Therapeutic hypothermia and myocardial infarction

Expérimentalement, l’hypothermie thérapeutique (32-34°C) constitue l’une des stratégies les plus puissantes pour prévenir le développement d’infarctus du myocarde. Néanmoins, ce bénéfice n’est observé que lorsque l’hypothermie est induite pendant l’ischémie et son induction au moment de la reperfusion n’entraîne pas de protection vis-à-vis de la mort cellulaire. L’application d’une hypothermie à la reperfusion est cependant associée à d’autres bénéfices comme l’inhibition de l’installation du no-reflow, de l’inflammation locale et du remodelage. Le mécanisme sous-jacent à cette protection par l’hypothermie est encore inconnu mais la mitochondrie, notamment au travers de la production des espèces réactives de l’oxygène, pourrait jouer un rôle central. Jusqu’à présent le transfert clinique de cette stratégie n’a pas permis de démontrer de bénéfices chez l’Homme, en raison de la difficulté à refroidir suffisamment rapidement les patients pour obtenir un état d’hypothermie avant la reperfusion. Le développement de nouvelles stratégies de refroidissement ultra-rapide comme la ventilation liquide totale pourrait alors constituer une solution prometteuse.Therapeutic hypothermia (32-34°C) is one of the most potent experimental cardioprotective strategies in animal models of myocardial infarction. Yet, it is only able to reduce infarct size when induced during ischemia, i.e. before the reperfusion. Its induction after the onset of reperfusion is not associated with any inhibition of myocardial necrosis but rather attenuation of functional benefits including no-reflow inhibition, mitigation of inflammation and ventricular remodeling. The mechanism underlying cardioprotection by hypothermia is unknown but is probably associated with mitochondrial preservation and reactive oxygen species inhibition. Until now, clinical trials investigating therapeutic hypothermia failed to demonstrated cardioprotective benefit. This is probably due to the delay of institution and the cooling rate achievable in human patients, making it impossible to reach 32°C before reperfusion. Development of new cooling methods including total liquid ventilation could represent a promising perspective in this context

Head and thorax elevation prevents the rise of intracranial pressure during extracorporeal resuscitation in swine

Aim: Head and thorax elevation during cardiopulmonary resuscitation improves cerebral hemodynamics and ultimate neurological outcome after cardiac arrest. Its effect during extracorporeal cardiopulmonary resuscitation (E-CPR) is unknown. We tested whether this procedure could improve hemodynamics in swine treated by E-CPR. Methods and Results: Pigs were anesthetized and submitted to 15 minutes of untreated ventricular fibrillation followed by E-CPR. Animals randomly remained in flat position (flat group) or underwent head and thorax elevation since E-CPR institution (head-up group). Electric shocks were delivered after 30 minutes until the return of spontaneous circulation (ROSC). They were followed during 120 minutes after ROSC. After 30 minutes of E-CPR, ROSC was achieved in all animals, with no difference regarding blood pressure, heart rate, and extracorporeal membrane of oxygenation flow among groups. The head-up group had an attenuated increase in ICP as compared with the flat group after cardiac arrest (13 ± 1 vs. 26 ± 2 mm Hg at the end of the follow-up, respectively). Cerebral perfusion pressure tended to be higher in the head-up versus flat group despite not achieving statistical difference (66 ± 1 vs 46 ± 1 mm Hg at the end of the follow-up). Carotid blood flow and cerebral oxygen saturation were not significantly different among groups. Conclusion: During E-CPR, head and thorax elevation prevents ICP increase. Whether it could improve the ultimate neurological outcome in this situation deserves further investigation.The study was supported by grants LIVE-RESP and AREG-SHOCK from Agence Nationale pour la Recherche. Y. Levy was supported by ADEREMVeterinari

Evaluation of lung recovery after static administration of three different perfluorocarbons in pigs.

