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We investigated the relationship between the severity of postresuscitation (PR) myocardial tissue injury and myocardial dysfunction after the administration of epinephrine as well as the protective effects of α- and β-adrenergic blocking agents. Forty male Sprague-Dawley rats were randomized into 6 groups: (1) placebo; (2) epinephrine; (3) epinephrine pretreated with α 1 -blocker (prazosin); (4) epinephrine pretreated with α 2 -blocker (yohimbine); (5) epinephrine pretreated with β-blocker (propranolol); and (6) epinephrine pretreated with β- plus α 1 -blocker (propranolol and prazosin). Cardiopulmonary resuscitation was initiated after 8 minutes of untreated ventricular fibrillation and continued for an additional 8 minutes. The myocardial function and the serum concentrations of troponin I (Tn I) and N-terminal probrain natriuretic peptide (NT-proBNP) were measured at baseline and after resuscitation. After resuscitation, both Tn I and NT-proBNP were significantly increased in all groups, especially in the epinephrine and epinephrine pretreated with α 2 -blocker groups. Significantly better PR myocardial function and neurologic deficit score were observed in epinephrine pretreated with the α 1 - or β-blocker with decreased releases of Tn I and NT-proBNP. However, the most significant improvements were observed in the animals pretreated with β- plus α 1 -blocker. The present study demonstrated that myocardial stunning may not be the only mechanism of PR myocardial dysfunction. Administration of epinephrine increased the severity of PR myocardial tissue injury and dysfunction. The β- and β- plus α 1 -blocker pretreatment significantly reduced the severity of PR myocardial tissue injury and myocardial dysfunction with better neurologic function and prolonged duration of survival.

Objectives Cardiac arrest and resuscitation are models of whole body ischemia reperfusion injury. Postresuscitation myocardial and cerebral dysfunction are major causes of high mortality and morbidity. Remote ischemic postconditioning has been proven to provide potent protection of the heart and brain against ischemia reperfusion injury. In this study, we investigated the effects of remote ischemic postconditioning on postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation. Design Prospective, randomized, controlled experimental study. Setting University-affiliated animal research institution. Subjects Twenty-eight healthy male Sprague-Dawley rats. Interventions The animals were randomized into four groups: 1) remote ischemic preconditioning initiated 40 minutes before induction of ventricular fibrillation, 2) remote ischemic postconditioning initiated coincident with the start of cardiopulmonary resuscitation, 3) remote ischemic postconditioning initiated 5 minutes after successful resuscitation, and 4) control. Remote ischemic pre- and postconditioning was induced by four cycles of 5 minutes of limb ischemia, followed by 5 minutes of reperfusion. Ventricular fibrillation was induced and untreated for 6 minutes while defibrillation was attempted after 8 minutes of cardiopulmonary resuscitation. The animals were then monitored for 4 hours and observed for an additional 68 hours after resuscitation. Measurements and main results Hemodynamic measurements and myocardial function, including cardiac output, left ventricular ejection fraction, and myocardial performance index, were measured at baseline and hourly for 4 hours after resuscitation. Postresuscitation cerebral function was evaluated by neurologic deficit score at 24-hour intervals for a total of 72 hours. Consequently, significantly better myocardial and cerebral function with a longer duration of survival were observed in the three groups treated with remote ischemic pre- and postconditioning. Conclusions In a rat model of cardiac arrest and resuscitation, remote ischemic pre-and postconditioning attenuated postresuscitation myocardial and cerebral dysfunction and improved the duration of survival.

OBJECTIVES To investigate the mechanisms of improved myocardial and neurological function and survival following i.v. administration of cannabinoid receptor agonist, WIN55, 212-2 in a rat model of cardiac arrest. DESIGN Prospective randomized controlled experimental study. SETTING University-affiliated research institute. SUBJECTS Thirty male Sprague-Dawley rats. INTERVENTIONS Ventricular fibrillation was electrically induced in 30 male Sprague-Dawley rats weighing between 450 and 550 g. Cardiopulmonary resuscitation was initiated after 6 minutes of untreated ventricular fibrillation. The precordial compression was performed with a pneumatically driven mechanical chest compressor. No pharmacological agent was used during cardiopulmonary resuscitation. After 8 minutes of cardiopulmonary resuscitation, up to three 2-J defibrillations were attempted. The animals were then randomized into three groups: 1) WIN55, 212-2 hypothermia, 2) WIN55, 212-2 with normal body temperature, and 3) placebo control. Either WIN55, 212-2 (1.0 mg/kg/hr) or saline placebo was continuously infused for 2 hours. Except for the WIN55, 212-2 hypothermia group, the body temperature in the other two groups was maintained at 37.0 ± 0.2°C using an external heating lamp. Postresuscitation myocardial function was measured by echocardiogram. Neurological deficit scores and survival time were observed for up to 72 hours. MEASUREMENTS AND MAIN RESULTS Blood temperatures decreased from 37°C to 33°C in 4 hours in animals in WIN55, 212-2 hypothermia group. Myocardial function, as measured by cardiac output, ejection fraction, and myocardial performance index, was significantly impaired in all animals after successful resuscitation when compared with the baseline values. There was a significant improvement in myocardial function in the animals treated with WIN55, 212-2 hypothermia beginning at 1 hour after start of infusion. However, no improvement was observed in the groups of WIN55, 212-2 with normal body temperature and placebo control. WIN55, 212-2 hypothermia group was associated with significantly improved neurologic deficit scores and survival time when compared with placebo control group and WIN55, 212-2 with normal body temperature group. CONCLUSIONS In a rat model of cardiac arrest, better postresuscitation myocardial function, neurological deficit scores, and longer duration of survival were observed by the pharmacologically induced hypothermia with WIN55, 212-2. The improved outcomes of cardiopulmonary resuscitation following administration of WIN55, 212-2 appeared to be the results from its temperature reduction effects.

