Molar Sodium Lactate Attenuates the Severity of Postcardiac Arrest Syndrome: A Preclinical Study.

OBJECTIVES: To determine whether continuous IV infusion of molar sodium lactate would limit cardiac arrest-induced neurologic injury and cardiovascular failure. DESIGN: Randomized blinded study (animal model). SETTING: University animal research facility. SUBJECTS: Twenty-four adult male "New Zealand White" rabbits. INTERVENTIONS: Anesthetized rabbits underwent 12.5 minutes of asphyxial cardiac arrest and were randomized to receive either normal saline (control group, n = 12) or molar sodium lactate (molar sodium lactate group, n = 12) at a rate of 5 mL/kg/hr during the whole 120-minute reperfusion period. MEASUREMENTS AND MAIN RESULTS: Pupillary reactivity (primary outcome), levels of S100ß protein, in vitro brain mitochondria functions, cardiovascular function, and fluid balance were assessed. Molar sodium lactate reduced brain injury, with a higher proportion of animals exhibiting pupillary reactivity to light (83% vs 25% in the CTRL group, p = 0.01) and lower S100ß protein levels (189 ± 42 vs 412 ± 63 pg/mL, p < 0.01) at the end of the protocol. Molar sodium lactate significantly prevented cardiac arrest-induced decrease in oxidative phosphorylation and mitochondrial calcium-retention capacity compared with controls. At 120 minutes of reperfusion, survival did not significantly differ between the groups (10/12, 83% in the molar sodium lactate group vs nine of 12, 75% in the control group; p > 0.99), but hemodynamics were significantly improved in the molar sodium lactate group compared with the control group (higher mean arterial pressure [49 ± 2 vs 29 ± 3 mm Hg; p < 0.05], higher cardiac output [108 ± 4 vs 58 ± 9 mL/min; p < 0.05], higher left ventricle surface shortening fraction [38% ± 3% vs 19% ± 3%; p < 0.05], and lower left ventricular end-diastolic pressure [3 ± 1 vs 8 ± 2 mm Hg; p < 0.01]). While fluid intake was similar in both groups, fluid balance was higher in control animals (11 ± 1 mL/kg) than that in molar sodium lactate-treated rabbits (1 ± 3 mL/kg; p < 0.01) due to lower diuresis. CONCLUSIONS: Molar sodium lactate was effective in limiting the severity of the postcardiac arrest syndrome. This preclinical study opens up new perspectives for the treatment of cardiac arrest.

Outcome Related to Level of Targeted Temperature Management in Postcardiac Arrest Syndrome of Low, Moderate, and High Severities: A Nationwide Multicenter Prospective Registry.

OBJECTIVES: The optimal target temperature during targeted temperature management for patients after cardiac arrest remains under debate. The aim of this study was to evaluate the association between targeted temperature management at lower target temperatures and the neurologic outcomes among patients classified by the severity of postcardiac arrest syndrome. DESIGN: A multicenter observational study from the out-of-hospital cardiac arrest registry of the Japanese Association for Acute Medicine, which is a nationwide prospective registry of out-of-hospital cardiac arrest patients. SETTING: A total of 125 critical care medical centers or hospitals with an emergency care department across Japan. PATIENTS: A total of 1,111 out-of-hospital cardiac arrest patients who had received targeted temperature management. MEASUREMENTS AND MAIN RESULTS: We divided all 1,111 postcardiac arrest syndrome patients treated with targeted temperature management into two groups: those who received targeted temperature management at a lower target temperature (33-34°C) and those who received targeted temperature management at a higher target temperature (35-36°C). In regard to classification of the patients, we divided the patients into three categories of severity (low, moderate, and high severities) using the risk classification tool, post-Cardiac Arrest Syndrome for Therapeutic hypothermia, which was previously validated. The primary outcome was the percentage of patients with a good neurologic outcome at 30 days, and the secondary outcome was the survival rate at 30 days. Multivariate analysis showed that targeted temperature management at 33-34°C was significantly associated with a good neurologic outcome and survival at 30 days in the moderate severity (odds ratio, 1.70 [95% CI, 1.03-2.83] and 1.90 [95% CI, 1.15-3.16], respectively), but not in the patients of low or high severity (pinteraction = 0.033). Propensity score analysis also showed that targeted temperature management at 33-34°C was associated with a good neurologic outcome in the moderate-severity group (p = 0.022). CONCLUSIONS: Targeted temperature management at 33-34°C was associated with a significantly higher rate of a good neurologic outcome in the moderate-severity postcardiac arrest syndrome group, but not in the low- or high-severity group.

