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Visual Abstract, Highlights • A large animal model that recapitulates the clinical heterogeneity of HFpEF has been developed. • Multiple comorbidities, including obesity, hypercholesterolemia, pre-diabetic phenotype, as well as pulmonary and systemic arterial hypertension, were induced in adult female Göttingen minipigs by mineralocorticoid excess and a diet high in cholesterol, fat, fructose, and salt. • Severity of each comorbidity was titrated, such that marked left ventricular and left atrial diastolic dysfunction, profound left ventricular concentric remodeling, impaired coronary vasorelaxation, and extensive multiorgan fibrosis were achieved over a relatively short time. • This novel heart failure model was generated in Göttingen minipigs to allow for translational studies of novel pharmacological agents and for human-sized device testing in adult-aged animals. • This novel “multihit” minipig heart failure model enabled investigations into the pathology of HFpEF without the confounding effects inherent with invasive surgical procedures or the administration of agents that induce hypertension and end-organ damage in an artificial manner., Summary A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt−induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

Supplemental Digital Content is available in the text., Background: Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models. Methods: Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet. Results: The KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P

Due to its high energy consumption and limited ability to store ATP, the heart is highly dependent of exogenous metabolic substrates. Prior in vivo studies have reported that the development of heart failure is accompanied by a transition from the normal preferential metabolism of free fatty acids (FFA) to increases in glucose utilization and even ketone bodies, which normally provide a modest contribution to energy balance. However, the functional significance of the upregulated ketone metabolism in the failing heart is poorly understood. Recognizing that nearly all prior studies examining isolated cardiomyocyte physiology have used glucose as the sole metabolic substrate, we initiated studies to examine the impact of alternative metabolic substrates on contractility in isolated human cardiomyocytes. To understand the role of substrate alteration cardiomyocyte functionalities, we employed freshly isolated adult human left ventricular cardiomyocytes from 11 non-failing hearts (NF) obtained from organ donors and 13 failing hearts (HF) obtained from transplant recipients. Cardiomyocytes were resuspended in a conventional 5mM Glucose Tyrode solution with alternative substrates (Glucose, FFA, R-3-OHB or Mix (Glucose + FFA + 3-OHB)). Myocytes were field stimulated at 1 Hz and sarcomere length, fractional shortening, contraction velocity and relaxation velocity were measured using a video-based sarcomere length detection system (IonOptix Corp). Studies using isolated cardiac myocyte contractility as readout confirm that myocytes from NF human hearts are omnivorous: high levels of myocyte fractional shortening (FS) can be achieved under unstressed conditions (1 Hz, unloaded) with any substrate (FS Glucose : 0.1315±0.012; FS FFA : 0.1428±0.0127; FS 3OHB : 0.1343±0.014; FS MIX : 0.15467±0.02). In the failing heart, glucose alone is insufficient to produce normal unstressed myocyte fractional shortening (FS Glucose : 0.088±0.009***, pFFA : 0.109±0.0127; FS 3OHB : 0.107±0.012; FS MIX : 0.112±0.016). These results suggest that future comparisons of NF vs. HF human myocyte contractility should include conditions with a physiological mix of metabolic substrates.

Rationale: The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the fetal shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell–derived cardiac myocytes. Objective: To delineate transcriptional drivers of cardiac maturation. Methods and Results: We hypothesized that ERR (estrogen-related receptor) α and γ, known transcriptional regulators of postnatal mitochondrial biogenesis and function, serve a role in the broader cardiac maturation program. We devised a strategy to knockdown the expression of ERRα and γ in heart after birth (pn-csERRα/γ [postnatal cardiac-specific ERRα/γ]) in mice. With high levels of knockdown, pn-csERRα/γ knockdown mice exhibited cardiomyopathy with an arrest in mitochondrial maturation. RNA sequence analysis of pn-csERRα/γ knockdown hearts at 5 weeks of age combined with chromatin immunoprecipitation with deep sequencing and functional characterization conducted in human induced pluripotent stem cell–derived cardiac myocytes (hiPSC-CM) demonstrated that ERRγ activates transcription of genes involved in virtually all aspects of postnatal developmental maturation, including mitochondrial energy transduction, contractile function, and ion transport. In addition, ERRγ was found to suppress genes involved in fibroblast activation in hearts of pn-csERRα/γ knockdown mice. Disruption of Esrra and Esrrg in mice during fetal development resulted in perinatal lethality associated with structural and genomic evidence of an arrest in cardiac maturation, including persistent expression of early developmental and noncardiac lineage gene markers including cardiac fibroblast signatures. Lastly, targeted deletion of ESRRA and ESRRG in hiPSC-CM derepressed expression of early (transcription factor 21 or TCF21) and mature (periostin, collagen type III) fibroblast gene signatures. Conclusions: ERRα and γ are critical regulators of cardiac myocyte maturation, serving as transcriptional activators of adult cardiac metabolic and structural genes, an.d suppressors of noncardiac lineages including fibroblast determination.

Highlights •The Minnesota Resuscitation Consortium has established a protocol for rapid transport of patients with refractory out-of-hospital VF cardiac arrest to the cardiac catheterization laboratory for rapid evaluation and stabilization often requiring ECMO. This protocol provides new challenges to treatment paradigms that were created to rapidly achieve return of spontaneous circulation in the field. •A porcine model of refractory VF cardiac arrest was developed, including initiation of VF using endovascular occlusion of the proximal LAD followed by 5 min of untreated VF. Resuscitation begins with 10 min of high-quality CPR followed by 35 min of ACLS and reconstitution of coronary flow. •A 2 × 2 study design was used with animals randomized to use of epinephrine or placebo during ACLS and then again randomized to ECMO or no ECMO at the time of reinitiation of coronary flow. •ECMO-facilitated coronary reperfusion and hemodynamic stabilization improved 4-h survival compared with CPR-facilitated reperfusion and standard ACLS in a porcine model of refractory VF cardiac arrest. •Repeated epinephrine boluses provided in accordance with standard ACLS protocols increased systemic blood pressure and coronary perfusion pressure but provided no benefit in survival compared with placebo. •Over 50% of the animals receiving ECMO met criteria for decannulation at 4 h, suggesting that rapid cardiac and hemodynamic recovery is possible in severely injured animals treated with ECMO.