Aims of study We have previously demonstrated that early intra-nasal cooling improved post-resuscitation neurological outcomes. The present study utilizing a porcine model of prolonged cardiac arrest investigated the effects of intra-nasal cooling initiated at the start of cardiopulmonary resuscitation (CPR) on resuscitation success. Our hypothesis was that rapid nasal cooling initiated during “low-flow” improves return of spontaneous resuscitation (ROSC). Methods In 16 domestic male pigs weighing 40 ± 3 kg, VF was electrically induced and untreated for 15 min. Animals were randomized to either head cooling or control. CPR was initiated and continued for 5 min before defibrillation was attempted. Coincident with starting CPR, the hypothermic group was cooled with a RhinoChill™ device which produces evaporative cooling in the nasal cavity of pigs. No cooling was administrated to control animals. If ROSC was not achieved after defibrillation, CPR was resumed for 1 min prior to the next defibrillation attempt until either successful resuscitation or for a total of 15 min. Main results Seven of eight animals in the hypothermic group (87.5%) and two of eight animals in control group (25%) ( p = 0.04) were successfully resuscitated. At ROSC, brain temperature was increased from baseline by 0.3 °C in the control group, and decreased by 0.1 °C in the hypothermic animals. Pulmonary artery temperature was above baseline in both groups. Conclusion Intra-nasal cooling initiated at the start of CPR significantly improves the success of resuscitation in a porcine model of prolonged cardiac arrest. This may have occurred by preventing brain hyperthermia.

Objective: Observational studies have shown that muscular stimulation contracting the thoracic cage may produce coronary perfusion pressures equal to manual chest compressions. This study examined electrical cardiopulmonary resuscitation for coronary perfusion pressures during ventricular fibrillation in a porcine model of cardiac arrest Design: Prospective randomized controlled study. Setting: University affiliated research institute. Subjects: Domestic male pigs. Interventions: In seven domestic male pigs (40 ± 2 kg), ventricular fibrillation was induced electrically and untreated for 10 sees. For each ventricular fibrillation episode, one of 16 electrical cardiopulmonary resuscitation stimulation protocols (pulse trains) or manual chest compression was applied. Each compression protocol was applied for 20 secs, followed by a defibrillation shock. The experimental procedure was performed across one or more randomized complete blocks. The electrical cardiopulmonary resuscitation pulse trains were defined by four two-level factors: pulse width (0.15 and 7.5 msec), pulse period (15 and 30 msec), train width (50 and 200 msec), and train rate (60 or 120 compressions per min). Pulse trains comprised two groups, based on pulse width (skeletal-based, 0.15 msec; cardiac-based, 7.5 msec). Measurements and Main Results: Train width was the significant design parameter for producing efficacious levels of coronary perfusion pressures for the skeletal-based electrical cardiopulmonary resuscitation pulse trains (p = 0.02). Both train width and train rate were significant design parameters for producing efficacious levels of coronary perfusion pressures for the cardiac-based electrical cardiopulmonary resuscitation pulse trains (p < 0.001, p = 0.5, respectively). Optimal skeletal-based and cardiac-based electrical cardiopulmonary resuscitation pulse trains were significantly better than ventricular fibrillation (p = 0.01, p = 0.01, respectively) and equivalent to manual chest compression (p = 0.2, p = 0.7, respectively) for sufficient coronary perfusion pressure levels. Conclusions: Optimal skeletal-based and cardiac-based electrical cardiopulmonary resuscitation pulse train parameters generated levels of coronary perfusion pressure significantly greater than ventricular fibrillation and comparable with manual chest compression over a short interval of untreated cardiac arrest.