Nitric Oxide in Post-cardiac Arrest Syndrome.

Sudden cardiac arrest is a leading cause of death worldwide. Although the methods of cardiopulmonary resuscitation have been improved, mortality is still unacceptably high, and many survivors suffer from lasting neurological deficits due to the post-cardiac arrest syndrome (PCAS). Pathophysiologically, generalized vascular endothelial dysfunction accompanied by platelet activation and systemic inflammation has been implicated in the pathogenesis of PCAS. Because endothelial-derived nitric oxide (NO) plays a central role in maintaining vascular homeostasis, the role of NO-dependent signaling has been a focus of the intense investigation. Recent preclinical studies showed that therapeutic interventions that increase vascular NO bioavailability may improve outcomes after cardiac arrest complicated with PCAS. In particular, NO inhalation therapy has been shown to improve neurological outcomes and survival in multiple species. Clinical studies examining the safety and efficacy of inhaled NO in patients sustaining PCAS are warranted.

Prediction of regaining consciousness despite an early epileptiform EEG after cardiac arrest.

OBJECTIVE: After cardiac arrest (CA), epileptiform EEG, occurring in about 1/3 of patients, often but not invariably heralds poor prognosis. We tested the hypothesis that a combination of specific EEG features identifies patients who may regain consciousness despite early epileptiform patterns. METHODS: We retrospectively analyzed a registry of comatose patients post-CA (2 Swiss centers), including those with epileptiform EEG. Background and epileptiform features in EEGs 12-36 hours or 36-72 hours from CA were scored according to the American Clinical Neurophysiology Society nomenclature. Best Cerebral Performance Category (CPC) score within 3 months (CPC 1-3 vs 4-5) was the primary outcome. Significant EEG variables were combined in a score assessed with receiver operating characteristic curves, and independently validated in a US cohort; its correlation with serum neuron-specific enolase (NSE) was also tested. RESULTS: Of 488 patients, 107 (21.9%) had epileptiform EEG <72 hours; 18 (17%) reached CPC 1-3. EEG 12-36 hours background continuity ≥50%, absence of epileptiform abnormalities (p < 0.00001 each), 12-36 and 36-72 hours reactivity (p < 0.0001 each), 36-72 hours normal background amplitude (p = 0.0004), and stimulus-induced discharges (p = 0.0001) correlated with favorable outcome. The combined 6-point score cutoff ≥2 was 100% sensitive (95% confidence interval [CI], 78%-100%) and 70% specific (95% CI, 59%-80%) for CPC 1-3 (area under the curve [AUC], 0.98; 95% CI, 0.94-1.00). Increasing score correlated with NSE (ρ = -0.46, p = 0.0001). In the validation cohort (41 patients), the score was 100% sensitive (95% CI, 60%-100%) and 88% specific (95% CI, 73%-97%) for CPC 1-3 (AUC, 0.96; 95% CI, 0.91-1.00). CONCLUSION: Prognostic value of early epileptiform EEG after CA can be estimated combining timing, continuity, reactivity, and amplitude features in a score that correlates with neuronal damage.

Somatosensory Evoked Potentials and Neuroprognostication After Cardiac Arrest.