Evidence has emerged that the failing heart increases utilization of ketone bodies. We sought to determine whether this fuel shift is adaptive. Mice rendered incapable of oxidizing the ketone body 3-hydroxybutyrate (3OHB) in the heart exhibited worsened heart failure in response to fasting or a pressure overload/ischemic insult compared with WT controls. Increased delivery of 3OHB ameliorated pathologic cardiac remodeling and dysfunction in mice and in a canine pacing model of progressive heart failure. 3OHB was shown to enhance bioenergetic thermodynamics of isolated mitochondria in the context of limiting levels of fatty acids. These results indicate that the heart utilizes 3OHB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure.

Introduction: Sodium nitroprusside enhanced CPR (SNPeCPR) is a novel CPR method that includes a potent vasodilator, active compression-decompression CPR, an inspiratory impedance threshold device and abdominal binding. SNPeCPR has been shown to improve vital organ flow and functional survival outcomes compared to standard CPR methods in animals. We hypothesize that one of the main effects of SNPeCPR mediated increase in cardiac output during prolonged resuscitation is profound pulmonary artery vasodilation. Methods: After electrically induced VF was left untreated for 3 min, 20 (44-48Kg) pigs were randomized to receive SNPeCPR (10) or standard CPR (10) for a total of 30 min; the first 10 minutes were BLS CPR followed by twenty minutes of ACLS. During ACLS, animals were given IV SNP (1mg bolus) or standard epinephrine (0.5mg) q5 min until ROSC or 45 min total CPR. Shocks were delivered after 30 minutes of CPR at 300J. If ROSC was achieved, animal was monitored until 4-hour endpoint. Ventilations were provided with 10ml/kg at 10/min with a mechanical ventilator. Initially during CPR, room air was used and FiO2 was adjusted q5 minutes to maintain O 2 %saturation &gt 92% based on ABG. Lactic acid was also measured. Aortic, right atrial, and coronary artery pressures and carotid blood flow were recorded continuously. A-a oxygen gradient was measured with standard technique. Results: SNPeCPR animals documented a significantly higher mean CPP, lower lactic acid and 3x higher carotid blood flow over 30 minutes compared to standard CPR as previously documented. A-a oxygen gradient was dramatically increased in the SNPeCPR and coincided with a decreased lactate level (see Figure 1). Discussion: SNPeCPR causes profound pulmonary vasodilation and increases flow through non-ventilated lung areas. Despite that, the overall increase in forward flow leads to higher minute O 2 delivery and improved tissue perfusion. SNPeCPR should be used with 100% oxygen in the first human clinical trial.

Brain injury is a leading cause of death and disability in children and adults in their most productive years. Use of intrathoracic pressure regulation (IPR) to generate negative intrathoracic pressure during the expiratory phase of positive pressure ventilation improves mean arterial pressure and 24-h survival in porcine models of hemorrhagic shock and cardiac arrest and has been demonstrated to decrease intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in these models. Application of IPR for 240 min in a porcine model of intracranial hypertension (ICH) will increase CPP when compared with controls. Twenty-three female pigs were subjected to focal brain injury by insertion of an epidural Foley catheter inflated with 3 mL of saline. Animals were randomized to treatment for 240 min with IPR set to a negative expiratory phase pressure of -12 cmH2O or no IPR therapy. Intracranial pressure, mean arterial pressure, CPP, and cerebral blood flow (CBF) were evaluated. Intrathoracic pressure regulation significantly improved mean CPP and CBF. Specifically, mean CPP after 90, 120, 180, and 240 min of IPR use was 43.7 ± 2.8 mmHg, 44.0 ± 2.7 mmHg, 44.5 ± 2.8 mmHg, and 43.1 ± 1.9 mmHg, respectively; a significant increase from ICH study baseline (39.5 ± 1.7 mmHg) compared with control animals in which mean CPP was 36.7 ± 1.4 mmHg (ICH study baseline) and then 35.9 ± 2.1 mmHg, 33.7 ± 2.8 mmHg, 33.9 ± 3.0 mmHg, and 36.0 ± 2.7 mmHg at 90, 120, 180, and 240 min, respectively (P < 0.05 for all time points). Cerebral blood flow, as measured by an invasive CBF probe, increased in the IPR group (34 ± 4 mL/100 g-min to 49 ± 7 mL/100 g-min at 90 min) but not in controls (27 ± 1 mL/100 g-min to 25 ± 5 mL/100 g-min at 90 min) (P = 0.01). Arterial pH remained unchanged during the entire period of IPR compared with baseline values and control values. In this anesthetized pig model of ICH, treatment with IPR significantly improved CPP and CBF. This therapy may be of clinical value by noninvasively improving cerebral perfusion in states of compromised cerebral perfusion.

Background Out-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10%. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after 15 min of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR). Methods A total of 63 swine were randomized to no ischemia (Naive), 19 min of ventricular fibrillation (VF) CA without CPR (Untreated VF), or 15 min of CA with 4 min of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue. Results Compared to Naive, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to Untreated VF, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to Untreated VF, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain. Conclusions Fifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4 min of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs.

Purpose of review Survival with favorable neurological function after cardiac arrest remains low. The purpose of this review is to identify recent advances that focus on neuroprotection during cardiopulmonary resuscitation (CPR). Recent findings Multiple strategies have been shown to enhance neuroprotection during CPR. Brain perfusion during CPR is increased with therapies such as active compression decompression CPR and intrathoracic pressure regulation that improve cardiac preload and decrease intracranial pressure. Head Up CPR has been shown to decrease intracranial pressure thereby increasing cerebral perfusion pressure and cerebral blood flow. Sodium nitroprusside enhanced CPR increases cerebral perfusion, facilitates heat exchange, and improves neurologic survival in swine after cardiac arrest. Postconditioning has been administered during CPR in laboratory settings. Poloxamer 188, a membrane stabilizer, and ischemic postconditioning have been shown to improve cardiac and neural function after cardiac arrest in animal models. Postconditioning with inhaled gases protects the myocardium, with more evidence mounting for the potential for neural protection. Summary Multiple promising neuroprotective therapies are being developed in animal models of cardiac arrest, and are in early stages of human trials. These therapies have the potential to be bundled together to improve rates of favorable neurological survival after cardiac arrest.

