RESUMO
OBJECTIVES: Brain mitochondrial dysfunction limits neurologic recovery after cardiac arrest. Brain polyunsaturated cardiolipins, mitochondria-unique and functionally essential phospholipids, have unprecedented diversification. Since brain cardiolipins are not present in plasma normally, we hypothesized their appearance would correlate with brain injury severity early after cardiac arrest and return of spontaneous circulation. DESIGN: Observational case-control study. SETTING: Two medical centers within one city. PARTICIPANTS (SUBJECTS): We enrolled 41 adult cardiac arrest patients in whom blood could be obtained within 6 hours of resuscitation. Two subjects were excluded following outlier analysis. Ten healthy subjects were controls. Sprague-Dawley rats were used in asphyxial cardiac arrest studies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed a high-resolution liquid chromatography/mass spectrometry method and determined cardiolipins speciation in human brain, heart, and plasma within 6 hours of (return of spontaneous circulation) from 39 patients with cardiac arrest, 5 with myocardial infarction, and 10 healthy controls. Cerebral score was derived from brain-specific cardiolipins identified in plasma of patients with varying neurologic injury and outcome. Using a rat model of cardiac arrest, cardiolipins were quantified in plasma, brain, and heart. Human brain exhibited a highly diverse cardiolipinome compared with heart that allowed the identification of brain-specific cardiolipins. Nine of 26 brain-specific cardiolipins were detected in plasma and correlated with brain injury. The cerebral score correlated with early neurologic injury and predicted discharge neurologic/functional outcome. Cardiolipin (70:5) emerged as a potential point-of-care marker predicting injury severity and outcome. In rat cardiac arrest, a significant reduction in hippocampal cardiolipins corresponded to their release from the brain into systemic circulation. Cerebral score was significantly increased in 10 minutes versus 5 minutes no-flow cardiac arrest and naïve controls. CONCLUSIONS: Brain-specific cardiolipins accumulate in plasma early after return of spontaneous circulation and proportional to neurologic injury representing a promising novel biomarker.
Assuntos
Lesões Encefálicas/metabolismo , Cardiolipinas/sangue , Cardiomiopatias/metabolismo , Mitocôndrias Cardíacas/metabolismo , Animais , Reanimação Cardiopulmonar/métodos , Estudos de Casos e Controles , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Parada Cardíaca/metabolismo , Humanos , Masculino , Oxirredução , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: Limited data exist on the effects of therapeutic hypothermia on renal function and pharmacokinetics in pediatric patients after cardiac arrest. The objective was to describe the differences in vancomycin disposition in pediatric patients following cardiac arrest treated with either therapeutic hypothermia or normothermia using population pharmacokinetic modeling. DESIGN: Single-center, retrospective cohort study. SETTING: A tertiary care hospital pediatric and cardiac ICU. PATIENTS: Fifty-two pediatric patients (30 d to 17 yr old) who experienced a cardiac arrest, received vancomycin, and were treated with therapeutic hypothermia (32-34°C) or normothermia (36.3-37.6°C) between January 1, 2010, and September 30, 2014, were reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data despite high variability due to the small sample size. The typical value of clearance in this study was 4.48 L/hr (0.19 L/hr/kg) for a normothermic patient weighing 70 kg and a glomerular filtration rate of 90 mL/min/1.73 m. Patients treated with normothermia but with reduced or poor renal function (≤ 90 mL/min/1.73 m) had up to an 80% reduction in vancomycin clearance compared to those with normal renal function (90-140 mL/min/1.73 m). Patients with normal renal function but treated with therapeutic hypothermia versus normothermia experienced up to 25% reduction in vancomycin clearance. Patients treated with therapeutic hypothermia and with poor renal function experienced up to an 84% reduction in vancomycin clearance. CONCLUSIONS: Patients receiving hypothermia and/or with decreased renal function had lower vancomycin clearances based on a retrospectively fitted two-compartment model in children who experience cardiac arrest.