Objective: Allogeneic bone marrow mesenchymal stem cells were previously shown to improve myocardial function when administered intravenously after resuscitation from cardiac arrest in rats. Coincidental evidence of improved brain function prompted the present study. Design: Prospective, randomized, controlled study. Setting: University-affiliated research institute. Subjects: Male Sprague-Dawley rats. Interventions: Using an established model in 20 male Sprague-Dawley rats in which 6 mins of untreated cardiac arrest was followed by cardiopulmonary resuscitation, animals were randomized to receive 5 x 10 6 mesenchymal stem cells labeled with PKH26 in phosphate buffer solution or phosphate buffer solution alone as a placebo at 2 hrs after restoration of spontaneous circulation. The stem cells or buffer diluent were injected into a catheter advanced from the jugular vein into the right atrium. Measurements and Main Results: Outcome measurements in addition to 35-day survival included somatosensor testing of capability for removal of an adhesive patch applied to both front paws, testing of motor function using a rotating cylinder, and observational scoring of the severity of neurologic impairment. Labeled mesenchymal stem cells were subsequently identified and counted in 5 μm sections obtained from defined sites in the harvested brain. Immunohistochemistry was used to identify neural cells differentiation of mesenchymal stem cells. Adhesive removal, motor function test, neurologic severity score, and 35-day survival were each significantly improved in comparison with control animals. Labeled mesenchymal stem cells were identified in the hippocampus, cortex, pons, medulla, and cerebellum and expressed protein markers phenotypic neural cells. Conclusions: Mesenchymal stem cells injected into the right atrium of rats after resuscitation from cardiac arrest were identified in brains harvested 35 days later. Brain function was significantly improved. Accordingly, venous injection of mesenchymal stem cells after cardiopulmonary resuscitation has promise of minimizing the severity of postresuscitation neurologic impairment.

Objectives Current automated external defibrillations require interruptions in chest compressions to avoid artifacts during electrocardiographic analyses and to minimize the risk of accidental delivery of an electric shock to the rescuer. The earlier three-shock algorithm, with prolonged interruptions of chest compressions, compromised outcomes and increased severity of postresuscitation myocardial dysfunction. In the present study, we investigated the effect of timing of minimal automated external defibrillation-mandated interruptions of chest compressions on cardiopulmonary resuscitation outcomes, using a single-shock algorithm. We hypothesized that an 8-sec interruption of chest compressions for a single shock, as mandated by automated external defibrillations, would not impair initial resuscitation and outcomes of cardiopulmonary resuscitation. Design Randomized prospective animal study. Setting University affiliated research laboratory. Subjects Domestic pigs. Measurements and main results In 24 domestic male pigs weighing 41 +/- 2 kg, ventricular fibrillation was induced by left anterior descending coronary artery occlusion and untreated for 7 min. Cardiopulmonary resuscitation, including chest compressions and ventilation with oxygen, was then performed for an interval of 2 min before attempted defibrillation. Animals were randomized into three groups: A) interruption immediately before defibrillation; B) interruption after 1 min of cardiopulmonary resuscitation; or C) no interruption. Chest compressions were delivered with the aid of a mechanical chest compressor at a rate of 100 compressions/min and compression/ventilation ratio of 30:2. Defibrillation was attempted with a single biphasic 150-J shock. Each animal was successfully resuscitated and survived for >72 hr. No differences in the number of shocks before return of spontaneous circulation, frequency of recurrent ventricular fibrillation, duration of cardiopulmonary resuscitation, and severity of postresuscitation myocardial dysfunction were observed. Conclusions In this experimental model of cardiac arrest and cardiopulmonary resuscitation, minimal automated external defibrillation-mandated interruption of chest compressions for a single-shock algorithm did not have adverse effects on postresuscitation myocardial or neurologic function. All animals, whether subjected to cardiopulmonary resuscitation interruptions or not, survived.

Summary Aim To examine changes in cerebral cortical macro- and microcirculation and their relationship to the severity of brain ischaemia during and following resuscitation from a short duration of cardiac arrest. Methods Bilateral cranial windows were created in eight domestic pigs weighing 41 ± 1 kg, exposing the frontoparietal cortex for orthogonal polarization spectral imaging together with estimation of cortical-tissue partial pressure of carbon dioxide, a quantitator of the severity of cerebral ischaemia. After 3 min of untreated ventricular fibrillation, cardiopulmonary resuscitation was begun and continued for 4 min before defibrillation. Aortic pressure, end-tidal and cortical-tissue partial pressure of carbon dioxide, and cortical microcirculatory blood flow in vessels of less and more than 20 μm in diameter were continuously measured. Results Cerebral microcirculatory blood flow progressively decreased over the 3-min interval that followed onset of ventricular fibrillation. Chest compression restored cortical microvascular flow to approximately 40% of the pre-arrest value. Following return of spontaneous circulation, microvascular flow velocity was restored to baseline values over 3 min. Reversal of cerebral ischaemia with normalisation of cerebral cortical-tissue partial pressure of carbon dioxide occurred over 7 min after resuscitation. Cortical microcirculatory blood flow in microvessels less than 20 μm was highly correlated with flow in vessels more than 20 μm together with mean aortic pressure and end-tidal partial pressure of carbon dioxide. Conclusion Cerebral cortical microcirculatory flow ceased only 3 min after onset of cardiac arrest. Flow was promptly restored to 40% of its pre-arrest value after start of chest compression. After resuscitation, both macro- and microcirculatory flows were fully restored over 3 min, but cerebral ischaemia reversed more slowly.

