °C) according to the groups. Hemodynamic parameters, left ventricular ejection fraction, blood samples and myocardial tissues were assessed. At 24 h after the post-ROSC treatments, the pigs treated with hyperthermia showed increments in heart rate and plasma cardiac troponin I, and decreases in mean arterial pressure, cardiac index, and left ventricular ejection fraction, compared to those with the controlled normothermia pigs. However, the deterioration of the above parameters can be attenuated by TMH. The pigs in the TMH group also had a reduced percentage of apoptotic cardiomyocytes, an increased anti-apoptotic Bcl-2/Bax ratio and a decreased caspase-3 activity in myocardium, as compared with both controlled normothermia and hyperthermia pigs. In conclusion, hyperthermia is associated with a worse myocardial dysfunction. TMH improves hyperthermia-induced myocardial dysfunction by attenuating apoptosis in a porcine model of cardiac arrest.

Abstract 15563: Analysis of the Ventricular Fibrillation Waveform Can Guide Resuscitation in Cardiac Arrest by Identifying the Precipitating Cause and Estimating the Underlying Hemodynamics

Background: Patients presenting with out of hospital cardiac arrest (OHCA) and prolonged (>30 min) cardiopulmonary resuscitation (CPR) face nearly 100% mortality. In patients presenting with ventricular fibrillation (VF), coronary ischemia is thought to be the cause in up to 60%. As conventional CPR does not reverse a coronary ischemia, CPR often must be done until a patient can be brought to a cardiac catheterization laboratory (CCL) where the underlying cause (acute ischemia) can be treated. In a porcine model of cardiac arrest, we have previously demonstrated that machine learning (ML) targeting invasive hemodynamic monitoring, could significantly improve CPR quality. To advance the clinical relevance of the machine-controlled CPR methods, we developed ML algorithms that can diagnose coronary ischemia during VF, and infer the underlying hemodynamics while performing CPR. Methods: In a porcine model of cardiac arrest, VF was induced via high-grade coronary occlusion (ischemia) or electrical stimulation (dysrhythmia). The animals (n = 72) were left in VF for 3 minutes prior to intervention and the ECG waveform was collected. The VF signal was converted to the frequency domain using a fast-fourier transformation and an ensemble classifier was developed to detect underlying ischemia. CPR was then initiated and the VF waveform was continuously monitored along with the coronary perfusion pressure (CPP). We then developed a 20-layer convolutional neural network (CNN) to non-invasively infer the CPP from a 10-second VF waveform. Results: Animal studies were split into training and test sets. When using the developed ML technique to detect ischemia from the VF waveform, evaluation of the test set yielded an area under the curve (AUC) of 0.81 on a ROC. When we used the CNN to infer the underlying hemodynamics, we demonstrated a high correlation between measured and predicted CPP in the test set. The AUC for the ROC when predicting a CPP of >15 mmHg was 0.85. Conclusion: Survival for patients with OHCA secondary to coronary ischemia will improve with rapid diagnosis and high quality CPR. Our results demonstrate the proof-of-concept that the VF waveform contains features that can guide resuscitation for cause identification and hemodynamic improvement.

Abstract 106: Neurological Effects Of Methylene Blue In A Porcine Model Of Cardiac Arrest