The combination of the LUCAS 2 (L-CPR) automated CPR device and an impedance threshold device (ITD) has been widely implemented in the clinical field. This animal study tested the hypothesis that the addition of an ITD on L-CPR would enhance cerebral and coronary perfusion pressures.Ten female pigs (39.0 ± 2.0 kg) were sedated, intubated, anesthetized with isofluorane, and paralyzed with succinylcholine (93.3 μg/kg/min) to inhibit the potential confounding effect of gasping. After 4 min of untreated ventricular fibrillation, 4 min of L-CPR+an active ITD or L-CPR+a sham ITD was initiated and followed by another 4 min of the alternative method of CPR. Systolic blood pressure (SBP), diastolic blood pressure (DBP), diastolic right atrial pressure (RAP), intracranial pressure (ICP), airway pressure, and end tidal CO2 (ETCO2) were recorded continuously. Data expressed as mean mmHg ± SD.Decompression phase airway pressure was significantly lower with L-CPR+active ITD versus L-CPR+sham ITD (-5.3 ± 2.2 vs. -0.5 ± 0.6; p0.001). L-CPR+active ITD treatment resulted in significantly improved hemodynamics versus L-CPR+sham ITD: ETCO2, 35 ± 6 vs. 29 ± 7 (p=0.015); SBP, 99 ± 9 vs. 93 ± 15 (p=0.050); DBP, 24 ± 12 vs. 19 ± 15 (p=0.006); coronary perfusion pressure, 29 ± 8 vs. 26 ± 7 (p=0.004) and cerebral perfusion pressure, 24 ± 13 vs. 21 ± 12 (p=0.028).In pigs undergoing L-CPR the addition of the active ITD significantly reduced intrathoracic pressure and increased vital organ perfusion pressures.

Anaesthetic postconditioning (APoC) attenuates myocardial injury following coronary ischaemia/reperfusion. We hypothesised that APoC at the initiation of cardiopulmonary resuscitation (CPR) will improve post resuscitation myocardial function along with improved mitochondrial function in a pig model of prolonged untreated ventricular fibrillation.In 32 pigs isoflurane anaesthesia was discontinued prior to induction of ventricular fibrillation that was left untreated for 15 min. At the initiation of CPR, 15 animals were randomised to controls (CON), and 17 to APoC with 2 vol% sevoflurane during the first 3 min CPR. Pigs were defibrillated after 4 min of CPR. After return of spontaneous circulation (ROSC), isoflurane was restarted at 0.8-1.5 vol% in both groups. Systolic and diastolic blood pressures were measured continuously. Of the animals that achieved ROSC, eight CON and eight APoC animals were randomised to have their left ventricular ejection fraction (LVEF%) assessed by echocardiography at 4h. Seven CON and nine APoC were randomised to euthanasia 15 min after ROSC to isolate mitochondria from the left ventricle for bioenergetic studies.ROSC was achieved in 10/15 CON and 15/17 APoC animals. APoC improved haemodynamics during CPR and post-CPR LVEF%. Mitochondrial ATP synthesis, coupling of oxidative phosphorylation and calcium retention capacity were improved in cardiac mitochondria isolated after APoC.In a porcine model of prolonged untreated cardiac arrest, APoC with inhaled sevoflurane at the initiation of CPR, is associated with preserved mitochondrial function and improved post resuscitation myocardial dysfunction. Approved by the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation of Hennepin County Medical Center (protocol number 11-05).

Introduction Sodium nitroprusside (SNP) enhanced CPR (SNPeCPR) demonstrates increased vital organ blood flow and survival in multiple porcine models. We developed a new, coronary occlusion/ischemia model of prolonged resuscitation, mimicking the majority of out-of-hospital cardiac arrests presenting with shockable rhythms. Hypothesis SNPeCPR will increase short term (4-h) survival compared to standard 2015 Advanced Cardiac Life Support (ACLS) guidelines in an ischemic refractory ventricular fibrillation (VF), prolonged CPR model. Methods Sixteen anesthetized pigs had the ostial left anterior descending artery occluded leading to ischemic VF arrest. VF was untreated for 5 min. Basic life support was performed for 10 min. At minute 10 (EMS arrival), animals received either SNPeCPR (n = 8) or standard ACLS (n = 8). Defibrillation (200J) occurred every 3 min. CPR continued for a total of 45 min, then the balloon was deflated simulating revascularization. CPR continued until return of spontaneous circulation (ROSC) or a total of 60 min, if unsuccessful. SNPeCPR animals received 2 mg of SNP at minute 10 followed by 1 mg every 5 min until ROSC. Standard ACLS animals received 0.5 mg epinephrine every 5 min until ROSC. Primary endpoints were ROSC and 4-h survival. Results All SNPeCPR animals (8/8) achieved sustained ROSC versus 2/8 standard ACLS animals within one hour of resuscitation (p = 0.04). The 4-h survival was significantly improved with SNPeCPR compared to standard ACLS, 7/8 versus 1/8 respectively, p = 0.0019. Conclusion SNPeCPR significantly improved ROSC and 4-h survival compared with standard ACLS CPR in a porcine model of prolonged ischemic, refractory VF cardiac arrest.

OBJECTIVES: Ischemic postconditioning (PC) with “stuttering” reintroduction of blood flow after prolonged ischemia has been shown to offer protection from ischemia reperfusion injury to the myocardium and brain. We hypothesized that four 20-s pauses during the first 3 min of standard CPR would improve post resuscitation cardiac and neurological function, in a porcine model of prolonged untreated cardiac arrest. METHODS: 18 female farm pigs, intubated and isoflurane anesthetized had 15 min of untreated ventricular fibrillation followed by standard CPR (SCPR). Nine animals were randomized to receive PC with four, controlled, 20-s pauses, during the first 3 min of CPR (SCPR + PC). Resuscitated animals had echocardiographic evaluation of their ejection fraction after 1 and 4 h and a blinded neurological assessment with a cerebral performance category (CPC) score assigned at 24 and 48 h. All animals received 12 h of post resuscitation mild therapeutic hypothermia. RESULTS: SCPR + PC animals had significant improvement in left ventricular ejection fraction at 1 and 4 h compared to SCPR (59 ± 11% vs 35 ± 7% and 55 ± 8% vs 31 ± 13% respectively, p < 0.01). Neurological function at 24 h significantly improved with SCPR + PC compared to SCPR alone (CPC: 2.7 ± 0.4 vs 3.8 ± 0.4 respectively, p = 0.003). Neurological function significantly improved in the SCPR + PC group at 48 h and the mean CPC score of that group decreased from 2.7 ± 0.4 to 1.7 ± 0.4 (p < 0.00001). CONCLUSIONS: Ischemic postconditioning with four 20-s pauses during the first 3 min of SCPR improved post resuscitation cardiac function and facilitated neurological recovery after 15 min of untreated cardiac arrest in pigs.

