Postresuscitation Survival Research Articles

Abstract 127: Severity of Postresuscitation Myocardial Dysfunction Is Dependent on the Duration of Untreated Cardiac Arrest

Introduction: The duration of untreated ventricular fibrillation (VF) is one of the major determinant for outcome of cardiac arrest (CA). We investigated the relationship between different durations of untreated VF and post-resuscitation myocardial dysfunction and survival in a pig model. Methods: An established model of myocardial infarction followed by CA and CPR was used. Twenty pigs(35-43 Kg) were subjected to 3 different untreated VF intervals, prior to mechanical CPR and defibrillation: 8-10 min; 12-13 min; or 14-15 min. Arterial and central venous pressures were invasively monitored. Ejection fraction (EF) was echocardiographically assessed together with termodilution cardiac output (CO) and high sensitivity cardiac troponin T (hs-cTnT) assay. Ninety six hr survival was evaluated. Results: All the animals were resuscitated, except for 2 in the 14-15 min VF duration (Table). More than 80% of animals survived when the duration of VF was below 13 min, compared to only 17% after 14-15 min (Fig A). The duration of untreated VF correlated with the number of defibrillations required prior to resuscitation (r=0.60, p=0.01, Table). Longer durations of VF were characterized by higher post-resuscitation heart rate and right atrium pressure and by lower post-resuscitation CO and EF (p<0.01, Table). Ninety six hr EF recovered in all animals except in the pig that survived after 14-15 min VF. EF correlated with the number of defibrillation delivered (Fig B) and with hs-cTnT release (r=-0.84, p<0.0001). Conclusions: In this model, post-resuscitation myocardial dysfunction and survival were affected by the duration of untreated VF in a time-dependent manner.

Abstract 18729: Comparative Analysis of the Use of Extracorporeal Membrane Oxygenation During Cardiopulmonary Resuscitation Within a Pediatric Cardiac Intensive Care Unit

Background: Mechanical support to aid in restoration of circulation during cardiopulmonary resuscitation (CPR) is increasingly common in the pediatric cardiac intensive care unit (CICU). We sought to both identify and quantify factors predicting the implementation of extracorporeal membrane oxygenation to support CPR (eCPR). Methods and Results: Events associated with CPR from July 2010 through December 2013 within our pediatric CICU were retrospectively reviewed. Of 135 arrests among 88 patients, 84% were among postsurgical patients and 98% (n=133) resulted in a return of circulation, either spontaneous (n=100, 74%) or with the assistance of mechanical support (n=33, 24%). Median age at arrest was 106 days (interquartile range [IQR] 26-207 days) and weight was 3.9 kg (IQR 3.0-6.0 kg). Median length of stay (LOS) at the time of arrest was 5 days (IQR 1-49 days). Common primary causes included low cardiac output (38%), respiratory failure (33%), and arrhythmia (15%). Univariate predictors of an eCPR arrest included smaller size (3.3 v. 4.3 kg, p=0.004), younger age (25 v. 130 days, p<0.001), shorter length of stay at time of arrest (1 v. 8.5 days, p=0.001), single ventricle physiology (30% v. 14% among biventricular physiology arrests, p=0.04), and arrests not related to respiratory failure (34% v. 5% eCPR among respiratory failure arrests, p<0.001). Unit factors not associated with an increased frequency of arrests resulting in eCPR included unit capacity, night shift, and the experience levels of both the bedside nurse and attending. Among patients with at least one arrest, median ICU LOS was 18 days (IQR 9-72 days) and overall survival to ICU discharge was 72%. Survival to ICU discharge was not significantly different with respect to use of eCPR as compared to conventional CPR (60% v. 77% respectively, p=0.11). Conclusions: We report predictors of the need for mechanical support during cardiopulmonary resuscitation within a pediatric CICU, and demonstrate comparable post-resuscitation survival to ICU discharge among those rescued with eCPR. Further longitudinal investigation is necessary to identify potential eCPR-associated differences in morbidity and neurocognitive outcomes following a CICU arrest.