Purpose To investigate the neuroprotective effects of methylene blue (MB) in a clinically relevant porcine model of cardiac arrest. Method: 40 anaesthetized pigs were subjected to myocardial infarction and seven minutes of untreated cardiac arrest. Animals were randomized into three groups: one group received saline only (control), one group received 2 mg/kg MB and saline (MB+saline), and one group received two doses of 2 mg/kg MB (MB+MB). The first intervention was given after the 3rd rhythm analysis, while the second dose was administered one hour after achieving return of spontaneous circulation (ROSC). The main investigator was blinded during resuscitation and the first hour after ROSC. Animals underwent intensive care and observation for 6 hours. Neurological outcomes were evaluated by cerebral microdialysis and serum-neuron specific enolase (NSE). Normality was assessed by qq-plot and histograms. Pointwise data were analyzed using Kruskal-Wallis test as data did not assume normal distribution. Data are presented as medians and 25 th and 75 th percentiles. A value of p<0.05 was considered statistically significant. Results: The proportion of animals achieving ROSC was similar across groups: 11/13 (85%) in the control group, 10/13 (77%) in the MB+saline group, and 12/14 (86%) in the MB+MB group (p=0.81). Cerebral lactate and pyruvate levels increased after ROSC in all groups. Lactate/pyruvate ratios were comparable between groups two hours after ROSC (control: 25 (22;31); MB+saline: 24 (22;36); MB+MB: 23 (20;28); p=0.43). Cerebral glycerol levels initially increased in all groups with the highest levels at two hours after ROSC (control: 454 μmol/L (319;507); MB+saline 351 μmol/L (241;420); MB+MB 347 μmol/L (256;478); p=0.35). Glycerol levels decreased over time with no difference 6 hours after ROSC (control: 210 μmol/L (138;293); MB+saline (146 μmol/L (61;156); MB+MB: 105 μmol/L (63;159); p=0.07). Serum-NSE levels 6 hours after ROSC were not different between groups (control: 0.9 μg/L (0.7;1.5); MB+saline 1.5 μg/L (1.0;2.0); MB+MB: 1.0 μg/L (0.7;1.2); p=0.13). Conclusion Contrary to previous publications the current porcine trial did not observe any neuroprotective effects of MB when evaluated by cerebral microdialysis and NSE levels.

Abstract 107: Systemic Allogeneic Mesenchymal Stem Cell Administration Does Not Attenuate Early Post-resuscitation Brain Injury Or Inflammation In A Porcine Model Of Cardiac Arrest

Introduction: Based on emerging evidence that systemic inflammation exacerbates post-resuscitation organ injury, we recently tested the efficacy of allogeneic mesenchymal stem cell (MSC) administration early after return of spontaneous circulation (ROSC) in a porcine model of cardiac arrest (CA). Initial results indicate that MSCs attenuate post-ROSC cardiac dysfunction, but it is unclear if these protective effects extend to the brain. Accordingly, we aimed to determine if systemic allogeneic MSCs reduce early post-ROSC brain injury and inflammation in swine. Methods: Swine (n=33) were subjected to 10 min CA followed by mechanical CPR with defibrillation and epinephrine (EPI; 0.015 mg/kg iv). Animals that achieved ROSC (n=19) were blindly randomized to intra-arterial saline (n=9) or allogeneic bone marrow-derived MSCs (55±2 x 10 6 ; n=10) 30 min post-ROSC. Blood sampling was performed for 4 hours post-ROSC to quantify serum neurofilament light chain (NFL) levels, after which brain tissue was collected for post-mortem quantification of regional neuronal injury (H&E), activated microglia (IBA-1), and inflammatory gene expression (PCR) vs. healthy control swine (n=8). Results: Animals resuscitated from CA exhibited a significant increase in neuronal injury throughout the brain vs. controls that was not affected by MSC treatment ( A ). Similarly, the post-ROSC rise in serum NFL was not different between saline-treated and MSC-treated animals (2.5±0.6 vs. 2.5±0.8 fold-change vs. baseline; p=0.94). A significant increase in activated microglia ( B ) and inflammatory gene expression ( C ) was observed throughout the brain in both CA groups vs. healthy controls, with particularly prominent changes in the striatum but no notable differences between treatment groups. Conclusions: Despite favorable effects on the heart, systemic allogeneic MSC therapy after ROSC does not significantly affect early markers of brain injury and inflammation in a porcine model of CA.

Abstract 137: Effect Of Chest Compression Release Velocity On Cerebral Perfusion Pressure In A Porcine Experimental Model Of Cardiac Arrest.