Hemorrhagic shock is a common cause of mortality and morbidity in the pediatric population. Intrathoracic pressure regulation (IPR) lowers intrathoracic pressure thereby decreasing intracranial pressure and increasing venous return, cardiac output, and cerebral perfusion without the need for immediate fluid resuscitation. We hypothesized that IPR would improve hemodynamics and 24-hour survival in a pediatric porcine model of hemorrhagic shock. Twenty piglets were subjected to a 50% total blood volume hemorrhage over 15 minutes and then randomized to treatment with either IPR or no treatment. After 60 minutes, survivors were auto-transfused, weaned from the ventilator and assessed and autopsied at 24 hours. Mean arterial pressures (MAP), cardiac index (CI), and arterial blood gases were recorded. MAP (mmHg) was significantly higher in the IPR group (60.8 ± 3.7) vs. controls (41.2 ± 4.6, p

Objective: The purpose of this study is to: 1) describe a newly discovered mechanism of blood flow to the brain during cardiopulmonary resuscitation using the impedance threshold device in a piglet model of cardiac arrest, and 2) describe the survival benefits in humans of applying all of the highly recommended changes in the 2005 guidelines related to increasing circulation during cardiopulmonary resuscitation, including use of the impedance threshold device, from six emergency medical services systems in the United States. Design: Animal studies prospective trial with each piglet serving as its own control. Historical controls were used for the human studies. Subjects: Piglets and patients with out-of-hospital cardiac arrest. Interventions: Piglets (10-12 kg) were treated with an active (n = 9) or sham (n = 9) impedance threshold device after 6 mins of ventricular fibrillation. Humans were treated with cardiopulmonary resuscitation per the American Heart Association 2005 guidelines and the impedance threshold device. Measurements and Main Results: Animals: The primary endpoint in the piglet study was carotid blood flow which increased from 59 mL/min without an impedance threshold device to 91 mL/min (p = 0.017) with impedance threshold device use. Airway pressures during the chest recoil phase decreased from -0.46 mm Hg to -2.59 mm Hg (p = 0.0006) with the active impedance threshold device. Intracranial pressure decreased more rapidly and to a greater degree during the decompression phase of cardiopulmonary resuscitation with the active impedance threshold device. Humans: Conglomerate quality assurance data were analyzed from six emergency medical services systems in the United States serving a population of 3 million people. There were 920 patients treated for cardiac arrest after implementation of the 2005 American Heart Association guidelines, including impedance threshold device use, and 1750 patients in the control group during the year before implementation. Demographics were similar between the two groups. Survival to hospital discharge was 9.3% in the control group versus 13.6% in the intervention group. The odds ratio, 95% confidence interval, and p value were 1.54 (1.19-1.99) and p = 0.0008, respectively. This survival advantage was conferred to patients with a presenting cardiac arrest rhythm of ventricular fibrillation (28.5% vs. 18.0%, p = 0.0008). Conclusions: Use of the impedance threshold device in piglets increased carotid blood flow and coronary and cerebral perfusion pressures and reduced intracranial pressure during the decompression phase of cardiopulmonary resuscitation at a faster rate than controls, resulting in a longer duration of time when intracranial pressures are at their nadir. Patients in six emergency medical services systems treated with the impedance threshold device together with the renewed emphasis on more compressions, fewer ventilations, and complete chest wall recoil had a nearly 50% increase in survival rates after out-of-hospital cardiac arrest compared with historical controls.

Ischemic postconditioning (IPC) during cardiopulmonary resuscitation (CPR) increases neurologically intact survival in a porcine cardiac arrest model. We investigated the effect of IPC on mitochondrial respiration, an important therapeutic target for resuscitation, during CPR in this model. Blood pressure and ECG were continuously recorded. After 15 min of ventricular fibrillation, animals received standard CPR +/- IPC. IPC consisted of 3 cycles of 20 sec compression / 20 sec pause for the first 2 min of CPR. Cardiac mitochondria were isolated after 4 min. Closed-cell respiration was measured for complex I (pyruvate+malate) and II (succinate+rotenone). In IPC-treated animals vs. standard CPR, complex I and II respiratory control indices (RCI), calculated as the ratio of state 3:4 respiration, were higher (6.7±0.8 and 3.1±0.6 vs. 4.3±0.7 and 2.4±0.2, respectively) and complex I and II state 4 respiration (µmol O2*hr-1*mg-1) were lower (1.7±0.2 and 2.7±0.3 vs. 2.3±0.5 and 3.3±0.5, respectively). Blood press...

Objective Ischemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15min of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. Methods Following 17min of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) ( n =8) or Bundle therapy with stutter ACD CPR+ITD+sevoflurane+P188 ( n =12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. Results Bundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48h), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48h). Conclusions Bundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17min of untreated cardiac arrest in pigs. All studies were performed with approval from the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation (protocol #12-11).

Objectives: The aim of this study was to assess the effect of sodium nitroprusside–enhanced cardiopulmonary resuscitation on heat exchange during surface cooling. We hypothesized that sodium nitroprusside–enhanced cardiopulmonary resuscitation would decrease the time required to reach brain temperature less than 35°C compared to active compression-decompression plus impedance threshold device cardiopulmonary resuscitation alone, in the setting of intra–cardiopulmonary resuscitation cooling. We further hypothesized that the addition of epinephrine during sodium nitroprusside–enhanced cardiopulmonary resuscitation would mitigate heat exchange. Design: Prospective randomized animal investigation. Setting: Preclinical animal laboratory. Subjects: Female farm pigs (n = 28). Interventions: After 10 minutes of untreated ventricular fibrillation, animals were randomized to three different protocols: sodium nitroprusside–enhanced cardiopulmonary resuscitation (n = 8), sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine (n = 10), and active compression-decompression plus impedance threshold device alone (control, n = 10). All animals received surface cooling at the initiation of cardiopulmonary resuscitation. Sodium nitroprusside–enhanced cardiopulmonary resuscitation included active compression-decompression plus impedance threshold device plus abdominal binding and 2 mg of sodium nitroprusside at 1, 4, and 8 minutes of cardiopulmonary resuscitation. No epinephrine was used during cardiopulmonary resuscitation in the sodium nitroprusside–enhanced cardiopulmonary resuscitation group. Control and sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine groups received 0.5 mg of epinephrine at 4.5 and 9 minutes of cardiopulmonary resuscitation. Defibrillation occurred after 10 minutes of cardiopulmonary resuscitation. After return of spontaneous circulation, an Arctic Sun (Medivance, Louiseville, CO) was applied at maximum cooling on all animals. The primary endpoint was the time required to reach brain temperature less than 35°C beginning from the time of cardiopulmonary resuscitation initiation. Data are presented as mean ± SEM. Measurements and Main Results: The time required to reach a brain temperature of 35°C was decreased with sodium nitroprusside–enhanced cardiopulmonary resuscitation versus control or sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine (24 ± 6 min, 63 ± 8 min, and 50 ± 9 min, respectively; p = 0.005). Carotid blood flow was higher during cardiopulmonary resuscitation in the sodium nitroprusside–enhanced cardiopulmonary resuscitation group (83 ± 15 mL/min vs 26 ± 7 mL/min and 35 ± 5 mL/min in the control and sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine groups, respectively; p = 0.001). Conclusions: This study demonstrates that sodium nitroprusside–enhanced cardiopulmonary resuscitation facilitates intra–cardiopulmonary resuscitation hypothermia. The addition of epinephrine to sodium nitroprusside–enhanced cardiopulmonary resuscitation during cardiopulmonary resuscitation reduced its improvement in heat exchange.