Summary Objectives To develop a clinically relevant experimental model of cardiac arrest and CPR in which a partial occlusion of the left anterior descending coronary artery (LAD) is maintained during the resuscitation procedure and the initial post-resuscitation interval. Materials and methods Ventricular fibrillation (VF) was induced by LAD occlusion with a balloon tipped catheter in 16 domestic male pigs weighing 41 ± 2 kg. After a 7 min interval of untreated VF, the LAD balloon occlusion was deflated and the catheter withdrawn in eight animals. The LAD balloon was deflated in the remaining eight animals but the catheter was kept in place in order to maintain a partial occlusion of the LAD, which was approximately 75% of the internal lumen. CPR, including chest compressions and ventilations with oxygen, was then performed for 2 min before a defibrillation attempt. Thirty minutes following successful resuscitation the LAD catheter was withdrawn in the animals with partial occlusion of the LAD. Results In the animals that had the LAD totally unoccluded before to starting CPR, each animal was resuscitated successfully and survived for more than 72 h with better neurological recovery during the initial 24 h post-resuscitation than did the partially occluded group. When a partial occlusion of the LAD was maintained during CPR, six of eight animals were resuscitated and only four of these survived for 72 h. A significantly greater number of electrical shocks prior to ROSC were required when a partial occlusion of the LAD was maintained during CPR. Significantly greater severity of post-resuscitation myocardial dysfunction was observed in animals resuscitated with a partial occlusion of the LAD. Conclusions In this model of prolonged untreated cardiac arrest, maintaining a partial occlusion of the LAD during CPR and the initial post-resuscitation interval required a greater number of shocks before ROSC, increased severity of post-resuscitation myocardial dysfunction significantly and yielded less favourable outcomes.

Our group has developed a rat model of cardiac arrest and cardiopulmonary resuscitation (CPR). However, the current rat model uses healthy adult animals. In an effort to more closely reproduce the event of cardiac arrest and CPR in humans with chronic coronary disease, a rat model of coronary artery constriction was investigated during cardiac arrest and CPR. Left coronary artery constriction was induced surgically in anesthetized, mechanically ventilated Sprague-Dawley rats. Echocardiography was used to measure global cardiac performance before surgery and 4 wk postsurgery. Coronary constriction provoked significant decreases in ejection fraction, increases in left ventricular end-diastolic volume, and increases left ventricular end-systolic volume at 4 wk postintervention, just before induction of ventricular fibrillation (VF). After 6 min of untreated VF, CPR was initiated on three groups: 1) coronary artery constriction group, 2) sham-operated group, and 3) control group (without preceding surgery). Defibrillation was attempted after 6 min of CPR. All the animals were resuscitated. Postresuscitation myocardial function as measured by rate of left ventricular pressure increase at 40 mmHg and the rate of left ventricular pressure decline was more significantly impaired and left ventricular end-diastolic pressure was greater in the coronary artery constriction group compared with the sham-operated group and the control group. There were no differences in the total shock energy required for successful resuscitation and duration of survival among the groups. In summary, this rat model of chronic myocardial ischemia was associated with ventricular remodeling and left ventricular myocardial dysfunction 4 wk postintervention and subsequently with severe postresuscitation myocardial dysfunction. This model would suggest further clinically relevant investigation on cardiac arrest and CPR.

Summary Objectives When ventricular fibrillation is cardioverted to pulseless electrical activity (PEA), PEA has been regarded as a non-resuscitatable rhythm. Yet, recent reports and our earlier observations suggested otherwise. We therefore investigated outcomes after postcountershock PEA, and aimed to develop a scoring system for outcome classification at the onset of initial postcountershock PEA. Methods Data from 215 domestic pigs were retrospectively reviewed. VF was induced and untreated for 7 min. Defibrillation was attempted with up to three 150 J biphasic shocks. Failing to restore spontaneous circulation (ROSC), 1 min of CPR preceded subsequent sequences of shocks until animals were resuscitated or for a total of 15 min. Fifty-nine instances of PEA followed defibrillation, including 29 animals that attained ROSC. Results ROSC animals required a shorter interval between the first shock and the initial postcountershock PEA, fewer shocks prior to onset of initial postcountershock PEA, demonstrated a greater VF wavelet amplitude prior to onset of initial PEA, smaller QRS intervals, and higher heart rates. Using Fisher's linear discriminant analysis, 79.3% of the ROSC and 63.3% of non-ROSC cases were predicted correctly. A total of 71.2% of all cases were classified correctly. Conclusions Animals in which postcountershock PEA was converted to ROSC required shorter intervals from first shock to initial postcountershock PEA, fewer shocks prior to onset of initial postcountershock PEA, had greater VF wavelet amplitude prior to initial postcountershock PEA, small QRS intervals, and higher heart rates. Fisher's discriminant analysis is helpful in predicting the likelihood of ROSC for an individual animal presenting with postcountershock PEA.

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.