Most Important Outcomes Research Papers on Cardiac Arrest and Cardiopulmonary Resuscitation

Cardiac arrest is a common and treatable cause of death and disability. Each year ≈424 000 people experience emergency medical services (EMS)-assessed out-of-hospital cardiac arrest (OHCA) in the United States.1 The actual burden of OHCA is likely significantly higher because a substantial number go unassessed. In a prospective analysis of deaths in a US county, 5.6% of annual mortality was attributable to cardiac arrest.2 Many patients who suffer OHCA do not receive prompt cardiopulmonary resuscitation (CPR). Among those who receive CPR, a large number do not survive because of an inability to restore spontaneous circulation, or anoxic cerebral injury even after restoration of circulation. Nevertheless, when timely interventions are provided, a small proportion of patients (10.4% of all EMS-treated OHCA) recover to resume normal lives. The key therapeutic interventions that make the difference between life and death, metaphorically characterized as the 5 links in a chain of survival by the American Heart Association, include: (1) immediate recognition of cardiac arrest and activation of the EMS, (2) early CPR with emphasis on chest compression, (3) rapid defibrillation, (4) effective advanced life support, and (5) integrated postcardiac arrest care.3 Resuscitation science has undergone major advances since the origins of modern CPR >50 years ago.4 The field continues to be dynamic with emergence of new therapies such as therapeutic hypothermia5 and improvements in systems of care. However, many questions remain on issues such as optimum compression rate, efficacy of chest compression only CPR (CCCPR), dispatcher-assisted CPR, and benefits of postresuscitation measures such as hypothermia. A critical challenge also lies in the translation of resuscitation science into practice. To improve outcomes, each of the links in the chain of survival needs to be executed promptly and effectively. There remain several lacunae, which need to be overcome to develop an …

Near infrared spectrophotometry (cerebral oximetry) in predicting the return of spontaneous circulation in out-of-hospital cardiac arrest

AimWe assessed out-of-hospital cardiac arrest patients’ cerebral oxygenation during cardiopulmonary resuscitation (CPR) using near infrared spectrophotometry (NIRS). We evaluated the relation between a rise in patients’ cerebral saturation values between the start and end of CPR and return of spontaneous circulation. Materials and methodsTwenty-three patients with unwitnessed out-of-hospital cardiac arrest and brought to our emergency department by emergency ambulance were evaluated. Cerebral saturations from time of start of CPR were measured using NIRS. CPR was performed for a maximum of 30 min. The relation between cerebral saturations in patients with or without return of spontaneous circulation was then evaluated. ResultsTwenty-three patients, 12 (52.2%) female and 11 (47.8%) male, with a mean age of 64.09 ± 13.66 were included. A correlation was determined between a rise in cerebral saturation measured throughout CPR and the return of spontaneous circulation (P < .001). ConclusionPatients whose cerebral saturation values measured with NIRS rise during CPR have a higher post-resuscitation survival rate. Monitoring of patients during CPR with this non-invasive technique may be a good method for predicting return of spontaneous circulation.

Initial middle latency auditory evoked potentials index helps to predict resuscitated outcomes in patients with cardiac arrest