International audienceBackground: The respiratory properties of perfluorocarbons (PFC) have been widely studied for liquid ventilation inhumans and animals. Several PFC were tested but their tolerance may depend on the species. Here, the effects of asingle administration of liquid PFC into pig lungs were assessed and compared. Three different PFC having distinctevaporative and spreading coefficient properties were evaluated (Perfluorooctyl bromide [PFOB], perfluorodecalin[PFD] and perfluoro-N-octane [PFOC]).Methods: Pigs were anesthetized and submitted to mechanical ventilation. They randomly received an intra-trachealadministration of 15 ml/kg of either PFOB, PFD or PFOC with 12 h of mechanical ventilation before awakening andweaning from ventilation. A Control group was submitted to mechanical ventilation with no PFC administration. Allanimals were followed during 4 days after the initial PFC administration to investigate gas exchanges and clinicalrecovery. They were ultimately euthanized for histological analyses and assessment of PFC residual concentrationswithin the lungs using dual nuclei fluorine and hydrogen Magnetic Resonance Imaging (MRI). Sixteen animals wereincluded (4/group).Results: In the PFD group, animals tended to be hypoxemic after awakening. In PFOB and PFOC groups, blood gaseswere not significantly different from the Control group after awakening. The poor tolerance of PFD was likely related toa large amount of residual PFC, as observed using MRI in all lung samples (≈10% of lung volume). This percentage waslower in the PFOB group (≈1%) but remained significantly greater than in the Control group. In the PFOC group, thepercentage of residual PFC was not significantly different from that of the Control group (≈0.1%). Histologically, themost striking feature was an alveolar infiltration with foam macrophages, especially in the groups treated by PFD orPFOB.Conclusions: Of the three tested perfluorocarbons, PFOC offered the best tolerance in terms of lung function, gasexchanges and residuum in the lung. PFOC was rapidly cleared from the lungs and virtually disappeared after 4 dayswhereas PFOB persisted at significant levels and led to foam macrophage infiltration. PFOC could be relevant for shortterm total liquid ventilation with a rapid weaning

Metabolomic Profiling in Acute ST-Segment-Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia-Reperfusion Injury.

BACKGROUND: Ischemia-reperfusion injury following ST-segment-elevation myocardial infarction (STEMI) is a leading determinant of clinical outcome. In experimental models of myocardial ischemia, succinate accumulation leading to mitochondrial dysfunction is a major cause of ischemia-reperfusion injury; however, the potential importance and specificity of myocardial succinate accumulation in human STEMI is unknown. We sought to identify the metabolites released from the heart in patients undergoing primary percutaneous coronary intervention for emergency treatment of STEMI. METHODS AND RESULTS: Blood samples were obtained from the coronary artery, coronary sinus, and peripheral vein in patients undergoing primary percutaneous coronary intervention for acute STEMI and in control patients undergoing nonemergency coronary angiography or percutaneous coronary intervention for stable angina or non-STEMI. Plasma metabolites were analyzed by targeted liquid chromatography and mass spectrometry. Metabolite levels for coronary artery, coronary sinus, and peripheral vein were compared to derive cardiac and systemic release ratios. In STEMI patients, cardiac magnetic resonance imaging was performed 2 days and 6 months after primary percutaneous coronary intervention to quantify acute myocardial edema and final infarct size, respectively. In total, 115 patients undergoing acute STEMI and 26 control patients were included. Succinate was the only metabolite significantly increased in coronary sinus blood compared with venous blood in STEMI patients, indicating cardiac release of succinate. STEMI patients had higher succinate concentrations in arterial, coronary sinus, and peripheral venous blood than patients with non-STEMI or stable angina. Furthermore, cardiac succinate release in STEMI correlated with the extent of acute myocardial injury, quantified by cardiac magnetic resonance imaging. CONCLUSION: Succinate release by the myocardium correlates with the extent of ischemia

Experimental study of hypothermic total liquid ventilation after shockable and non-shockable cardiac arrest