Assuntos
Antibacterianos/farmacocinética , Cuidados Críticos/métodos , Parada Cardíaca/terapia , Hipotermia Induzida , Ressuscitação/métodos , Vancomicina/farmacocinética , Adolescente , Antibacterianos/uso terapêutico , Temperatura Corporal , Peso Corporal , Criança , Pré-Escolar , Terapia Combinada , Feminino , Parada Cardíaca/metabolismo , Humanos , Lactente , Rim/fisiologia , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Estudos Retrospectivos , Vancomicina/uso terapêuticoRESUMO
Although therapeutic hypothermia is an effective treatment for post-resuscitation brain injury after cardiac arrest (CA), the underlying mechanism remains unclear. Vacuolar H(+)-ATPase (V-ATPase) plays a key role in cellular adaption to a hypoxic environment. This study sought to evaluate the effect of mild hypothermia on V-ATPase and its involvement in neuroprotection after CA. Male Sprague-Dawley rats were subjected to a 6-min CA, resuscitated successfully, and then assigned to either the normothermia (NT) group or the hypothermia (HT) group. Rats were further divided into 2 subgroups based on the time of euthanasia, either 3 or 24 h after CA (NT-3 h, HT-3 h; NT-24 h, HT-24 h). Mild hypothermia was induced following CA and maintained at 33°C for 2 h. Neurologic deficit scores were used to determine the status of neurological function. Brain specimens were analyzed by TUNEL assay, western blotting, and immunohistochemistry. V-ATPase activity was estimated by subtracting total ATP hydrolysis from the bafilomycin-sensitive activity. Mild hypothermia improved the neurological outcome (HT-24 h: 34.3 ± 16.4 vs NT-24 h: 50.3 ± 17.4) and significantly decreased neurocyte apoptosis 24 h after resuscitation. Mild hypothermia significantly increased V0a1 compared to NT-3 h; V0a1 expression was associated with a decrease in the cleaved caspase 3 expression. These findings suggested that mild hypothermia inhibits CA-induced apoptosis in the hippocampus, which may be associated with reduced V-ATPase impairment. These data provide new insights into the protective effects of hypothermia in vivo.
Assuntos
Lesões Encefálicas/terapia , Parada Cardíaca/terapia , Hipotermia Induzida , ATPases Vacuolares Próton-Translocadoras/biossíntese , Animais , Apoptose/genética , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Caspase 3/biossíntese , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Parada Cardíaca/complicações , Parada Cardíaca/metabolismo , Parada Cardíaca/patologia , Humanos , Masculino , Ratos , Ressuscitação , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/isolamento & purificaçãoRESUMO
Autonomic nerves release ATP, which is processed into adenosine in the synaptic cleft. Adenosine and ATP exert a negative chronotropic effect in the heart. This study aims to evaluate adenosine and P2 receptors and cellular signalling in cardiac arrest produced by purines in the heart. Right atria of adult Wistar rats were used to evaluate the effects of adenosine, ATP and CPA (an adenosine A1 receptor agonist), in the presence and absence of DPCPX, an adenosine A1 receptor antagonist. Effects of adenosine A2 and A3 receptors agonists and antagonists were also investigated. Finally, involvement of calcium and potassium channels in these responses was assessed using BayK 8644 and 4-Aminopyridine. Cumulative concentration-effect curves of adenosine and CPA resulted in a negative chronotropic effect culminating in cardiac arrest at 1000µM (adenosine) and 1µM (CPA). Furthermore, ATP produced a negative chronotropic effect at 1-300µM and cardiac arrest at 1000µM in the right atrium. ATPγS (a non-hydrolysable analogue of ATP) reduced chronotropism only. The effects of adenosine, CPA and ATP were inhibited by DPCPX, a selective adenosine A1 receptor antagonist. The selective adenosine A2 and A3 receptors antagonists did not alter the chronotropic response of adenosine. 4-Aminopyridine, a blocker of potassium channels at 10mM, prevented the cardiac arrest produced by adenosine and ATP, while BayK 8644, activator of calcium channels, did not prevent cardiac arrest. Adenosine A1 receptor activation by adenosine and ATP produces cardiac arrest in the right atrium of Wistar rats predominantly through activation of potassium channels.