IntroductionWe speculated that initial middle latency auditory evoked potentials index (MLAEPi) can indicate cerebral function and predict the restoration of spontaneous circulation (ROSC), postresuscitation survival or of neurologic outcomes among patients with cardiac arrest. MethodsThis prospective study included 61 patients with cardiac arrest who received basic life support and did not achieve ROSC until arrival at the emergency center between September 2010 and September 2011. All patients were then administered advanced cardiac life support at the emergency department. Initial MLAEPi was immediately measured using an MLAEP monitor (aepEX plus; Audiomex, Glasgow, Scotland, UK) during the first cycle of advanced cardiac life support. Prediction of the ROSC, survival, and good outcome were investigated. ResultsSixteen patients achieved ROSC (ROSC group), and 45 did not achieve ROSC at the scene (non-ROSC group). The initial MLAEPi was significantly higher in the ROSC than in the non-ROSC group (33 vs 28, P < .01). Four survivors in the ROSC group were classified as good outcomes (Cerebral Performance Category 1 and 2). Initial MLAEPi in survivors were significantly higher than that in nonsurvivors (43 vs 29, P < .01). The receiver operating characteristic curves for the initial MLAEPi with area under the curves was 0.75 (95% confidence interval [CI], 0.62-0.88; P < .01) for ROSC, 0.94 (95% CI, 0.88-1.00; P < 0.01) for survival, and 0.96 (95% CI, 0.89-1.03; P < .01) for a good outcome, respectively. ConclusionsInitial MLAEPi represented by simple numerical values upon presentation at emergency facilities could predict ROSC, survival, and neurologic outcomes among patients with cardiac arrest.

Anesthesia Literature Review

Anesthesia Literature Review

Outcome of Prolonged Ventricular Fibrillation and CPR in a Rat Model of Chronic Ischemic Left Ventricular Dysfunction

Patients with chronic left ventricular (LV) dysfunction are assumed to have a lower chance of successful CPR and lower likelihood of ultimate survival. However, these assumptions have rarely been documented. Therefore, we investigated the outcome of prolonged ventricular fibrillation (VF) and CPR in a rat model of chronic LV dysfunction. Sprague-Dawley rats were randomized to (1) chronic LV dysfunction: animals underwent left coronary artery ligation; and (2) sham control. Echocardiography was used to measure cardiac performance before surgery and 4 weeks after surgery. Four weeks after surgical intervention, 8 min of VF was induced and defibrillation was delivered after 8 min of CPR. LV dilation and low ejection fraction were observed 4 weeks after coronary ligation. With optimal chest compressions, coronary perfusion pressure values during CPR were well maintained and indistinguishable between groups. There were no differences in resuscitability and numbers of shock required for successful resuscitation between groups. Despite the significantly decreased cardiac index in LV dysfunction animals before induction of VF, no differences in cardiac index were observed between groups following resuscitation, which was associated with the insignificant difference in postresuscitation survival. In conclusion, the outcomes of CPR were not compromised by the preexisting chronic LV dysfunction.

Trends in Survival after In-Hospital Cardiac Arrest

BackgroundDespite advances in resuscitation care in recent years, it is not clear whether survival and neurologic function after in-hospital cardiac arrest have improved over time.MethodsWe identified all adults who had an in-hospital cardiac arrest at 374 hospitals in the Get with the Guidelines–Resuscitation registry between 2000 and 2009. Using multivariable regression, we examined temporal trends in risk-adjusted rates of survival to discharge. Additional analyses explored whether trends were due to improved survival during acute resuscitation or postresuscitation care and whether they occurred at the expense of greater neurologic disability in survivors.ResultsAmong 84,625 hospitalized patients with cardiac arrest, 79.3% had an initial rhythm of asystole or pulseless electrical activity, and 20.7% had ventricular fibrillation or pulseless ventricular tachycardia. The proportion of cardiac arrests due to asystole or pulseless electrical activity increased over time (P<0.001 for trend). Risk-adjusted rates of survival to discharge increased from 13.7% in 2000 to 22.3% in 2009 (adjusted rate ratio per year, 1.04; 95% confidence interval [CI], 1.03 to 1.06; P<0.001 for trend). Survival improvement was similar in the two rhythm groups and was due to improvement in both acute resuscitation survival and postresuscitation survival. Rates of clinically significant neurologic disability among survivors decreased over time, with a risk-adjusted rate of 32.9% in 2000 and 28.1% in 2009 (adjusted rate ratio per year, 0.98; 95% CI, 0.97 to 1.00; P=0.02 for trend).ConclusionsBoth survival and neurologic outcomes after in-hospital cardiac arrest have improved during the past decade at hospitals participating in a large national quality-improvement registry. (Funded by the American Heart Association.)