Introduction: Use of epinephrine and standard (S) CPR has not been shown to improve neurologically-sound survival after cardiac arrest. Treatment with the potent vasodilator sodium nitroprusside (SNP) improves neurologically intact survival rates in animals when combined with abdominal compression, active compression decompression (ACD) CPR, and an impedance threshold device (ITD). We recently observed that SNP combined with ACD-CPR and a new intrathoracic pressure regulator (IPR), which provides continuous negative intrathoracic pressure after each positive pressure ventilation, increases blood flow to the heart and brain in the absence of epinephrine or abdominal compression. We hypothesized that this combination of SNP plus ACD CPR plus IPR (S-A-I) would improve 24h survival with favorable neurologic function compared with S-CPR. Method: After 12 minutes of untreated ventricular fibrillation (VF), 14 pigs received 3 minutes of S-CPR and were then randomized to a) a bolus of epinephrine (0.05mcg/kg), 2 more minutes of S-CPR and up to 3 defibrillation shocks or b) S-A-I and up to 3 shocks 2 minutes later. All resuscitated animals received therapeutic hypothermia for 4 hours. The primary endpoint was favorable neurologic outcome 24h after resuscitation defined by a Cerebral Performance Category score ≤ 2 (CPC with 1 for no deficit and 5 as dead or unable to resuscitate) as determined by a blinded veterinarian. Hemodynamic parameters and left ventricular ejection fraction were recorded. Data are presented as mean±SEM. Results: At 24 hours, 0/7 pigs in the S-CPR group vs. 5/7 pigs in S-A-I had favorable outcome (p=0.02). One pig survived 24 hours in the S-CPR group with a CPC of 4 vs. 5 in the S-A-I group with a CPC of 1.4±0.2. Carotid blood flow and ETCO2 were higher with S-A-I_vs. S-CPR and epinephrine (127±32 vs. 22±4 ml/min, p=0.005, and 46±5 vs. 22±3 mmHg, respectively, p=0.001). Conclusion: After prolonged VF in pigs, treatment with the combination of ACD CPR, an intrathoracic pressure regulator and SNP, in the absence of epinephrine, significantly increased carotid flow, ETCO2 levels, and neurologically-favorable 24 hour survival rates compared with S-CPR and epinephrine. This novel and promising approach should be considered for a Phase 1 human trial.

Introduction: Intra-arrest cooling has been shown to improve survival and neurologic outcome in animal models. The aim of this study was to assess the effect of Sodium Nitroprusside enhanced Cardiopulmonary Resuscitation (SNPeCPR) on heat exchange during surface cooling. We hypothesized that SNPeCPR would decrease the time to reach brain temperature to Methods: After 10 minutes of untreated ventricular fibrillation, 26 animals were randomized to 3 different protocols: SNPeCPR (n=6), SNPeCPR plus epinephrine (SNP+EPI, n=10) and ACD+ITD alone (Control, n=10). All animals received surface cooling with ice bags at the initiation of CPR. SNPeCPR included ACD+ITD plus abdominal binding, 2mg of SNP every 4min, and no epinephrine during CPR. Control and SNP+EPI groups included 0.5mg of epinephrine every 4min during CPR. Defibrillation occurred after 10 minutes of CPR. After ROSC, an Arctic Sun® at maximum cooling was used on all animals. The primary endpoint was the time to reach brain temperature Results: Time to reach brain temperature of 35°C was decreased with SNPeCPR vs. Control or SNP+EPI (18 ± 6 min, 53 ± 8 min and 40 ± 9 min, respectively, p=0.03). All animals survived 2h in the SNPeCPR group and 9/10 in the two other groups. Carotid blood flow was higher during CPR in the SNPeCPR group (96 ± 16 ml/min versus 26 ± 7 and 35 ± 5 in the Control and SNP+EPI group, respectively p=0.04). There were no other differences in hemodynamic parameters. Conclusion: This study demonstrates that SNPeCPR facilitates intra-CPR hypothermia, with the brain reaching target temperature (35°C) in less than half of the time of controls without impairing hemodynamics. The addition of epinephrine to SNPeCPR during CPR attenuated its effect on heat exchange.

Cerebral perfusion is compromised during cardiopulmonary resuscitation (CPR). We hypothesized that beneficial effects of gravity on the venous circulation during CPR performed in the head-up tilt (HUT) position would improve cerebral perfusion compared with supine or head-down tilt (HDT).Twenty-two pigs were sedated, intubated, anesthetized, paralyzed and placed on a tilt table. After 6min of untreated ventricular fibrillation (VF) CPR was performed on 14 pigs for 3min with an automated CPR device called LUCAS (L) plus an impedance threshold device (ITD), followed by 5min of L-CPR+ITD at 0° supine, 5min at 30° HUT, and then 5min at 30° HDT. Microspheres were used to measure organ blood flow in 8 pigs. L-CPR+ITD was performed on 8 additional pigs at 0°, 20°, 30°, 40°, and 50° HUT.Coronary perfusion pressure was 19±2mmHg at 0° vs. 30±3 at 30° HUT (p0.001) and 10±3 at 30° HDT (p0.001). Cerebral perfusion pressure was 19±3 at 0° vs. 35±3 at 30° HUT (p0.001) and 4±4 at 30° HDT (p0.001). Brain-blood flow was 0.19±0.04mlmin(-1)g(-1) at 0° vs. 0.27±0.04 at 30° HUT (p=0.01) and 0.14±0.06 at 30° HDT (p=0.16). Heart blood flow was not significantly different between interventions. With 0, 10, 20, 30, 40 and 50° HUT, ICP values were 21±2, 16±2, 10±2, 5±2, 0±2, -5±2 respectively, (p0.001), CerPP increased linearly (p=0.001), and CPP remained constant.During CPR, HDT decreased brain flow whereas HUT significantly lowered ICP and improved cerebral perfusion. Further studies are warranted to explore this new resuscitation concept.