Objective For adults, 150-J fixed-energy, impedance-compensating biphasic truncated exponential (ICBTE) shocks are now effectively used in automated defibrillators. However, the high energy levels delivered by adult automated defibrillators preclude their use for pediatric patients. Accordingly, we investigated a method by which adult automated defibrillators may be adapted to deliver a 50-J ICBTE shock for pediatric defibrillation. Design Prospective, randomized study. Setting A university-affiliated research institution. Subject Domestic piglets. Interventions We initially investigated four groups of anesthetized mechanically ventilated piglets weighing 3.8, 7.5, 15, and 25 kg. Ventricular fibrillation was induced with an AC current delivered to the right ventricular endocardium. After 7 mins of untreated ventricular fibrillation, a conventional manual defibrillator was used to deliver up to three 50-J ICBTE shocks. If ventricular fibrillation was not reversed, a 1-min interval of precordial compression preceded a second sequence of up to three shocks. The protocol was repeated until spontaneous circulation was restored, or for a total of 15 mins. In a second set of experiments, we evaluated a 150-J biphasic adult automated defibrillator that was operated in conjunction with energy-reducing electrodes such as to deliver 50-J shocks. The same resuscitation protocol was then exercised on piglets weighing 3.7, 13.5, and 24.2 kg. Measurements and main results All animals were successfully resuscitated. Postresuscitation hemodynamic and myocardial function quickly returned to baseline values in both experimental groups, and all animals survived. Conclusion An adaptation of a 150-J biphasic adult automated defibrillator in which energy-reducing electrodes delivered 50-J shocks successfully resuscitated animals ranging from 3.7 to 25 kg without compromise of postresuscitation myocardial function or survival.

Background: We hypothesized that cariporide, a sodium-hydrogen exchange inhibitor, would be as cardioprotective during the global myocardial ischemia of prolonged cardiac arrest as it is in settings of coronary occlusion. Methods and Results: Fifteen Sprague-Dawley rats were randomized to receive bolus injections of cariporide or placebo in a dose of 3 mg.kg-1 into the right atrium either 5 minutes before, or at 8 minutes after, onset of ventricular fibrillation. Ventricular fibrillation was electrically induced and untreated for 8 minutes. Precordial compression, together with mechanical ventilation, was then started and continued for an interval of 8 minutes prior to attempted resuscitation. All but one placebo-treated animal were successfully resuscitated. Spontaneous defibrillation with restoration of circulation was observed in both cariporide-pretreatment and post-treatment groups but in none of the placebo-treated animals. Postresuscitation cardiac index, end-tidal CO2, mean aortic pressure, left ventricular systolic pressure, left ventricular end-diastolic pressure, and left ventricular contractile and lusitropic functions (dP/dt40, and -dP/dt) were significantly less impaired after cariporide, especially in the pretreated group, compared to electrically defibrillated controls. Postresuscitation ventricular premature beats were significantly reduced after cariporide. The duration of postresuscitation survival was significantly increased in animals pretreated with cariporide. Conclusions: Cariporide, when administered prior to and during cardiac arrest, improved both the success of resuscitation and postresuscitation myocardial function.

Objectives We hypothesized that progressive impairment in diastolic function during cardiopulmonary resuscitation (CPR) precedes evolution of the "stone heart" after failure of CPR. We therefore measured sequential changes in left ventricular (LV) volumes and free-wall thickness of the heart during CPR in an experimental model. Design Prospective, observational animal study. Setting Medical research laboratory in an university-affiliated research and educational institute. Subjects Domestic pigs. Methods Ventricular fibrillation (VF) was induced in 40 anesthetized male domestic pigs weighing between 38 kg and 43 kg. After 4 min, 7 min, or 10 min of untreated VF, electrical defibrillation was attempted. Failing to reverse VF in each instance, precordial compression at a rate of 80/min was begun coincident with mechanical ventilation. Coronary perfusion pressures (CPPs) were computed from the differences in time-coincident diastolic aortic and right atrial pressures. Left ventricular (LV) systolic and diastolic ventricular volumes and thickness of the LV free wall were estimated with transesophageal echocardiography. The stroke volumes (SVs) were computed from the differences in decompression diastolic and compression systolic volumes. Free-wall thickness was measured on the hearts at autopsy. Results Significantly greater CPPs were generated with the 4 min of untreated cardiac arrest. Progressive reductions in LV diastolic and SV and increases in LV free-wall thickness were documented with increasing duration of untreated VF. A stone heart was confirmed at autopsy in each animal that failed resuscitative efforts. Correlations with indicator dilution method and physical measurements at autopsy corresponded closely with the echocardiographic measurements. Conclusion Progressive impairment in diastolic function terminates in a stone heart after prolonged intervals of cardiac arrest.