TNF-α blockade improves early post-resuscitation survival and hemodynamics in a swine model of ischemic ventricular fibrillation

Aim of the studyInflammatory cytokines have been implicated in the pathophysiology of post cardiac arrest syndrome, including myocardial dysfunction and hypotension, often leading to multi-organ system dysfunction and death. We hypothesized that administration of infliximab after return of spontaneous circulation (ROSC) would ameliorate hypotension and myocardial dysfunction and prolong survival. MethodsDomestic swine were anesthetized and instrumented. Balloon occlusion of the LAD coronary artery just distal to the first septal perforator was performed and VF followed spontaneously in all animals. After 7min, chest compressions, defibrillation, and standard ACLS resuscitation was performed. Animals achieving ROSC (N=32) were randomized to receive infliximab (5mg/kg, n=16) or vehicle (250mL normal saline, n=16) immediately post-ROSC and survival and hemodynamics were monitored for 3h. ResultsThere were no differences in prearrest hemodynamic variables, TNF-α levels, or resuscitation variables between groups. Both groups demonstrated a time dependent decline in mean arterial pressure (MAP) and stroke work (SW) post-ROSC with a nadir at 1h followed by recovery over hours 2 and 3. This decline was blunted in infliximab-treated swine (1-h between group difference in MAP 21mm Hg, 95% CI 3–38mm Hg and SW 6.7gm-m, 95% CI 0.4–13 at 1h). Left ventricular systolic dp/dt fell in the vehicle group (−437mm Hg/s, 95% CI −183 to −690) but did not in the infliximab group. Tau rose only in the vehicle group (44ms, 95% CI 1–87). Short-term survival was higher in the infliximab group (Kaplan–Meier p=0.022). ConclusionsBlockade of TNF-α in the immediate post-ROSC period improved survival and hemodynamic parameters in this swine model of ischemic VF.

Circulating Cell-Free Nucleic Acids as Potential Biomarkers for Noninvasive Diagnosis of Diseases in the Future

Circulating Cell-Free Nucleic Acids as Potential Biomarkers for Noninvasive Diagnosis of Diseases in the Future

Circulating cell-free DNA levels correlate with postresuscitation survival rates in out-of-hospital cardiac arrest patients

Early prediction of prognosis is helpful in cardiac arrest patients. Plasma cell-free DNA, which increases rapidly after cell death, is a novel biomarker for the prognosis of critical ill patients. Changes in the plasma cell-free DNA level and its role for the early prognosis of cardiac arrest patients remain unclear. We prospectively enrolled adult out-of-hospital cardiac arrest (OHCA) patients with sustained return of spontaneous circulation. The resuscitation variables were recorded following the Utstein recommendation. The plasma cell-free DNA concentration was determined by quantitative real-time polymerase chain reaction assay of β-globin gene. A total of 42 patients were enrolled for the study. The plasma cell-free DNA level within 2h after cardiac arrest was higher in the non-survival group than the survival-to-discharge group (median level 1659.9g.e./mL vs. 1121.6g.e./mL, p=0.003 by non-parametric test). The plasma cell-free DNA level at 72h became no difference between these two groups. The optimal cutoff value of plasma cell-free DNA for predicting survival-to-discharge was 1170g.e./mL by ROC curve analysis (area under curve 0.752, p=0.010). A plasma cell-free DNA level higher than 1170g.e./mL and was an independent predictor for in-hospital mortality by multiple logistic regression analysis (adjusted odds ratio of 12.35, p=0.023) and was also associated with higher 90 day mortality (p=0.021 by log-rank test). In conclusion, the plasma cell-free DNA level increases during the early post-cardiac arrest phase and can be an early prognostic factor for OHCA patients.