Chaque année, environ 40000 patients subissent un arrêt cardiaque extra-hospitalier en France. Malgré l’amélioration de la prise en charge initiale, ces patients développent fréquemment une dysfonction neurologique, cardiaque et multi-viscérale, à l’origine d’une survie extrêmement faible. L’une des stratégies susceptible d’améliorer la survie chez les patients est l’induction d’une hypothermie thérapeutique modérée à 32-34°C. Cela présente néanmoins un bénéfice très limité chez l’Homme par rapport à celui décrit dans les études expérimentales. L’une des explications pourrait être la vitesse d’induction de l’hypothermie chez l’Homme par rapport à celle réalisée chez l’animal de laboratoire. Dans ce contexte, le laboratoire d’accueil étudie une approche capable de maximiser la vitesse de refroidissement par ventilation liquide totale (VLT). Cette stratégie consiste à ventiler les poumons avec des perfluorocarbones liquides et à utiliser cet organe comme bio-échangeur thermique, tout en assurant des échanges gazeux normaux.L’objectif de mon travail a été de d’étudier expérimentalement les conséquences de l’induction d’une hypothermie ultra-rapide dans différentes situation d’arrêt cardiaque chez le lapin. Cela permettrait à terme de déterminer la situation la plus pertinente pour le transfert clinique de la VLT.Nous avons tout d’abord étudié l’effet d’une hypothermie induite par de grande quantités de fluides froids pendant la réanimation cardio-pulmonaire après un arrêt cardiaque choquable. Cela n’a pas permis d’induire de bénéfice sur les chances de réanimation en l’absence d’administration d’adrénaline. Dans un second temps, nous avons démontré que la VLT était associée à une puissante neuroprotection et cardioprotection à la fois après un arrêt cardiaque choquable avec infarctus du myocarde sous-jacent, ou après un d’arrêt cardiaque non choquable d’origine respiratoire. Ce bénéfice s’exerçait très précocement au décours de l’arrêt cardiaque, par une inhibition de la perméabilité de la barrière hémato-encéphalique, de la production d’espèces réactives de l’oxygène, de l’hyperhémie cérébrale et de la réponse inflammatoire.Ces résultats démontrent l’existence d’une fenêtre thérapeutique très précoce, au cours de laquelle la VLT hypothermisante peut procurer une puissante protection neurologique et cardiaque à la suite d’un arrêt cardiaque. Dans la perspective d’un transfert clinique de la VLT, la situation de l’arrêt cardiaque non choquable serait particulièrement pertinente, en raison du pronostic très sombre qui lui est associé.Cardiac arrest is a major public health issue, concerning 40000 patients every year in France. Among the successfully resuscitated patients, most of them develop severe neurological, cardiac and multivisceral dysfunctions, leading to an aggravation of the prognosis. One of the strategies that could improve this prognosis is mild therapeutic hypothermia at 32-34 degres°C during 24 hours. However, recent clinical studies demonstrated limited benefits in patients, as compared to experimental studies. One of the explanations could be the relatively prolonged delay for hypothermia achievement in humans as compared to laboratory animals. In order to induce similar cooling rate in humans than animals, the laboratory is investigating a strategy for ultra-fast cooling through total liquid ventilation (TLV). This strategy consists in lungs ventilation with cold perfluorocarbons, which could use the lungs as a heat-exchanger while maintaining normal gas exchanges.The general goal of the present study was to experimentally investigate the consequences of ultra-fast cooling in different situations of cardiac arrest in rabbits. This could lead to determine the most relevant clinical setting for a further clinical translation of TLV in patients.Accordingly, we initially studied the effect of conventional hypothermia through fluid administration during cardiac massage in a rabbit model of shockable cardiac arrest. Such conventional hypothermia did not provide any benefit. Then, we investigated the effect of cooling induced by TLV in rabbits submitted to cardiac arrest from different causes. After ischemic cardiac arrest from shockable rhythm, TLV was associated with potent neuro- and cardioprotective effects, along with strong survival improvement and multivisceral dysfunction limitations. After cardiac arrest from respiratory and non-shockable cause, TLV provided potent neurological benefit. This was exerted very early after resuscitation through the reduction of the blood-brain barrier permeability, reactive oxygen species production, acute cerebral hyperhaemia or inflammatory response.In conclusion, TLV-induced cooling provides potent neurological and systemic benefits after experimental cardiac arrest from different causes in rabbits. These works describe the existence of a therapeutic window for hypothermia, very early after cardiac arrest. This strengthens the relevance of TLV for cooling induction. For a further clinical translation, non-shockable cardiac arrest could be a relevant clinical situation, considering the very poor prognosis