Despite decades of advances in prehospital and in-hospital medical care, patients with out-of-hospital cardiac arrest continue to have poor neurologic and cardiac function following otherwise successful resuscitation. This review examines the mechanisms and therapeutic strategies currently under development to activate the post-conditioning pathways and thereby improve survival and function.Post-conditioning utilizes the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways as common avenues to promote cell survival and function. Ischemic post-conditioning and multiple medications activate these pathways resulting in improved cardiac and neurological function in animal models of cardiac arrest.Detailed knowledge of the RISK and SAFE pathways can be used for further drug development. Human studies are now underway to test some of these strategies, but further clinical trials are necessary to translate these therapies to clinical practice.

One approach to improve outcomes after trauma and hemorrhage is to follow the principles of permissive hypotension by avoiding intravascular overpressure and thereby preventing dislodgement of platelet plugs early in the clotting process. We hypothesized that augmentation of negative intrathoracic pressure (nITP) by treatment with an impedance threshold device would improve hemodynamics without compromising permissive hypotension or causing hemodilution, whereas aggressive fluid resuscitation with normal saline (NS) would result in hemodilution and SBPs that are too high for permissive hypotension and capable of clot dislodgement.Thirty-four spontaneously breathing anesthetized female pigs (30.6 ± 0.5 kg) were subjected to a fixed 55% hemorrhage over 30 minutes; block randomized to nITP, no treatment, or intravenous bolus of 1-L NS; and evaluated over 30 minutes. Results are reported as mean ± SEM.Average systolic blood pressures (SBPs) (mm Hg) 30 minutes after the study interventions were as follows: nITP, 82.1 ± 2.9; no treatment, 69.4 ± 4.0; NS 89.3 ± 5.2. Maximum SBPs during the initial 15 minutes of treatment were as follows: nITP, 88.0 ± 4.3; no treatment, 70.8 ± 4.3; and NS, 131 ± 7.6. After 30 minutes, mean pulse pressure (mm Hg) was significantly higher in the nITP group (nITP, 32.3 ± 2.2) versus the no-treatment group (21.5 ± 1.5 controls) (p0.05), and the mean hematocrit was 25.2 ± 0.8 in the nITP group versus 19 ± 0.6 in the NS group (p0.001).In this porcine model of hemorrhagic shock, nITP therapy significantly improved SBP and pulse pressure for 30 minutes without overcompensation compared with controls with no treatment. By contrast, aggressive fluid resuscitation with NS but not nITP resulted in a significant rise in SBP to more than 100 mm Hg within minutes of initiating therapy that could cause a further reduction in hematocrit and clot dislodgment.

We investigated the effects of ischemic postconditioning (IPC) with and without cardioprotective vasodilatory therapy (CVT) at the initiation of cardiopulmonary resuscitation (CPR) on cardio-cerebral function and 48-h survival.Prospective randomized animal study. Following 15 min of ventricular fibrillation, 42 Yorkshire farm pigs weighing an average of 34 ± 2 kg were randomized to receive standard CPR (SCPR, n=12), SCPR+IPC (n=10), SCPR+IPC+CVT (n=10), or SCPR+CVT (n=10). IPC was delivered during the first 3 min of CPR with 4 cycles of 20s of chest compressions followed by 20-s pauses. CVT consisted of intravenous sodium nitroprusside (2mg) and adenosine (24 mg) during the first minute of CPR. Epinephrine was given in all groups per standard protocol. A transthoracic echocardiogram was obtained on all survivors 1 and 4h post-ROSC. The brains were extracted after euthanasia at least 24h later to assess ischemic injury in 7 regions. Ischemic injury was graded on a 0-4 scale with (0=no injury to 4 ≥ 50% neural injury). The sum of the regional scores was reported as cerebral histological score (CHS). 48 h survival was reported.Post-resuscitation left ventricular ejection (LVEF) fraction improved in SCPR+CVT, SCPR+IPC+CVT and SCPR+IPC groups compared to SCPR (59% ± 9%, 52% ± 14%, 52% ± 14% vs. 35% ± 11%, respectively, p0.05). Only SCPR+IPC and SCPR+IPC+CVT, but not SCPR+CVT, had lower mean CHS compared to SCPR (5.8 ± 2.6, 2.8 ± 1.8 vs. 10 ± 2.1, respectively, p0.01). The 48-h survival among SCPR+IPC, SCPR+CVT, SCPR+IPC+CVT and SCPR was 6/10, 3/10, 5/10 and 1/12, respectively (Cox regression p0.01).IPC and CVT during standard CPR improved post-resuscitation LVEF but only IPC was independently neuroprotective and improved 48-h survival after 15 min of untreated cardiac arrest in pigs.

Supraglottic airway devices (SGDs) are often used as an alternative to endotracheal tube (ETT) during cardiopulmonary resuscitation (CPR). SGDs can be inserted 'blindly' and rapidly, without stopping compressions. These devices utilize pressurized balloons to direct air to the trachea and prevent esophagus insufflation. We hypothesize that the use of a SGD will compress the carotid artery and decrease carotid blood flow (CBF) during CPR in pigs.Ventricular fibrillation (VF) was induced in 9 female pigs (32 ± 1 kg) followed by 4 min without compressions. CPR was then performed continuously for 3-6-min intervals. During each interval, an ETT was used for the first 3 min, followed by 3 min of each SGD (King LTS-D™, LMA Flexible™, Combitube™) in a random order. The primary endpoint was mean CBF (ml/min). Statistical comparisons among the 4 airway devices were performed by Wilcoxon Rank test. Post mortem carotid arteriographies were performed with SGDs in place.CBF (median ml/min; 25/75 percentile) was significantly lower with each SGD [King (10; 6/41), LMA (10; 4/39), and Combitube (5; -0.4/15)] versus ETT (21; 14/46) (p0.05 for each SGD compared with ETT). Arteriograms showed that with each SGD there was compression of the internal and external carotid vessels.The use of 3 different SGDs during CPR significantly decreased CBF in a porcine model of cardiac arrest. While the current study is limited to pigs, the findings suggest that further research on the effects of SGD use in humans and the effects on carotid artery blood flow is warranted.