Glucagon-like peptide-1 (GLP-1) attenuates post-resuscitation myocardial microcirculatory dysfunction

Aim of the study Post-resuscitation syndrome leads to death in approximately 2 out of every 3 successfully resuscitated victims, and myocardial microcirculatory dysfunction is a major component of this syndrome. The aim of this study was to determine if glucagon-like peptide-1 (GLP-1) improves post-resuscitation myocardial microcirculatory function. Methods Ventricular fibrillation (VF) was induced electrically in 20 anesthetized domestic swine (30–35 kg). Following 8 min of untreated VF, animals were resuscitated with aggressive advanced cardiac life support (ACLS). Animals were blindly randomized to receive a continuous infusion of either GLP-1 (10 pM/kg/min) or equal volume saline as placebo (PBO) for 4 h, beginning 1 min after return of spontaneous circulation (ROSC). Left ventricular (LV) haemodynamics, LV ejection fraction, cardiac output, and coronary flow reserve (CFR) [using a standard technique of intracoronary Doppler flow measurements before and after intracoronary administration of 60 μg adenosine] were performed pre-arrest and at 1 and 4 h post-resuscitation. In the present study, CFR is a measure of myocardial microcirculatory function since these swine had no obstructive coronary artery disease. Twenty-four hour post-resuscitation survival and neurological functional scores were also determined. Results CFR was significantly increased in GLP-1-treated animals, 1 h (1.79 ± 0.13 in control animals vs. 2.05 ± 0.12 in GLP-1-treated animals, P = < 0.05) and 4 h (1.82 ± 0.16 in control animals vs. 2.31 ± 0.13 in GLP-1-treated animals, P = < 0.05) after ROSC. In addition, compared to PBO-treated animals, GLP-1 increased cardiac output 1 h after ROSC (2.1 ± 0.1 in control animals vs. 2.7 ± 0.2 in GLP-1-treated animals, P = < 0.05). There was no statistically significant difference in survival between GLP-1-treated (100%) and PBO-treated animals (78%). Conclusions In this swine model of prolonged VF followed by successful resuscitation, myocardial microcirculatory function was enhanced with administration of GLP-1. However, GLP-1 treatment was not associated with a clinically significant improvement in post-resuscitation myocardial function.

Descriptive Analysis of the In-Hospital Course of Patients who Initially Survive Out-of-Hospital Cardiac Arrest but Die In-Hospital

To describe the postresuscitative hospital course of emergency department patients who initially survive nontraumatic out-of-hospital cardiac arrests (OOHCA) but die in the hospital. A 12-month case series of all nontraumatic OOHCA patients at two large urban Midwestern teaching hospitals who survived to hospital admission but died before discharge. Medical records from identified patients were reviewed for demographics, resuscitation sequelae, do-not-attempt-resuscitation (DNAR) code status, pain declarations, and withdrawal of life support. Descriptive statistics are reported. Between August 31, 2005 and July 31, 2006, there were 468 nontraumatic OOHCA patients treated at the study hospitals. Forty-one (8.8%) patients initially survived and were admitted to the hospital, of whom 32 (78.0%) expired before hospital discharge. Pain declarations were noted in 8 (25.0%) patients, of whom 4 had more than one assessment. Median postresuscitation survival time was 1.5 days (range, 9.3 hours to 18.6 days). Overall, 19 (59.4%) patients died after withdrawal of life support, 8 (25.0%) while actively on life support, and 5 (15.6%) died with subsequent cardiopulmonary resuscitation (CPR). Possible complications of CPR included pneumothorax in 2 (6.3%) and intracranial hemorrhage in 1 (3.1%). In this urban setting, approximately three of four OOHCA patients who are initially resuscitated do not survive to hospital discharge. This short in-hospital course post-CPR is often marked by pain and ends with the withdrawal of life support. This information may be an important component of advance planning discussions and may assist patients as they weigh the pros and cons associated with resuscitation preferences.

Racial differences in survival after in-hospital cardiac arrest.