Le trilostane

Le trilostane (Vetoryl®) est un inhibiteur de la synthèse du cortisol indiqué dans le traitement de l’hypercorticisme d’origine hypophysaire ou surrénalienne chez le chien. Son mode d’action repose sur l’inhibition de la synthèse du cortisol et, dans une moindre mesure, de la synthèse de l’aldostérone. Compte tenu de la grande variabilité de réponse et de pharmacocinétique de cette molécule, la surveillance des animaux traités au trilostane doit être fréquente et la dose doit être régulièrement ajustée. Le suivi thérapeutique repose essentiellement sur la clinique et la réalisation régulière de tests de stimulation à l’ACTH. Lors d’une absence de réponse à ce test, le traitement doit être arrêté. En revanche, lorsque les résultats de ce test sont dans les normes ou montrent une cortisolémie trop élevée, l’augmentation de la posologie doit reposer sur l’évaluation clinique de l’animal et la persistance de signes cliniques compatibles avec un hypercorticisme. Même si le trilostane est généralement bien toléré, un hypocorticisme réversible peut parfois apparaître au cours du suivi. Des troubles du ionogramme (hyperkaliémie et hyponatrémie) liés à la baisse de la concentration d’aldostérone circulante sont parfois observés.Le trilostane (Vetoryl®) est un inhibiteur de la synthèse du cortisol commercialisé pour le traitement de l’hypercorticisme chez le chien. Son utilisation nécessite un suivi thérapeutique régulier au cours du traitement

Resuscitative endovascular balloon occlusion of the aorta vs epinephrine in the treatment of non-traumatic cardiac arrest in swine

International audienceBackground: The administration of epinephrine in the management of non-traumatic cardiac arrest remains recommended despite controversial effects on neurologic outcome. The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) could be an interesting alternative. The aim of this study was to compare the effects of these 2 strategies on return of spontaneous circulation (ROSC) and cerebral hemodynamics during cardiopulmonary resuscitation (CPR) in a swine model of non-traumatic cardiac arrest.Results: Anesthetized pigs were instrumented and submitted to ventricular fibrillation. After 4 min of no-flow and 18 min of basic life support (BLS) using a mechanical CPR device, animals were randomly submitted to either REBOA or epinephrine administration before defibrillation attempts. Six animals were included in each experimental group (Epinephrine or REBOA). Hemodynamic parameters were similar in both groups during BLS, i.e., before randomization. After epinephrine administration or REBOA, mean arterial pressure, coronary and cerebral perfusion pressures similarly increased in both groups. However, carotid blood flow (CBF) and cerebral regional oxygenation saturation were significantly higher with REBOA as compared to epinephrine administration (+ 125% and + 40%, respectively). ROSC was obtained in 5 animals in both groups. After resuscitation, CBF remained lower in the epinephrine group as compared to REBOA, but it did not achieve statistical significance.Conclusions: During CPR, REBOA is as efficient as epinephrine to facilitate ROSC. Unlike epinephrine, REBOA transitorily increases cerebral blood flow and could avoid its cerebral detrimental effects during CPR. These experimental findings suggest that the use of REBOA could be beneficial in the treatment of non-traumatic cardiac arrest

Early Coronary Reperfusion Facilitates Return of Spontaneous Circulation and Improves Cardiovascular Outcomes After Ischemic Cardiac Arrest and Extracorporeal Resuscitation in Pigs

International audienceBACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is widely proposed for the treatment of refractory cardiac arrest. It should be associated with coronary angiography if coronary artery disease is suspected. However, the prioritization of care remains unclear in this situation. Our goal was to determine whether coronary reperfusion should be instituted as soon as possible in such situations in a pig model.METHODS AND RESULTS: Anesthetized pigs were instrumented and submitted to coronary artery occlusion and ventricular fibrillation. After 5 minutes of untreated cardiac arrest, conventional cardiopulmonary resuscitation (CPR) was started. Fifteen minutes later, ECPR was initiated for a total duration of 240 minutes. Animals randomly underwent either early or late coronary reperfusion at 20 or 120 minutes of ECPR, respectively. This timing was adapted to the kinetic of infarct extension in pigs. Return of spontaneous circulation was determined as organized electrocardiogram rhythm with systolic arterial pressure above 80 mm Hg. During conventional CPR, hemodynamic parameters were not different between groups. Carotid blood flow then increased by 70% after the onset of ECPR in both groups. No animal (0 of 7) elicited return of spontaneous circulation after late reperfusion versus 4 of 7 after early reperfusion (P=0.025). The hemodynamic parameters, such as carotid blood flow, were also improved in early versus late reperfusion groups (113±20 vs 43±17 mL/min after 240 minutes of ECPR, respectively; P=0.030), along with infarct size decrease (71±4% vs 84±2% of the risk zone, respectively; P=0.013).CONCLUSIONS: Early reperfusion improved hemodynamic status and facilitated return of spontaneous circulation in a porcine model of ischemic cardiac arrest treated by ECPR