Improved understanding of post-cardiac arrest syndrome and clinical practices such as targeted temperature management have led to improved mortality in this cohort. Attention has now been placed on development of tools to aid in predicting functional outcome in comatose cardiac arrest survivors. Current practice uses a multimodal approach including physical examination, neuroimaging, and electrophysiologic data, with a primary utility in predicting poor functional outcome. These modalities remain confounded by self-fulfilling prophecy and the withdrawal of life-sustaining therapies. To date, a reliable measure to predict good functional outcome has not been established or validated, but the use of quantitative somatosensory evoked potential (SSEP) shows potential for this use. MEDLINE and EMBASE search using words "Cardiac Arrest" and "SSEP," "Somato sensory evoked potentials," "qSSEP," "quantitative SSEP," "targeted temperature management in cardiac arrest" was conducted. Relevant recent studies on targeted temperature management in cardiac arrest, plus studies on SSEP in cardiac arrest in the setting of hypothermia and without hypothermia, were included. In addition, animal studies evaluating the role of different components of SSEP in cardiac arrest were reviewed. SSEP is a specific indicator of poor outcomes in post-cardiac arrest patients but lacks sensitivity and has not clinically been established to foresee good outcomes. Novel methods of analyzing quantitative SSEP (qSSEP) signals have shown potential to predict good outcomes in animal and human studies. In addition, qSSEP has potential to track cerebral recovery and guide treatment strategy in post-cardiac arrest patients. Lying beyond the current clinical practice of dichotomized absent/present N20 peaks, qSSEP has the potential to emerge as one of the earliest predictors of good outcome in comatose post-cardiac arrest patients. Validation of qSSEP markers in prospective studies to predict good and poor outcomes in the cardiac arrest population in the setting of hypothermia could advance care in cardiac arrest. It has the prospect to guide allocation of health care resources and reduce self-fulfilling prophecy.

Cyclosporine A Plus Ischemic Postconditioning Improves Neurological Function in Rats After Cardiac Resuscitation.

BACKGROUND AND OBJECTIVE: Attenuation of neuronal apoptosis helps maintain neurological function in patients after cardiac arrest. After ischemia-reperfusion, both cyclosporin A (CsA) and ischemic postconditioning independently protect mitochondria and thus reduce nerve injury. This study employed a rat model to evaluate the neuroprotective effect of combining ischemic postconditioning with CsA after cardiopulmonary resuscitation (CPR). METHODS: Rats were apportioned equally to model control, postconditioned, CsA-treated, or CsA + postconditioned groups. Asphyxial cardiac arrest was imposed using modified Utstein-style guidelines. In the appropriate groups, postconditioning was implemented by ischemia and reperfusion (clamping and loosening the left femoral artery); CsA treatment was delivered with a single intravenous dose. Neurological deficits were scored at different times after CPR. Histological evaluation and electron microscopy were used to evaluate tissue damage, and TUNEL and flow cytometry were used to measure the apoptotic rate of hippocampal neurons and size of the mitochondrial permeability transition pore (mPTP) opening. RESULTS: The apoptotic rate was significantly lower in the postconditioned and CsA-treated groups compared with the model control and lowest in the CsA + postconditioned group. By histological evaluation and electron microscopy, the least damage was observed in the CsA + postconditioned group. The neurological deficit score of the CsA + postconditioned group was significantly higher than that of the CsA-treated group, but the size of the mPTP openings of these two groups was comparable. CONCLUSION: Ischemic postconditioning combined with CsA exerted a better neuroprotective effect after CPR than did either postconditioning or CsA alone. Inhibiting the opening of the mPTP is not the only neuroprotective mechanism.

Prognostic value of 18F-FDG brain PET as an early indicator of neurological outcomes in a rat model of post-cardiac arrest syndrome.

Predicting neurological outcomes in patients with post-cardiac arrest syndrome (PCAS) is crucial for identifying those who will benefit from intensive care. We evaluated the predictive value of 18F-FDG PET. PCAS was induced in Sprague Dawley rats. Baseline and post-3-hour images were acquired. Standardized uptake value (SUV) changes before and after PCAS induction (SUVdelta) and SUV ratios (SUVR) of regional SUV normalized to the whole brain SUV were obtained. The Morris water maze (MWM) test was performed after 2 weeks to evaluate neurological outcomes and rats were classified into two groups based on the result. Of 18 PCAS rats, 8 were classified into the good outcome group. The SUVdelta of forebrain regions were significantly decreased in good outcome group (p < 0.05), while the SUVdelta of hindbrain regions were not significantly different according to outcomes. The SUVR of forebrain regions were significantly higher and the SUVR of hindbrain regions were significantly lower in good outcome group (p < 0.05). Forebrain-to-hindbrain ratio predicted a good neurological outcome with a sensitivity of 90% and specificity of 100% using an optimal cutoff value of 1.22 (AUC 0.969, p < 0.05). These results suggest the potential utility of 18F-FDG PET in the early prediction of neurological outcomes in PCAS.

Preconditioning but not postconditioning treatment with resveratrol substantially ameliorates post­resuscitation myocardial dysfunction through the PI3K/Akt signaling pathway.