Racial differences in survival have not been previously studied after in-hospital cardiac arrest, an event for which access to care is not likely to influence treatment. To estimate racial differences in survival for patients with in-hospital cardiac arrests and examine the association of sociodemographic and clinical factors and the admitting hospital with racial differences in survival. Cohort study of 10,011 patients with cardiac arrests due to ventricular fibrillation or pulseless ventricular tachycardia enrolled between January 1, 2000, and February 29, 2008, at 274 hospitals within the National Registry of Cardiopulmonary Resuscitation. Survival to hospital discharge; successful resuscitation from initial arrest and postresuscitation survival (secondary outcome measures). Included were 1883 black patients (18.8%) and 8128 white patients (81.2%). Rates of survival to discharge were lower for black patients (25.2%) than for white patients (37.4%) (unadjusted relative rate [RR], 0.73; 95% confidence interval [CI], 0.67-0.79). Unadjusted racial differences narrowed after adjusting for patient characteristics (adjusted RR, 0.81 [95% CI, 0.75-0.88]; P < .001) and diminished further after additional adjustment for hospital site (adjusted RR, 0.89 [95% CI, 0.82-0.96]; P = .002). Lower rates of survival to discharge for blacks reflected lower rates of both successful resuscitation (55.8% vs 67.4% for whites; unadjusted RR, 0.84 [95% CI, 0.81-0.88]) and postresuscitation survival (45.2% vs 55.5% for whites; unadjusted RR, 0.85 [95% CI, 0.79-0.91]). Adjustment for the hospital site at which patients received care explained a substantial portion of the racial differences in successful resuscitation (adjusted RR, 0.92 [95% CI, 0.88-0.96]; P < .001) and eliminated the racial differences in postresuscitation survival (adjusted RR, 0.99 [95% CI, 0.92-1.06]; P = .68). Black patients with in-hospital cardiac arrest were significantly less likely to survive to discharge than white patients, with lower rates of survival during both the immediate resuscitation and postresuscitation periods. Much of the racial difference was associated with the hospital center in which black patients received care.

Erythropoietin improved initial resuscitation and increased survival after cardiac arrest in rats

Introduction Recent data have demonstrated potent cardioprotective and neuroprotective effects of the application of growth hormones like erythropoietin (EPO) after focal cardiac or cerebral ischemia. In order to assess possible benefits regarding survival and resuscitation conditions, EPO was tested against placebo in a model of cardiac arrest in the rat. Methods Thirty-four male Wistar rats were randomized into two groups (EPO versus control; n = 17 per group). Under anesthesia, cardiac arrest was induced by asphyxia after neuromuscular blockade. After 6 min of global ischemia, animals were resuscitated by external chest compression combined with epinephrine administration. An intravenous bolus of recombinant human EPO (rhEPO, 3000 UI kg −1 body weight, i.v.) or saline (in control group) was performed 15 min before cardiac arrest, by a blinded investigator. Restoration of spontaneous circulation (ROSC), survival at 1, 24, 48 and 72 h and hemodynamic changes after cardiac arrest were studied. Results Survival to 72 h was significantly improved in the EPO group ( n = 15/17) compared to the control group ( n = 7/17). All the EPO-treated rats were successfully resuscitated whereas only 13 of 17 control animals resuscitated. EPO-treated animals required a significantly smaller dose of epinephrine before resuscitation, compared to control rats. Time course of systolic arterial blood pressure after resuscitation revealed no significant differences between both groups. Conclusion EPO, when administrated before cardiac arrest, improved initial resuscitation and increased the duration of post-resuscitation survival.