The vast majority of patients who suffer an out-of-hospital cardiac arrest die despite receiving cardiopulmonary resuscitation (CPR) for 20 –30 mins by emergency medical personnel at the scene (1–4). Such patients, when treated with the standard of care as recommended by the American Heart Association guidelines, typically receive epinephrine every 3–5 mins (5). While the standard of care for decades, this practice has recently been challenged by animal and clinical trials showing that use of epinephrine may actually have more detrimental than beneficial effects (6–9). In stark pharmacologic contrast to epinephrine, sodium nitroprusside (SNP) is a potent vasodilator. SNP is used to treat hypertensive emergencies and heart failure and it primary mode of action is the release of nitric oxide (10, 11). Use of SNP would typically be considered an anathema for the treatment of the profound hypotension associated with cardiac arrest and manual CPR. Contrary to current thinking, large doses of SNP during CPR do not cause a significant decrease in central aortic pressure (12). This can be explained by the way aortic pressure is generated during CPR. With chest compression, the resultant increase in intrathoracic pressure results in an instantaneous increase in the pressure of all of the intrathoracic vascular structures (13). Therefore, when arterial vascular resistance is decreased by SNP, forward blood flow can be significantly increased with each chest compression. The new approach, SNPeCPR or SNP-“enhanced” CPR (pronounced “snappy CPR”), incorporates three components: 1) active compression-decompression CPR with the use of an impedance threshold device (ACD CPR+ITD), which by actively decreasing intrathoracic pressure during the decompression phase decreases right atrial and intracranial pressures and improves vital organ perfusion (14, 15); 2) a potent vasodilator, SNP, which by decreasing vascular resistance promotes forward blood flow; and 3) lower abdominal binding (AB) that limits descending aortic blood flow and redirects the augmented cardiac output to the heart and brain, where it is needed the most. For simplicity, the combination of ACD CPR+ITD+AB without SNP will be called from here thereafter as eCPR. SNPeCPR consists of easily deployable components that can be readily applied during CPR. ACD CPR+ITD is currently clinically practiced. AB can be performed easily either manually or with a belt/ pneumatic bladder/compression clamp. SNP can be given intravenously or intraosseously as any other drug that is currently delivered during CPR without further complexity. We hypothesize that SNPeCPR will improve carotid blood flow, resuscitation rates, and 24-hr survival rates compared to standard CPR (S-CPR) plus epinephrine.

Introduction La reanimation cardiopulmonaire (RCP) avec combinaison du Lund University Cardiopulmonary Assist System (RCP-L, LUCAS) et la valve d’impedance inspiratoire (VII, ResQPOD) est utilise en clinique et a montre sa capacite d’ameliorer le taux de survie apres un arret cardiaque extrahospitalier. Malgre cette utilisation clinique, la synergie physiologique de ces technologies n’a pas ete etudiee dans un modele animal. Cette etude a teste l’hypothese que la combinaison RCP-L + VII agit en synergie pour ameliorer le pressions de perfusion cerebrale et coronaire par rapport a la RCP-L seul. Materiel et methodes Une fibrillation ventriculaire, non traite pendant 4 min, a ete induite chez 8 cochons femelles. L’ordre des interventions (RCP-L + VII et RCP-L seul), de 4 min chacune, a ete randomises. Les parametres hemodynamiques presentes dans les resultats ont ete mesures en continu et comparees au cours des 2 dernieres min des interventions. Les analyses statistiques ont ete realisees par un test t apparie ( Fig. 1 ). Resultats Comme le montre la Fig. 1 , les pressions des voies aeriennes (substitut de la pression intrathoracique) etaient significativement plus faibles et la pression aortique diastolique, la pression de perfusion coronaire et l’ETCO2 etaient significativement plus eleves avec la RCP-L + VII. Discussion Ces resultats confirment l’observation clinique que la combinaison RCP-L + VII est synergique chez les cochon en arret cardiaque.

To evaluate the effect of no assisted ventilation cardiopulmonary resuscitation on neurologically intact survival compared with ten positive pressure ventilations/minute cardiopulmonary resuscitation in a pig model of cardiac arrest.Prospective randomized animal study.Animal laboratory.Sixteen female intubated pigs (25.2 +/- 2.1 kg) anesthetized with propofol.: fter 8 mins of untreated ventricular fibrillation, the intubated animals were randomized to 8 mins of continuous chest compressions (100/min) and either no assisted ventilation (n = 9) or 10 positive pressure ventilations/min (Smart Resuscitator Bag with 100% O2 flow at 10 L/min) (n = 7). The primary end point, neurologically intact 24-hr survival, was evaluated using a pig cerebral performance category score by a veterinarian blinded to the cardiopulmonary resuscitation method. MEASUREMENTS, AND MAIN RESULTS: During cardiopulmonary resuscitation, aortic and coronary perfusion pressure were similar between groups but cerebral perfusion pressure was significantly higher in the positive pressure ventilation group (33 +/- 15 vs. 14 +/- 14, p = .04). After 7.5 mins of cardiopulmonary resuscitation, arterial pO2 (mm Hg) and mixed venous O2 saturation (%) were significantly higher in the positive pressure ventilation compared with the no assisted ventilation group (117 +/- 29 and 41 +/- 21 vs. 40 +/- 24 and 10.8 +/- 7; p = .01 for both). Paco2 was significantly lower in the positive pressure ventilation group (48 +/- 10 vs. 77 +/- 26, p = .01). After 24 hrs, four of nine no assisted ventilation pigs were alive with a mean cerebral performance category score of 3 +/- 0 vs. five of seven alive and neurologically intact positive pressure ventilation pigs with a cerebral performance category score of 1 +/- 0.3 (p.001 for cerebral performance category score).No assisted ventilation cardiopulmonary resuscitation results in profound hypoxemia, respiratory acidosis, and significantly worse 24-hr neurologic outcomes compared with positive pressure ventilation cardiopulmonary resuscitation in pigs.