Post­resuscitation myocardial dysfunction (PRMD) is a severe complication that arises in patients after cardiac arrest (CA). However, there are no safe or effective treatment strategies that are currently available to treat these patients. In the present study, it was investigated whether resveratrol administration could inhibit myocardial nitrative stress to alleviate PRMD. CA was induced in Sprague­Dawley rats by trans­oesophageal alternating electrical stimulation, followed by cardiopulmonary resuscitation. Rats were then randomly divided into a preconditioning or a postconditioning group. Left ventricular function (+dP/dtmax and ­dP/dtmin) was recorded for 4 h after the return of spontaneous circulation (ROSC), after which the animals were euthanized. Myocardial nitrative stress was analysed using enzyme­linked immunosorbent assay, western blotting and immunohistochemistry. Wortmannin (a PI3K inhibitor) was used to investigate the involvement of the PI3k/Akt signalling pathway in the cardio­protective activity of resveratrol. After ROSC, resveratrol improved PRMD compared to the vehicle control; however, resveratrol administration significantly improved PRMD in the preconditioning group compared to the postconditioning group. Likewise, resveratrol preconditioning significantly decreased the expression of iNOS and nitrotyrosine in rat hearts but did not significantly ameliorate myocardial nitrative stress. Wortmannin partially inhibited the protective effect of resveratrol preconditioning and resulted in the deterioration of cardiac function and increase in iNOS and nitrotyrosine levels. Resveratrol preconditioning could alleviate PRMD by inhibiting myocardial nitrative stress. The PI3K/Akt signalling pathway may be partially involved in the process.

The post-cardiac arrest syndrome: A case for lung-brain coupling and opportunities for neuroprotection.

Systemic inflammation and multi-organ failure represent hallmarks of the post-cardiac arrest syndrome (PCAS) and predict severe neurological injury and often fatal outcomes. Current interventions for cardiac arrest focus on the reversal of precipitating cardiac pathologies and the implementation of supportive measures with the goal of limiting damage to at-risk tissue. Despite the widespread use of targeted temperature management, there remain no proven approaches to manage reperfusion injury in the period following the return of spontaneous circulation. Recent evidence has implicated the lung as a moderator of systemic inflammation following remote somatic injury in part through effects on innate immune priming. In this review, we explore concepts related to lung-dependent innate immune priming and its potential role in PCAS. Specifically, we propose and investigate the conceptual model of lung-brain coupling drawing from the broader literature connecting tissue damage and acute lung injury with cerebral reperfusion injury. Subsequently, we consider the role that interventions designed to short-circuit lung-dependent immune priming might play in improving patient outcomes following cardiac arrest and possibly other acute neurological injuries.

Early Initiation of Continuous Renal Replacement Therapy Induces Fast Hypothermia and Improves Post-Cardiac Arrest Syndrome in a Porcine Model.

Rapid induction of hypothermia early after resuscitation can be an effective strategy against post-cardiac arrest syndrome (PCAS). Preliminary data suggested that continuous renal replacement therapy (CRRT) might be an efficient method to rapidly induce hypothermia. In this study, we investigated the efficacy of cooling induced by CRRT and its effects on the outcomes of PCAS in a porcine model.Thirty-two male domestic pigs weighing 36 ±â€Š2 kg were randomized into 4 groups: sham control (n = 5), normothermia (n = 9), surface cooling (SC, n = 9), and CRRT (n = 9). Sham animals underwent the surgical preparation only. The animal model was established by 8 min of untreated ventricular fibrillation and then 5 min of cardiopulmonary resuscitation. At 5 min after resuscitation, the animals were cooled by either the combination of an earlier 8-h CRRT and later 16-h SC or the whole 24-h SC in the 2 hypothermic groups. For the other 2 groups, a normal temperature of 38.0 ±â€Š0.5°C was maintained throughout the experiment.Blood temperature was decreased to 33°C within 28 min in animals treated with CRRT, which was significantly faster than that in the SC group requiring 185 min to achieve target temperature. Post-resuscitation myocardial dysfunction, brain injury, and systemic inflammation were significantly improved in the 2 hypothermic groups compared to the normothermia group. However, the improvement was significantly greater in the CRRT group than in the SC group.In conclusion, fast hypothermia was successfully induced by CRRT and significantly alleviated the severity of PCAS in a porcine model.