Statistical analysis of joint short-term and long-term survival in resuscitation research

To develop statistical tools that use combined initial survival data and post-resuscitation survival data to test the null hypothesis that true, population-wide outcomes following experimental CPR interventions are not different from control. A new test statistic, d(2), for evaluating Type 1 error is derived from a bivariate, two-dimensional analysis of categorical initial resuscitation and post-resuscitation survival data, which are statistically independent because they are obtained during non-overlapping periods of time. The d(2) test statistic, which is distributed as a chi-squared distribution, is derived from first principles and validated using Monte Carlo methods of computer simulation for thousands of clinical trials. Under the null hypothesis, the normalized difference in the proportions of patients surviving the initial resuscitation period and the normalized difference in the proportions of such short-term survivors that also survive the post-resuscitation period are jointly distributed in a two-dimensional space as a bivariate standard normal distribution, against which observed intervention and control outcomes can be compared in a test of statistical significance. Typically this two-dimensional approach has greater statistical power to detect true differences, compared to conventional one-dimensional tests. Smaller group sizes (Ns) are usually required to reach statistical significance when both initial survival and post-resuscitation survival are considered together. Such two-dimensional analysis is easily extended to meta-analysis of multiple trials. A straightforward, easy-to-use bivariate test for Type I errors in statistical inference can be done for resuscitation studies reporting both short-term and long-term survival data. Acceptance of such two-dimensional tests of the null hypothesis, as proposed by Hallstrom, can save time, money, effort, and disappointment in the difficult and sometimes frustrating field of resuscitation research.

δ-Opioid–induced pharmacologic myocardial hibernation during cardiopulmonary resuscitation

Cardiac arrest and cardiopulmonary resuscitation is an event of global myocardial ischemia and reperfusion, which is associated with severe postresuscitation myocardial dysfunction and fatal outcome. Evidence has demonstrated that mammalian hibernation is triggered by cyclic variation of a delta-opiate-like compound in endogenous serum, during which the myocardial metabolism is dramatically reduced and the myocardium tolerates the stress of ischemia and reperfusion without overt ischemic and reperfusion injury. Previous investigations also proved that the delta-opioid agonist elicited the cardioprotection in a model of regional ischemic intact heart or myocyte. Accordingly, we were prompted to search for an alternative intervention of pharmacologically induced myocardial hibernation that would result in rapid reductions of myocardial metabolism and therefore minimize the myocardial ischemic and reperfusion injury during cardiac arrest and cardiopulmonary resuscitation. Prospective, controlled laboratory study. University-affiliated research laboratory. In the series of studies performed in the established rat and pig model of cardiac arrest and cardiopulmonary resuscitation, the delta-opioid receptor agonist, pentazocine, was administered during ventricular fibrillation. : The myocardial metabolism reflected by the concentration of lactate, or myocardial tissue PCO2 and PO2, is dramatically reduced during cardiac arrest and cardiopulmonary resuscitation. These are associated with less severe postresuscitation myocardial dysfunction and longer duration of postresuscitation survival. delta-Opioid-induced pharmacologic myocardial hibernation is an option to minimize the myocardial ischemia and reperfusion injury during cardiac arrest and cardiopulmonary resuscitation.

Mechanism by which activation of δ-opioid receptor reduces the severity of postresuscitation myocardial dysfunction

Postresuscitation myocardial dysfunction has been recognized as a leading cause of early death after initially successful cardiopulmonary resuscitation. We have previously demonstrated that opening adenosine triphosphate (ATP)-sensitive K (KATP) channels or activation of delta-opioid receptors minimized the severity of postresuscitation myocardial dysfunction and increased the duration of postresuscitation survival. In the present study, we investigated the potential mechanism of myocardial protection following delta-opioid receptor activation in a rat model of cardiac arrest and cardiopulmonary resuscitation. Randomized prospective animal study. Animal research laboratory. Male Sprague-Dawley rats. Ventricular fibrillation was induced in 24 Sprague-Dawley rats. Mechanical ventilation and precordial compression were initiated after 8 mins of untreated ventricular fibrillation. Defibrillation was attempted after 6 mins of cardiopulmonary resuscitation. The animals were randomized to four groups: a) pentazocine (0.3 mg/kg), a delta-opioid receptor agonist; b) pentazocine pretreated with KATP channel blocker, glibenclamide (0.3 mg/kg), administered 45 mins before induction of ventricular fibrillation; c) glibenclamide pretreated alone 45 mins before induction of ventricular fibrillation; and d) placebo. Pentazocine or saline placebo was injected into the right atrium after 5 mins of untreated ventricular fibrillation. Postresuscitation myocardial function, as measured by the rate of left ventricular pressure increase at 40 mm Hg, left ventricular end-diastolic pressure, and cardiac index, was significantly improved in pentazocine-treated animals. This was associated with significantly prolonged duration of survival. Except for ease of defibrillation, the beneficial effects of pentazocine were abolished by pretreatment with the KATP channel blocker glibenclamide. The postresuscitation myocardial protective effects provided by activation of delta-opioid receptor may be mediated via opening KATP channels.