Background: Previous studies have shown that chest compression release velocity (CCRV) of over 400mm/s is associated with improved survival and favorable neurologic outcome after cardiac arrest. However, it is uncertain whether CCRV during CPR is related to cerebral perfusion pressure (CePP). The purpose of this study was to evaluate the association between CCRV and CePP in a porcine cardiac arrest model. Methods: After 6 minutes of untreated ventricular fibrillation, 2 cycles of basic life support (BLS) and 12 cycles of advanced cardiovascular life support (ACLS) were conducted. During ACLS phase, CCRV was accelerated from 250mm/s to 450mm/s by 50mm/s (accelerating group) or decelerated from 450mm/s to 250mm/s by 50mm/s (decelerating group). Both groups performed BLS with the self-set value of the mechanical CPR device (LUCAS 2 chest compression system, CCRV of 170mm/s). Twenty-four pigs were randomly assigned to each group. Macrovascular circulation (CePP) and microvascular circulation using laser doppler flowmetry presented as a fraction of the baseline flow (f-LDF) were measured. We excluded the last 2 cycles of ACLS phase from the analysis due to time-dependent deterioration effects of hemodynamic outcomes. Linear mixed model was used to measure the median difference in CePP and f-LDF according to CCRV. Results: A total of 24 pigs were analyzed. Decelerating group of CCRV of 400mm/s showed significantly higher CePP values compared to the group of 170mm/s. Effect of changes in CCRV on CePP, stratified by groups, are as follows (median, [95% confidence intervals]): 1. Accelerating group: CCRV of 170mm/s; reference, 250mm/s; -1.98 [-10.78 - 11.79] mmHg, 300mm/s; -1.88 [-11.15 - 12.55] mmHg, 350mm/s; -2.55 [-11.46 - 12.24], 400mm/s; -6.05 [-5.59 - 16.86], and 2. Decelerating group: CCRV of 170mm/s; reference, 250mm/s; 5.71 [-16.27 - 27.11] mmHg, 300mm/s; 6.01 [-16.28 - 27.90] mmHg, 350mm/s; 6.96 [6.36 - 47.70], 400mm/s; 26.96 [6.36 - 47.70]. However, there was no significant CCRV effects on f-LDF (Accelerating CCRV of 400mm/s; 1.54 [ -0.03 - 3.10] and decelerating CCRV of 400mm/s; -2 [-4.42 - 0.34]). Conclusion: In a VF cardiac arrest porcine study, CCRV of 400mm/s at early phase of CPR has positive effects on CePP.

Abstract 305: Effect Of Initial Epinephrine Administration Time On Cerebral Perfusion In A Porcine Experimental Model Of Cardiac Arrest

Background: The effect of initial epinephrine administration time from cardiac arrest on cerebral perfusion pressure (CePP) during CPR is controversial. The purpose of this study was to evaluate the association between initial epinephrine administration time and CePP in a porcine cardiac arrest model. Methods: Initial administration time of epinephrine was divided into 3 groups based on time after inducing ventricular fibrillation (VF): 5 minutes (early group), 10 minutes (intermediate group), and 15 minutes (delayed group). Twenty-four pigs were randomly assigned to each group. After 4 minutes of untreated ventricular fibrillation, 2 cycles of BLS (BLS1 and BLS2 phase) and 10 cycles of ACLS (ACLS1~10 phase) were conducted. Macrovascular circulation (CePP) and microvascular circulation using laser doppler flowmetry presented as a fraction of the baseline flow (f-LDF) were measured. Linear mixed model was used to measure median difference in CePP and f-LDF between groups. Results: A total of 22 pigs were analyzed. Early group showed higher and earlier peak of CePP and f-LDF compared to those of intermediate or delayed groups. There was a significant group by phase interaction in CePP where the early group showed a higher CePP on earlier phase. (Early group: median 38.2 [95% confidence intervals 30.7-50.5] mmHg at BLS 2 phase, intermediate group: 27.1 [14.1-35.7] mmHg at ACLS1 phase, late group: 12.2 [2.2-34.9] mmHg at ACLS 4 phase), p< 0.001). There was no significant group by phase interaction in f-LDF; however, there was a tendency of decreased peak and delayed reach to peak with time. (Early group: median 5.7 [95% confidence interval 3.5-7.8] at ACLS 2 phase, intermediate group: 3.6 [1.5-5.1] at ACLS 4 phase, late group: 2.2 [0.9-3.3] at ACLS 6 phase, p =0.93). Conclusion: In this VF cardiac arrest porcine study, the early administration of epinephrine group showed higher and earlier peak of CePP and f-LDF compared to those of the intermediate and delayed groups.