Background — Current versions of automated external defibrillators (AEDs) require frequent stopping of chest compression for rhythm analyses and capacity charging. The present study was undertaken to evaluate the effects of these interruptions during the operation of AEDs. Methods and Results — Ventricular fibrillation was electrically induced in 20 male domestic swine weighing between 37.5 and 43 kg that were untreated for 7 minutes before CPR was started. Defibrillation was attempted with up to 3 sequential 150-J biphasic shocks, but each was preceded by 3-, 10-, 15-, or 20-second interruptions of chest compression. The interruptions corresponded to those that were mandated by commercially marketed AEDs for rhythm analyses and capacitor charge. The sequence of up to 3 electrical shocks and delays were repeated at 1-minute intervals until the animals were successfully resuscitated or for a total of 15 minutes. Spontaneous circulation was restored in each of 5 animals in which precordial compression was delayed for 3 seconds before the delivery of the first and subsequent shocks but in none of the animals in which the delay was >15 seconds before the delivery of the first and subsequent shocks. Longer intervals of CPR interventions were required, and there was correspondingly greater failure of resuscitation in close relationship to increasing delays. The durations of interruptions were inversely related to the durations of subthreshold levels of coronary perfusion pressure. Postresuscitation arterial pressure and left ventricular ejection fraction were more severely impaired with increasing delays. Conclusions — Interruptions of precordial compression for rhythm analyses that exceed 15 seconds before each shock compromise the outcome of CPR and increase the severity of postresuscitation myocardial dysfunction.

Although myocardial dysfunction after resuscitation from ventricular fibrillation (VF) has been extensively investigated, less is known of the function of the myocardium after asphyxial cardiac arrest. The present experimental study was designed to compare postresuscitation left ventricular (LV) function after cardiac arrest caused by asphyxia with that of cardiac arrest induced by dysrhythmia. Four groups of Sprague-Dawley rats, which included eight animals in each group, were investigated. In the first two groups, cardiac arrest followed asphyxia produced by neuromuscular blockade with and without airway obstruction. In a third group, cardiac arrest was induced by electrical fibrillation of the ventricle. The fourth group represented animals in which the duration of asphyxial cardiac arrest was maintained for a time interval corresponding to that of the VF group. The fourth group received approximately the same number of electrical shocks as the third (VF) group. All animals were successfully resuscitated with precordial compression and mechanical ventilation. Postresuscitation measurements, including cardiac output, LV end-diastolic pressure (LVEDP), rate of pressure rise at LV pressure of 40 mm Hg (LV dP/dt40), and negative LV dP/dt, demonstrated decreased myocardial function in each group. No differences in cardiac function were observed between the animals with primary respiratory arrest whether or not the airway was obstructed. However, disproportionate and consistently greater impairment in myocardial function followed primary cardiac arrest due to VF when compared with equal duration of asphyxial cardiac arrest. We conclude that in this healthy animal model, asphyxial cardiac arrest resulted in significantly lesser impairment of postresuscitation myocardial function when compared with cardiac arrest caused by VF.

To the Editor: In cardiac arrest, systemic hypothermia initiated after resuscitation has been shown to improve survival and long-term neurologic outcome ([1,2][1]). Systemic hypothermia established before cardiac arrest improved the defibrillation success and resuscitation outcome in a porcine model

Post-resuscitation syndrome has been recognized as one of the major causes of the poor outcomes of cardiopulmonary resuscitation. The aims of this study were to investigate the intestinal microcirculatory changes following cardiopulmonary resuscitation and relate those changes to sublingual microcirculation and the severity of post-resuscitation syndrome as measured by myocardial function and serum inflammatory cytokine levels.Twenty-five rats were randomized into three groups: (1) short duration of cardiac arrest (n=10): ventricular fibrillation (VF) was untreated for 4 min prior to 6 min of cardiopulmonary resuscitation (CPR); (2) long duration of cardiac arrest (n=10): VF was untreated for 8 min followed by 8 min of CPR; (3) sham control group (n=5): a sham operation was performed without VF induction and CPR. Intestinal and sublingual microcirculatory blood flow was visualized by a sidestream dark-field (SDF) imaging device at baseline and 1, 2, 4, 6, 8 h post-resuscitation. Myocardial function was measured by echocardiography and serum cytokine levels (TNF-α and IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).Both intestinal and sublingual microcirculatory blood flow decreased significantly with increasing duration of cardiac arrest and resuscitation. The decreases in intestinal microcirculatory blood flow were closely correlated with the reductions of sublingual microcirculatory blood flow (perfused small vessels density: r=0.772, p0.01; microcirculatory flow index: r=0.821, p0.01). The decreased microcirculatory blood flow was closely correlated with weakened myocardial function and elevated inflammatory cytokine levels.The severity of post-resuscitation intestinal microcirculatory dysfunction is closely correlated with that of myocardial function and inflammatory cytokine levels. The measurement of sublingual microcirculation reflects changes of intestinal microcirculation and may therefore provide a new option for post-resuscitation monitoring.