Levosimendan improves postresuscitation outcomes in a rat model of CPR

In this study we sought to determine whether a calcium sensitizer, levosimendan, would have a more favorable effect on postresuscitation myocardial function and, consequently, postresuscitation survival than beta-adrenergic dobutamine. The extreme decrease in survival before hospital discharge of resuscitated victims is attributed, in part, to postresuscitation myocardial failure, and dobutamine has been recommended for the management of postresuscitation myocardial failure. We studied a total of 15 animals. Ventricular fibrillation was induced in Sprague-Dawley rats weighing 450 to 550 g. Cardiopulmonary resuscitation (CPR), including chest compressions and mechanical ventilation, was begun after 8 minutes of untreated cardiac arrest. Electrical defibrillation was attempted after 6 minutes of CPR. Each animal was resuscitated. Animals were randomized to undergo treatment with levosimendan, dobutamine, or saline-solution placebo. These agents were administered 10 minutes after the return of spontaneous circulation. Levosimendan was administered in a loading dose of 12 microg kg(-1) over a 10-minute period, followed by infusion of 0.3 microg kg(-1) min(-1) over the next 230 minutes. Dobutamine was continuously infused at a dosage of 3 microg kg(-1) min(-1). Saline-solution placebo was administered in the same volume and over the same amount of time as levosimendan. Levosimendan and dobutamine produced comparable increases in cardiac output and rate of left-ventricular pressure increase. However, administration of levosimendan resulted in lower heart rates and lesser increases in left ventricular diastolic pressure compared with both dobutamine and placebo. The duration of postresuscitation survival was significantly greater with levosimendan (16 +/- 2 hours), intermediate with dobutamine (11 +/- 2 hours) and least with saline-solution placebo (8 +/- 1 hour). Levosimendan and dobutamine both improved postresuscitation myocardial function. However, levosimendan produced more favorable postresuscitation myocardial function and increased the duration of postresuscitation survival.

Levosimendan improves postresuscitation myocardial dysfunction after β-adrenergic blockade

In earlier studies, we found that a nonselective beta-adrenergic blocking agent, propranolol, facilitated cardiac resuscitation, reduced postresuscitation myocardial ectopy, and improved postresuscitation survival. However, the potential adverse effects and specifically the negative inotropic actions of propranolol prompted our further investigation of the potential value of a non-beta-adrenergic inotropic drug, levosimendan, in conjunction with propranolol, for minimizing postresuscitation myocardial dysfunction after successful resuscitation from cardiac arrest. Ventricular fibrillation was induced and untreated for 7 minutes in 15 domestic pigs, which were divided into propranolol, propranolol plus levosimendan, and control groups. Propranolol was administered as a bolus dose of 0.1 mg/kg during cardiac arrest. Electrical defibrillation was attempted after 12 minutes of cardiac arrest including 5 minutes of precordial compression. Levosimendan was administered at 10 minutes after successful resuscitation in a dose of 20 microg/kg and followed by infusion of 0.4 microg/kg/min over the ensuing 220 minutes. Propranolol reduced energies or numbers of defibrillatory shocks and postresuscitation myocardial ectopy, and it improved postresuscitation myocardial dysfunction. When levosimendan was added, postresuscitation myocardial contractile function was improved even more.