Abstract 114: Postconditioning With Argon Has No Direct Lung-protective Effect Against Ischemia Reperfusion In A Rat Isolated Lung Model

Cardiac arrest (CA) remains a significant medical problem with stagnating low survival rates. Ventilation with the noble gas Argon (Ar) after return of spontaneous circulation improved neurologically favorable survival in a porcine CA model. We hypothesized that postconditioning with Ar attenuates global ischemia reperfusion (IR) injury in a rat isolated lung model. Following Institutional Animal Care and Use Committee approval and conforming with the "Position of the American Heart Association on Research Animal Use", lungs of adult male Sprague Dawley rats (250-350 g) were isolated and positive-pressure ventilated (10 mL/kg body weight [BW]) at a respiration rate of 30 breaths/minute. Lungs were perfused with physiological crystalloid buffer at a constant flow of 40 mL/kg BW. The control (C) group (n=6-7) was ventilated with 65% N 2 , 5% CO 2 , 30% O 2 , the Ar group (n=6) with 65% Ar, 5% CO 2 , 30% O 2 before global no-flow ischemia for 8 min followed by reperfusion. Mean arterial (MAP) and airway pressures (AWP) were recorded continuously. Lung viability as survival time until development of fulminant pulmonary edema was noted. Data are mean +/- SEM. Statistics: Student's t-Test with *p< 0.05. IR significantly increased MAP and AWP throughout reperfusion compared to baseline; contrary to our hypothesis, though, ventilation with Ar did not signficantly increase survival time (panel A) or lower MAP (B) or AWP (C) of the isolated lung during reperfusion in this model. In-vivo models may be better-suited to assess Ar’s organ-protective effects following CA.

OR26 Effects of no-flow time on the pathophysiology of Cardiopulmonary resuscitation-associated lung edema (CRALE) in a porcine model of cardiac arrest

OR26 Effects of no-flow time on the pathophysiology of Cardiopulmonary resuscitation-associated lung edema (CRALE) in a porcine model of cardiac arrest

P051 Prognostic value of ETCO2 during cardiopulmonary resuscitation in a porcine model of cardiac arrest

P051 Prognostic value of ETCO2 during cardiopulmonary resuscitation in a porcine model of cardiac arrest

Abstract 11269: Recombinant Soluble Thrombomodulin in Prolonged Porcine Cardiac Arrest