Introduction La recuperation cerebrale etait consideree comme impossible apres 12 min d’ischemie globale jusqu’a recemment. Le Poloxamer 188 (P188) est un tensioactif synthetique connue pour minimiser les lesions de reperfusion. Il a ete montre que le postconditionnement ischemique (PCI) et le sevoflurane (SEV) reduisent les lesions de reperfusion secondaires a un arret cardiaque. Nous emettons l’hypothese qu’une therapie multiple (M-RCP) avec la combinaison de P188, PCI et SEV au debut de la reanimation cardiorespiratoire (RCP) ameliore l’hemodynamique durant la RCP, reduit la dysfonction ventriculaire post-reanimation, ameliore la survie sans sequelle neurologique a 24 h et reduit les dommages des organes vitaux apres un arret cardiaque prolonge dans un modele porcin. Materiel et methodes Apres une fibrillation ventriculaire (FV) de 15 min, une RCP standard a ete realisee chez les animaux temoins (n = 8) et comparee aux animaux du groupe M-RCP (n-13) qui ont subi une VF non traitee 17 min. La M-RCP etait constituee : a) P188 : bolus IV (250 mg/kg) au debut de la RCP suivie d’une perfusion de 250 mg/kg de P188 en 4 h apres le retour a une circulation spontanee (RACS), b) PCI : reanimation cardiopulmonaire avec compression decompression active, valve d’impedance inspiratoire pendant 20 s, puis 20 s de pause pendant 3 cycles et c) SEV : insufflation de SEV 2 % pendant les 3 premieres min. L’adrenaline (0,5 mg) a ete utilisee chez tous les animaux. La survie et le score de categorie de performance cerebrale (CPC) ont ete evalues a 24 h. La Troponine, CK-MB, creatinine et fonction hepatique ont ete evaluees a 4 h. Un test exact de Fischer et un test t non apparie ont ete utilises pour l’analyse statistique. Resultats L’hemodynamique est ameliore durant la M-RCP ( Fig. 1 ) durant la RCP. Tous les animaux atteints ont eu un RACS. La FEVG etait ameliore (63 ± 13 a 1 h, 61 ± 8 a 4 h) vs temoins (38 ± 12 a 1 h, 36 ± 18 a 4 h) (p Fig. 1 ). Discussion Une therapie multiple qui cible les lesions de reperfusion au niveau des membranes mitochondriale et cellulaire ameliore les parametres hemodynamiques au cours de RCP et facilite la reanimation cerebrale, cardiaque et des organes vitaux apres un arret cardiaque non traitee prolongee.

transfer in swine Patrick Shanley1, MS; Erik Kulstad2, MD, MS; Melissa Naiman3, PhD; D. Mark Courtney1, MD, MS; Anja Metzger4,6, PhD; Tim Matsuura4, PhD; Scott McKnite5, BS, Jennifer Rees6, PhD; Keith Lurie4,6, MD 1. Northwestern University; 2. Advocate Christ Medical Center; 3. U. of Illinois at Chicago; 4. U. of Minnesota; 5. Minneapolis Medical Research Foundation; 6. Advanced Circulatory Systems, Inc.

Measurement of temperature during treatment with therapeutic hypothermia can yield variable values depending on where temperature is measured. Measurements of temperature can be made rectally, intravascularly, vaginally, or from the bladder, but agreement between these sites is often uncertain. We measured temperature at multiple sites during experimental induction and reversal of hypothermia in swine with a novel esophageal cooling device, hypothesizing that agreement between sites would fall within standard acceptance criteria (average difference ± 1.96 standard deviation of the difference) in Bland-Altman analyses.

Aim of the study To evaluate a novel esophageal heat transfer device for use in inducing, maintaining, and reversing hypothermia. We hypothesized that this device could successfully induce, maintain (within a 1°C range of goal temperature), and reverse, mild therapeutic hypothermia in a large animal model over a 30-h treatment protocol. Methods Five female Yorkshire swine, weighing a mean of 65kg (range 61–70)kg each, were anesthetized with inhalational isoflurane via endotracheal intubation and instrumented. The esophageal device was connected to an external chiller and then placed into the esophagus and connected to wall suction. Reduction to goal temperature was achieved by setting the chiller to cooling mode, and a 24h cooling protocol was completed before rewarming and recovering the animals. Histopathologic analysis was scheduled for 3–14 days after protocol completion. Results Average baseline temperature for the 5 animals was 38.6°C (range 38.1–39.2°C). All swine were cooled successfully, with average rate of temperature decrease of 1.3°C/h (range 1.1–1.9)°C/h. Standard deviation from goal temperature averaged 0.2°C throughout the steady-state maintenance phase, and no treatment for shivering was necessary during the protocol. Histopathology of esophageal tissue showed no adverse effects from the device. Conclusion A new esophageal heat transfer device successfully and safely induced, maintained, and reversed therapeutic hypothermia in large swine. Goal temperature was maintained within a narrow range, and thermogenic shivering did not occur. These findings suggest a useful new modality to induce therapeutic hypothermia.

SummaryPoloxamer 188 (P188) is a nonionic triblock copolymer believed to prevent cellular injury after ischemia and reperfusion. This study compared intracoronary (IC) infusion of P188 immediately after reperfusion with delayed infusion through a peripheral intravenous catheter in a porcine model of ST-segment elevation myocardial infarction (STEMI). STEMI was induced in 55 pigs using 45 min of endovascular coronary artery occlusion. Pigs were then randomized to 4 groups: control, immediate IC P188, delayed peripheral P188, and polyethylene glycol infusion. Heart tissue was collected after 4 h of reperfusion. Assessment of mitochondrial function or infarct size was performed. Mitochondrial yield improved significantly with IC P188 treatment compared with control animals (0.25% vs. 0.13%), suggesting improved mitochondrial morphology and survival. Mitochondrial respiration and calcium retention were also significantly improved with immediate IC P188 compared with control animals (complex I respiratory control index: 7.4 vs. 3.7; calcium retention: 1,152 nmol vs. 386 nmol). This benefit was only observed with activation of complex I of the mitochondrial respiratory chain, suggesting a specific effect from ischemia and reperfusion on this complex. Infarct size and serum troponin I were significantly reduced by immediate IC P188 infusion (infarct size: 13.9% vs. 41.1%; troponin I: 19.2 μg/l vs. 77.4 μg/l). Delayed P188 and polyethylene glycol infusion did not provide a significant benefit. These results demonstrate that intracoronary infusion of P188 immediately upon reperfusion significantly reduces cellular and mitochondrial injury after ischemia and reperfusion in this clinically relevant porcine model of STEMI. The timing and route of delivery were critical to achieve the benefit.