Objective One of the major goals of cardiopulmonary resuscitation (CPR) is to provide adequate oxygen delivery to the brain for minimizing cerebral injury resulted from cardiac arrest. The optimal chest compression during CPR should effectively improve brain perfusion without compromising intracranial pressure (ICP). Our previous study has demonstrated that the miniaturized mechanical chest compressor improved hemodynamic efficacy and the success of CPR. In the present study, we investigated the effects of the miniaturized chest compressor (MCC) on calculated cerebral perfusion pressure (CerPP) and ICP. Methods Ventricular fibrillation was electrically induced and untreated for 7 min in 13 male domestic pigs weighing 39 ± 3 kg. The animals were randomized to receive mechanical chest compression with the MCC (n = 7), or the Thumper device (n = 6). CPR was performed for 5 min before defibrillation attempt by a single 150 J shock. At 2.5 min of CPR, the epinephrine at a dose of 20 μg/kg was administered. Additional epinephrine was administered at an interval of 3 min thereafter. If resuscitation was not successful, CPR was resumed for an additional 2 min prior to the next defibrillation until successful resuscitation or for a total of 15 min. Post-resuscitated animals were observed for 2 h. Results Significantly greater intrathoracic positive and negative pressures during compression and decompression phases of CPR were observed with the MCC when compared with the Thumper device. The MCC produced significantly greater coronary perfusion pressure and end-tidal carbon dioxide. There were no statistically significant differences in systolic and mean ICP between the two groups; however, both of the measurements were slightly greater in the MCC treated animals. Interestingly, the diastolic ICP was significantly lower in the MCC group, which was closely related to the significantly lower negative intrathoracic pressure in the animals that received the MCC. Most important, systolic, diastolic and mean calculated CerPP were all significantly greater in the animals receiving the MCC. Conclusions In the present study, mechanical chest compression with the MCC significantly improved calculated CerPP but did not compromise ICP during CPR. It may provide a safe and effective chest compression during CPR. Protocol number: P1205.

OBJECTIVES: To measure stroke volumes coincident with spontaneous gasping during untreated ventricular fibrillation and to evaluate the effects of gasping. DESIGN: Prospective study in laboratory animals. SETTING: University-affiliated research institute. SUBJECTS: Male Yorkshire-X domestic pigs. INTERVENTIONS: Pigs were anesthetized (ketamine, 20 mg/kg intramuscularly and sodium pentobarbital, 30 mg/kg intravenously), intubated, and mechanically ventilated. Ventricular fibrillation was electrically induced and untreated for 7 mins. The right femoral artery and vein were cannulated. A 5.5/7.5-MHz biplanar transesophageal echocardiography transducer was advanced into the esophagus. MEASUREMENTS AND MAIN RESULTS: Stroke volumes were measured as the product of the transaortic blood flow velocity and transesophageal echocardiographic measurements of valve area. In addition, left ventricular volumes were echocardiographically estimated at peak inspiration and at peak expiration of each gasp by transesophageal methods. The stroke volume produced by gasping averaged 23 +/- 6 mL, which represented approximately 60% of a precardiac arrest stroke volume (38 +/- 8 mL, p

Sudden cardiac arrest is the main manifestation of ischemic heart diseases, which is the leading cause of death worldwide. Each year an estimated 300,000 people suffer from cardiac arrest in the United States, with a variable incidence ranging from 36/100,000 to 128/100,000. Approximately 7.9% of cardiac arrest victims survive to hospital discharge in the United States, whereas fewer than half of patients dmitted to hospital achieve a favorable outcome. Permanent severe brain damage ccounts for the high mortality after successful resuscitation in the hospital. Mild hypothermia, defined here as a reduction of core temperature to 32°C to 34°C, s the only proven therapy to improve survival and neurologic outcome after sudden ardiac arrest in clinical trials, and recommended by the American Heart Association AHA) as the routine intervention for selected comatose adult victims of witnessed ut-of-hospital cardiac arrest. This article addresses the mechanism of neurorotection, phases of hypothermia, and cooling methods.

This study was to investigate whether optimal duration of CPR prior to defibrillation could be guided by Amplitude Spectrum Analysis (AMSA) in the setting of prolonged VF on outcome of CPR.VF was induced in thirty Sprague-Dawley rats and untreated for 8 minutes. Animals were then randomized into 3 groups prior to CPR: The duration of CPR prior to defibrillation was guided by AMSA (CC+AMSA); guidelines-based with delayed defibrillation that simulated the AED algorithm (GL+AED); and guidelines-based with immediate shock (GL+shock ready).Regardless of groups, the majority of the animals (85%) required over 5 min of CPR to achieve restoration of spontaneous circulation (ROSC). Significantly greater rate of ROSC after first defibrillation (70% vs 0%, p0.01), lesser CPR interruptions and the number of defibrillations were observed in the CC+AMSA group when compared to both guidelines-based groups (p0.001). This was associated with a significantly better post-resuscitation myocardial and neurological function and longer durations of survival.After prolonged VF, optimal duration of CPR prior to defibrillation guided by AMSA improves the outcome of CPR.