Introduction: Sudden Cardiac Arrest (CA) affects more than 400,000 people per year in the United States. Although a third of these patients survive to hospital admission, another 60-70% go on to die due to failed recovery of vital organ function. Microvascular thrombosis has been suggested as a potential contributor to prolonged organ dysfunction, but no antithrombotic therapies have been shown to be beneficial and coagulofibrinolytic abnormalities in prolonged CA remain poorly understood. Objectives: To establish key biomarkers of porcine coagulation and fibrinolysis in the setting of prolonged CA and cardiopulmonary resuscitation (CPR) and test the ability of ART-123 (recombinant human thrombomodulin alpha) to reverse these abnormalities. Methods: 15 pigs (n=5 per group) underwent 8 minutes of no-flow CA followed by 50 minutes of mechanical CPR. Animals were randomized to receive saline or ART-123 (~1mg/kg) pre-arrest (5 minutes prior to ventricular fibrillation) or post-arrest (2 minutes after initiation of CPR). Results: Robust and ongoing activation of coagulation and fibrinolysis were detected throughout the resuscitation. After 50 minutes of CPR, plasma tests suggested consumptive coagulopathy, while whole blood testing (thromboelastography) indicated a persistent hypercoagulable state. ART-123 had a clear anticoagulant effect irrespective of timing (TAT complexes 381±25 vs. 238±18 vs. 226±12, p<0.01, and d-dimer 4.86±0.54 vs. 2.39±0.2 vs. 2.46±0.21 for vehicle, pre-arrest, post-arrest, p = 0.05). A pro-fibrinolytic effect was also observed, but only when the drug was given before no-flow, with a significant increase in levels of free endogenous tPA (1.2±0.12 vs. 3.29±0.29 vs. 1.72±0.3, p < 0.001) and corresponding suppression of free PAI-1 (0.59±0.15 vs. 0.14±0.01 vs. 0.41±0.09, p < 0.001). Conclusion: Our porcine CA model provides an excellent platform for evaluating antithrombotic interventions. Plasma testing after prolonged CA/CPR suggests consumptive coagulopathy, although TEG indicates a persistent hypercoagulable state. ART-123 given before no-flow or just after CPR demonstrates antithrombotic effects, although the specific modes of action depending on the timing of administration.

Use of an end-tidal carbon dioxide-guided algorithm during cardiopulmonary resuscitation improves short-term survival in paediatric swine

AimTo evaluate an algorithm that uses an end-tidal carbon dioxide (ETCO2) target of ≥ 30 torr to guide specific changes in chest compression rate and epinephrine administration during cardiopulmonary resuscitation (CPR) in paediatric swine. MethodsSwine underwent asphyxial cardiac arrest followed by resuscitation with either standard or ETCO2-guided algorithm CPR. The standard group received chest compressions at a rate of 100/min and epinephrine every 4 min during advanced life support consistent with the American Heart Association paediatric resuscitation guidelines. In the ETCO2-guided algorithm group, chest compression rate was increased by 10 compressions/min for every minute that the ETCO2 was < 30 torr, and the epinephrine administration interval was decreased to every 2 min if the ETCO2 remained < 30 torr. Short-term survival and physiologic data during active resuscitation were compared. ResultsShort-term survival was significantly greater in the ETCO2-guided algorithm CPR group than in the standard CPR group (16/28 [57.1%] versus 4/28 [14.3%]; p = 0.002). Additionally, the algorithm group had higher predicted mean ETCO2, chest compression rate, diastolic and mean arterial pressure, and myocardial perfusion pressure throughout resuscitation. Swine in the algorithm group also exhibited significantly greater improvement in diastolic and mean arterial pressure and cerebral perfusion pressure after the first dose of epinephrine than did those in the standard group. Incidence of resuscitation-related injuries was similar in the two groups. ConclusionsUse of a resuscitation algorithm with stepwise guidance for changes in the chest compression rate and epinephrine administration interval based on a goal ETCO2 level improved survival and intra-arrest hemodynamics in this porcine cardiac arrest model.

Impact of lung structure on airway opening index during mechanical versus manual chest compressions in a porcine model of cardiac arrest