Assuntos
Trifosfato de Adenosina/farmacologia , Adenosina/farmacologia , Canais de Cálcio/metabolismo , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/metabolismo , Átrios do Coração/efeitos dos fármacos , Canais de Potássio/metabolismo , Animais , Relação Dose-Resposta a Droga , Parada Cardíaca/patologia , Parada Cardíaca/fisiopatologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Agonistas do Receptor Purinérgico P1/farmacologia , Ratos , Ratos Wistar , Receptores Purinérgicos P1/metabolismoRESUMO
BACKGROUND: End-tidal carbon dioxide (ETCO2) correlates with systemic blood flow and resuscitation rate during cardiopulmonary resuscitation (CPR) and may potentially direct chest compression performance. We compared ETCO2-directed chest compressions with chest compressions optimized to pediatric basic life support guidelines in an infant swine model to determine the effect on rate of return of spontaneous circulation (ROSC). METHODS AND RESULTS: Forty 2-kg piglets underwent general anesthesia, tracheostomy, placement of vascular catheters, ventricular fibrillation, and 90 seconds of no-flow before receiving 10 or 12 minutes of pediatric basic life support. In the optimized group, chest compressions were optimized by marker, video, and verbal feedback to obtain American Heart Association-recommended depth and rate. In the ETCO2-directed group, compression depth, rate, and hand position were modified to obtain a maximal ETCO2 without video or verbal feedback. After the interval of pediatric basic life support, external defibrillation and intravenous epinephrine were administered for another 10 minutes of CPR or until ROSC. Mean ETCO2 at 10 minutes of CPR was 22.7±7.8 mm Hg in the optimized group (n=20) and 28.5±7.0 mm Hg in the ETCO2-directed group (n=20; P=0.02). Despite higher ETCO2 and mean arterial pressure in the latter group, ROSC rates were similar: 13 of 20 (65%; optimized) and 14 of 20 (70%; ETCO2 directed). The best predictor of ROSC was systemic perfusion pressure. Defibrillation attempts, epinephrine doses required, and CPR-related injuries were similar between groups. CONCLUSIONS: The use of ETCO2-directed chest compressions is a novel guided approach to resuscitation that can be as effective as standard CPR optimized with marker, video, and verbal feedback.
Assuntos
Dióxido de Carbono/metabolismo , Reanimação Cardiopulmonar/métodos , Expiração , Parada Cardíaca/terapia , Hemodinâmica , Monitorização Fisiológica/métodos , Respiração Artificial , Fatores Etários , Animais , Animais Recém-Nascidos , Percepção Auditiva , Biomarcadores/metabolismo , Testes Respiratórios , Capnografia , Modelos Animais de Doenças , Retroalimentação Psicológica , Parada Cardíaca/diagnóstico , Parada Cardíaca/metabolismo , Parada Cardíaca/fisiopatologia , Valor Preditivo dos Testes , Suínos , Análise e Desempenho de Tarefas , Fatores de Tempo , Gravação em Vídeo , Percepção VisualRESUMO
To evaluate the effect of reperfusison with hypertonic-hyperosmotic solution, cardiectomy was performed in 25 New Zealand white rabbits. Seven isolated hearts were submitted to 30 min of global ischemia and reperfused with oxygenated uffer for 60 min. Myoglobin and isoensyme MB of creatine kinase concnetrations were each measured in the effluent 15 min, and values were correlated (r=0.5011, p=0.015). After this procedure, 18 isolated hearts were radomized in two groups. Hearts of group I were reperfused with hypertonic-hyperosmotic solution (NaCl 7.5 percent dextran 60,000 MW) diluted in oxygenated buffer, and group II with oxygenated buffer. Myoglobin and coronary flow were measured in both groups, group I showed lower levels of myoglobin (p=0.0069) and higher coronary flow (p = 0.028) than group II. In conclusion, changes in myoglobin concentration in the heart effluent are more sensitive than changes in isoenxyme MB of creatine kinase; thus, evaluation of this parameter may be useful in the detection of ishcemia reperfusion injury. Additionally, hypertonic-hyperosmotic solution improves the coronary flow and has a protective effect against ichemia-reperfusion injury