Comparative effect of hypothermia and adrenaline during cardiopulmonary resuscitation in rabbits.: Intra-arrest hypothermia and cold saline infusion

International audienceBACKGROUND: Therapeutic hypothermia was shown to facilitate resumption of spontaneous circulation when instituted during cardiac arrest. Here, we investigated whether it directly improved the chance of successful resuscitation independently of adrenaline administration in rabbits. We further evaluated the direct effect of hypothermia on vascular function in vitro. METHODS: In a first set of experiments, four groups of anesthetized rabbits were submitted to 15 min of cardiac arrest and subsequent cardiopulmonary resuscitation (CPR). The "control" group underwent CPR with only cardiac massage and defibrillation attempts. Two other groups received cold or normothermic saline infusion during CPR (20 mL/kg of NaCl 0.9% at 4°C or 38°C, respectively). In a last group, the animals received adrenaline (15 µg/kg intravenously) during CPR. In a second set of experiments, we evaluated at 32°C vs. 38°C the vascular function of aortic rings withdrawn from healthy rabbits or after cardiac arrest. RESULTS: In the first set of experiments, cardiac massage efficiency was improved by adrenaline but neither by hypothermic nor normothermic saline administration. Resumption of spontaneous circulation was observed in five of eight animals after adrenaline as compared with none of eight in other groups. Defibrillation rates were conversely similar among groups (7/8 or 8/8). In the second set of experiments, in vitro hypothermia (32°C) was not able to prevent the dramatic alteration of vascular function observed after cardiac arrest. It also did not directly modify vasocontractile or the vasodilating functions in healthy conditions. CONCLUSION: In rabbits, hypothermia did not exert a direct hemodynamic or vascular effect that might explain its beneficial effect during CPR

Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

International audienceBackground: 5-fluorocytosine is a pyrimidine and a fluorinated cytosine analog mainly used as an antifungal agent. It is a precursor of 5-fluorouracil, which possesses anticancer properties. To reduce systemic toxicity of 5-fluorouracil during chemotherapy, 5-fluorocytosine can be used as a targeted anticancer agent. Expression of cytosine deaminase by a viral vector within a tumor allows targeted chemotherapy by converting 5-fluorocytosine into the cytotoxic chemotherapeutic agent 5-fluorouracil. However, little is known about the tolerance of 5-fluorocytosine in dogs after prolonged administration. Results: In three healthy Beagle dogs receiving 100 mg/kg of 5-fluorocytosine twice daily for 14 days by oral route, noncompartmental pharmacokinetics revealed a terminal elimination half-life of 164.5 ± 22.5 min at day 1 and of 179.2 ± 11.5 min, after 7 days of administration. Clearance was significantly decreased between day 1 and day 7 with 0.386 ± 0.031 and 0.322 ± 0.027 ml/min/kg, respectively. Maximal plasma concentration values were below 100 µg/ml, which is considered within the therapeutic margin for human patients. 5-fluorouracil plasma concentration was below the limit of detection at all time points. The main adverse events consisted of depigmented, ulcerated, exudative, and crusty cutaneous lesions 10 to 13 days after beginning 5-fluorocytosine administration. The lesions were localized to the nasal planum, the lips, the eyelids, and the scrotum. Histological analyses were consistent with a cutaneous lupoid drug reaction. Complete healing was observed 15 to 21 days after cessation of 5-fluorocytosine. No biochemical or hematological adverse events were noticed. Conclusions: Long term administration of 5-fluorocytosine was associated with cutaneous toxicity in healthy dogs. It suggests that pharmacotherapy should be adjusted to reduce the toxicity of 5-fluorocytosine in targeted chemotherapy