ObjectivesThe exhaled CO2 signal provides guidance during cardiopulmonary resuscitation. The Airway opening index (AOI) has been recently used to quantify chest-compression (CC) induced expired CO2 oscillations. We aimed to determine whether levels of intrathoracic pressures developed during CC or parameters related to lung structure may affect AOI. MethodsSecondary analysis of a randomized animal study (n = 12) in a porcine model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) during ambulance transport. Animals were randomized to 18-min of manual or mechanical CCs. Changes in AOI and right atrial pressure (ΔRAP) were recorded during CCs in animals undergoing manual (n = 6) or mechanical (n = 6) CCs. Lung CT scan and measurement of the respiratory system compliance (Cpl,rs) were performed immediately after return of spontaneous circulation. ResultsAnimals undergoing mechanical CCs had a lower AOI compared to animals treated with manual CCs (p < 0.001). AOI negatively correlated with the swings of intrathoracic pressure, as measured by the change in ΔRAP (ρ=−0.727, p = 0.007). AOI correlated with the lung density (ρ=−0.818, p = 0.001) and with the Cpl,rs (ρ = 0.676, p = 0.016). Animals with cardiopulmonary resuscitation associated lung edema (CRALE) (i.e. mean CT≥−500 HU) showed lower levels of AOI compared to animals without it (29 ± 12 % versus 50 ± 16 %, p = 0.025). ConclusionsAnimals undergoing mechanical CCs had lower levels of AOI compared to animals undergoing manual CCs. A higher swing of intrathoracic pressure during CC, a denser and a stiffer lung were associated with an impaired CO2 exhalation during CC as observed by a lower AOI.

Compression depth of 30 mm has similar efficacy and fewer complications versus 50 mm during mechanical chest compression with miniaturized chest compressor in a porcine model of cardiac arrest.

BackgroundCurrent guidelines recommend a 50 mm or greater compression depth for manual chest compression in adults. However, whether this uniform compression depth is a suitable requirement for mechanical CPR remains to be determined. We hypothesized that a relatively shallow compression depth (30 mm) would have similar hemodynamic efficacy but fewer complications versus the standard compression depth (50 mm) during mechanical cardiopulmonary resuscitation (CPR) with the miniaturized chest compressor (MCC) in a porcine model.MethodsIn the current study, we used a total of 16 domestic male pigs (38±2 kg). All pigs were exposed to 7 min of ventricular fibrillation (VF) followed by 5 min of CPR. Then the animals were randomly assigned to the shallow (30 mm) group and the standard (50 mm) group. At the second min of CPR, every pig was given epinephrine (20 µg/kg) through the femoral vein and repeated every 3 min. First defibrillation was delivered with a single 120 J shock at 5 min of CPR. Hemodynamics, carotid blood flow (CBF), end-tidal carbon dioxide (ETCO2), coronary perfusion pressure (CPP), intrathoracic pressure (ITP) and arterial blood gas were measured. Rib fractures and lung injuries, as indicated by ground-glass opacification (GGO), as well as intense parenchymal opacification (IPO), were assessed and calculated by quantitative computed tomography (QCT) scan.ResultsWe found no significant differences in CPP, CBF, or ETCO2 between the both groups throughout the CPR period. After administration of epinephrine, the CPP of all animals increased while ETCO2 and CBF decreased during CPR. A significantly lower intrathoracic positive pressure (ITPP) and systolic artery pressure (SAP) were measured in the shallow group at the first min of CPR. However, we didn’t find remarkable differences in these values between the both groups for the next 4 min of CPR. All animals were successfully resuscitated. The shallow group had significantly lower IPO QCT scores compared with the standard group. We found no significant differences in GGO QCT scores after resuscitation between both groups.ConclusionsRelatively shallow compression depth has similar hemodynamic efficacy but fewer complications versus the standard compression depth.

Adrenaline improves regional cerebral blood flow, cerebral oxygenation and cerebral metabolism during CPR in a porcine cardiac arrest model using low-flow extracorporeal support

BackgroundThe effects of adrenaline on cerebral blood vessels during cardiopulmonary resuscitation (CPR) are not well understood. We developed an extracorporeal CPR model that maintains constant low systemic blood flow while allowing adrenaline-associated effects on cerebral vasculature to be assessed at different mean arterial pressure (MAP) levels independently of the effects on systemic blood flow. MethodsAfter eight minutes of cardiac arrest, low-flow extracorporeal life support (ECLS) (30 ml/kg/min) was started in fourteen pigs. After ten minutes, continuous adrenaline administration was started to achieve MAP values of 40 (n = 7) or 60 mmHg (n = 7). Measurements included intracranial pressure (ICP), cerebral perfusion pressure (CePP), laser-Doppler-derived regional cerebral blood flow (CBF), cerebral regional oxygen saturation (rSO2), brain tissue oxygen tension (PbtO2) and extracellular cerebral metabolites assessed by cerebral microdialysis. ResultsDuring ECLS without adrenaline, regional CBF increased by only 5% (25th to 75th percentile: −3 to 14; p = 0.2642) and PbtO2 by 6% (0–15; p = 0.0073) despite a significant increase in MAP to 28 mmHg (25–30; p < 0.0001) and CePP to 10 mmHg (8–13; p < 0.0001). Accordingly, cerebral microdialysis parameters showed a profound hypoxic-ischemic pattern. Adrenaline administration significantly improved regional CBF to 29 ± 14% (p = 0.0098) and 61 ± 25% (p < 0.001) and PbtO2 to 15 ± 11% and 130 ± 82% (both p < 0.001) of baseline in the MAP 40 mmHg and MAP 60 mmHg groups, respectively. Importantly, MAP of 60 mmHg was associated with metabolic improvement. ConclusionThis study shows that adrenaline administration during constant low systemic blood flow increases CePP, regional CBF, cerebral oxygenation and cerebral metabolism.

Cerebral perfusion and metabolism with mean arterial pressure 90 vs. 60 mmHg in a porcine post cardiac arrest model with and without targeted temperature management

AimTo determine whether targeting a mean arterial pressure of 90 mmHg (MAP90) would yield improved cerebral blood flow and less ischaemia compared to MAP 60 mmHg (MAP60) with and without targeted temperature management at 33 °C (TTM33) in a porcine post-cardiac arrest model. MethodsAfter 10 min of cardiac arrest, 41 swine of either sex were resuscitated until return of spontaneous circulation (ROSC). They were randomised to TTM33 or no-TTM, and MAP60 or MAP90; yielding four groups. Temperatures were managed with intravasal cooling and blood pressure targets with noradrenaline, vasopressin and nitroprusside, as appropriate. After 30 min of stabilisation, animals were observed for two hours. Cerebral perfusion pressure (CPP), cerebral blood flow (CBF), pressure reactivity index (PRx), brain tissue pCO2 (PbtCO2) and tissue intermediary metabolites were measured continuously and compared using mixed models. ResultsAnimals randomised to MAP90 had higher CPP (p < 0.001 for both no-TTM and TTM33) and CBF (no-TTM, p < 0.03; TH, p < 0.001) compared to MAP60 during the 150 min observational period post-ROSC. We also observed higher lactate and pyruvate in MAP60 irrespective of temperature, but no significant differences in PbtCO2 and lactate/pyruvate-ratio. We found lower PRx (indicating more intact autoregulation) in MAP90 vs. MAP60 (no-TTM, p = 0.04; TTM33, p = 0.03). ConclusionIn this porcine cardiac arrest model, targeting MAP90 led to better cerebral perfusion and more intact autoregulation, but without clear differences in ischaemic markers, compared to MAP60. Institutional protocol numberFOTS, id 8442.

Esmolol during cardiopulmonary resuscitation reduces neurological injury in a porcine model of cardiac arrest

Primary vasopressor efficacy of epinephrine during cardiopulmonary resuscitation (CPR) is due to its α-adrenergic effects. However, epinephrine plays β1-adrenergic actions, which increasing myocardial oxygen consumption may lead to refractory ventricular fibrillation (VF) and poor outcome. Effects of a single dose of esmolol in addition to epinephrine during CPR were investigated in a porcine model of VF with an underlying acute myocardial infarction. VF was ischemically induced in 16 pigs and left untreated for 12 min. During CPR, animals were randomized to receive epinephrine (30 µg/kg) with either esmolol (0.5 mg/kg) or saline (control). Pigs were then observed up to 96 h. Coronary perfusion pressure increased during CPR in the esmolol group compared to control (47 ± 21 vs. 24 ± 10 mmHg at min 5, p < 0.05). In both groups, 7 animals were successfully resuscitated and 4 survived up to 96 h. No significant differences were observed between groups in the total number of defibrillations delivered prior to final resuscitation. Brain histology demonstrated reductions in cortical neuronal degeneration/necrosis (score 0.3 ± 0.5 vs. 1.3 ± 0.5, p < 0.05) and hippocampal microglial activation (6 ± 3 vs. 22 ± 4%, p < 0.01) in the esmolol group compared to control. Lower circulating levels of neuron specific enolase were measured in esmolol animals compared to controls (2[1–3] vs. 21[16–52] ng/mL, p < 0.01). In this preclinical model, β1-blockade during CPR did not facilitate VF termination but provided neuroprotection.

Post‐Resuscitation Neuroinflammation in a Porcine Model of Cardiac Arrest: Effect of Systemic Allogeneic Mesenchymal Stem Cell Therapy

Objective Although advances in cardiopulmonary resuscitation (CPR) have increased the likelihood of achieving return of spontaneous circulation (ROSC) after cardiac arrest (CA), >50% of initially resuscitated patients die before hospital discharge. Based on emerging evidence that a systemic inflammatory response exacerbates post-ROSC injury, we recently tested the efficacy of allogeneic mesenchymal stem cell (MSC) administration early after ROSC in a porcine model of CA. Initial results indicate that MSCs attenuate post-ROSC cardiac dysfunction, but it is unclear if these protective effects extend to the brain. Accordingly, the objective of this study was to determine if systemic allogeneic MSCs reduce post-resuscitation neuroinflammation in swine. Methods Swine (n=33) were subjected to 10 min CA followed by mechanical CPR with defibrillation and intravenous epinephrine (EPI; 0.015 mg/kg). Animals that achieved ROSC (n=19) were blindly randomized to intra-arterial saline (n=9) or allogeneic bone marrow-derived MSCs (55±2 x 106; n=10) 30 min post-ROSC. Serial blood sampling was performed for 4 hours post-ROSC to quantify circulating leukocytes and inflammatory cytokines (IL-6, TNF-α, CRP), after which animals underwent diffusion-weighted brain MRI (DWI) to assess cytotoxic edema via apparent diffusion coefficient (ADC) mapping. Five hours post-ROSC, brain tissue samples were collected from the frontal cortex and hippocampus for quantification of inflammatory gene expression via RT-PCR. Gene expression data were normalized to ß-2 microglobulin and compared to results from healthy control swine (n=8). Results Following ROSC, we observed a significant ~3-fold increase in circulating neutrophils and monocytes that was similar between treatment groups (A). Plasma concentrations of inflammatory cytokines also increased post-ROSC and did not differ significantly between groups, although MSCs tended to attenuate the rise in circulating IL-6 (p=0.09; B). A significant ~2-4-fold increase in inflammatory gene expression was observed in the frontal cortex and hippocampus in both CA groups compared with healthy controls, without notable differences between treatment groups (C). DWI showed significantly lower cortical ADC values in saline-treated animals (736±32 x106 mm2/s) vs. normal controls (809±24 x106 mm2/s), consistent with cytotoxic edema. In contrast, cortical ADC values in MSC-treated animals (791±20 x106 mm2/s) did not differ vs. controls (p=0.52). However, between-group differences were not observed in the hippocampus or when ADC thresholds were applied across the entire brain. Conclusions Despite favorable effects on the heart, systemic allogeneic MSC therapy after resuscitation from CA does not significantly affect multiple parameters of neuroinflammation within the first several hours post-ROSC. Although these findings should be confirmed after a longer follow-up duration, the present results suggest that alternative neuroprotective interventions may be necessary to reduce brain inflammation and injury after resuscitation from CA.