Aim of Study: The quality of cardiopulmonary resuscitation (CPR) is an important factor in the outcome of cardiac arrest. Our objective was to compare outcomes following either immediate low-quality (LQ) CPR or delayed high-quality (HQ) CPR. We hypothesized that delayed HQ CPR will improve the outcomes of CPR in comparison to immediately performing LQ CPR. Methods: Eighteen Sprague-Dawley rats were randomized into two groups: (1) Delayed HQ CPR (HQ group, n = 9). (2) Immediate LQ CPR (LQ group, n = 9). Ventricular fibrillation (VF) was induced and untreated for 8 mins. CPR was immediately performed in LQ group for 5 mins. Compression depth was set at 70% of the “optimal compression depth”. VF was untreated for an additional 5 mins in HQ group. HQ CPR was started together with ventilation (100% oxygen) and external hypothermia for 8 mins in both groups. The “optimal compression depth” was approximately 30% of the anteroposterior chest diameter. Epinephrine was administrated 3 mins prior to defibrillation attempt. Restoration of spontaneous circulation, postresuscitation myocardial function and survival time were monitored. Results: All animals in the LQ group and 7 of 9 animals in the HQ group were resuscitated. Myocardial function, including ejection fraction and cardiac output was better in the LQ group than in the HQ group (p < 0.05) and survival time was longer in the LQ group (p < 0.05). Conclusion: The outcomes after immediate LQ CPR, were better than those after delayed HQ CPR in this rat model of cardiac arrest and resuscitation.

It is widely held that mechanical ventilation is essential for cardiopulmonary resuscitation (CPR). However, cardiac output and therefore pulmonary blood flow is reduced to less than one-third of normal during CPR. We therefore reasoned that ventilatory requirements are correspondingly reduced and postulated that gas exchange may be maintained during precordial compression with oxygen passively delivered to the airway in the absence of mechanical ventilation. After tracheal intubation, Sprague-Dawley rats were randomized. Fifteen animals were maintained on positive-pressure ventilation with room air and an additional 15 animals breathed spontaneously. Cardiac arrest was induced by electrical fibrillation. The inspired gas concentration of oxygen was then increased to 100% in both groups. Precordial compression was begun after 4 min of untreated ventricular fibrillation. After an additional 6 min of precordial compression, resuscitation was attempted by DC countershock. During cardiac resuscitation, there were no significant differences in coronary perfusion pressure between mechanically ventilated and spontaneously breathing animals, but arterial PO2 was significantly lower and arterial PCO2 was significantly higher in the absence of positive-pressure ventilation. However, neither resuscitability nor 24-h survival were affected. Postresuscitation myocardial contractility, reflected in the maximally generated dP/dt40, was also not adversely affected. In the unventilated group, only resuscitated animals developed spontaneous gaspings at an average frequency of 17 +/- 2/min-1. The current emphasis on mechanical ventilation as the highest priority for cardiopulmonary resuscitation is therefore not fully supported under the experimental conditions of this study.

Background— Current studies have demonstrated that applying therapeutic hypothermia for 12 to 24 hours after resuscitation from cardiac arrest improves the outcomes of cardiopulmonary resuscitation. The present study investigated whether a shorter duration of therapeutic hypothermia induced quickly and early after resuscitation would provide an equal improvement in the outcomes of cardiopulmonary resuscitation. Methods and Results— Ventricular fibrillation was induced and untreated for 8 minutes in 24 male Sprague-Dawley rats. Defibrillation was attempted after 8 minutes of cardiopulmonary resuscitation. Seven minutes after resuscitation, animals were randomized into 4 groups (n=6 each): normothermic, hypothermic–2 hours, hypothermic–5 hours, and hypothermic–8 hours. Animals in the hypothermic groups received rapid cooling, which was started 7 minutes after restoration of spontaneous circulation and maintained at 33±0.5°C for 2, 5, or 8 hours. Normothermic animals were maintained at 37±0.2°C. All animals were anesthetized and ventilated for 8 hours after resuscitation. Blood temperature was significantly decreased in the hypothermic groups. Postresuscitation myocardial function, neurological deficit scores, and 72-hour survival were significantly better in animals treated with hypothermia regardless of the duration of cooling. However, significantly better postresuscitation tissue microcirculation, myocardial ejection fraction, and neurological deficit scores were observed in the hypothermic–2 hours animals. Conclusions— In a rat model of cardiopulmonary resuscitation, a shorter duration of mild hypothermia induced rapidly and early after restoration of spontaneous circulation improved postresuscitation microcirculation, myocardial and cerebral functions, and survival as well as, or better than, prolonged duration of hypothermia after resuscitation.

Aim The nonselective Cannabinoid (CB) receptor agonist, WIN55, 212-2, was demonstrated to induce hypothermia and improve post-resuscitation outcomes in a rat post-cardiac arrest model. The present study was to explore the potential mechanisms of WIN55, 212-2 on thermoregulation following resuscitation and to investigate which class of CB receptors was involved in WIN55, 212-2-induced hypothermia. Methods Ventricular fibrillation (VF) was induced and untreated for 6 min in 20 male Sprague-Dawley rats. Defibrillation was attempted after 8 min of Cardiopulmonary resuscitation (CPR). Five min post-resuscitation, resuscitated animals were randomized to receive an intramuscular injection of selective CB1 receptors antagonist, SR141716A (5 mg kg −1 ); selective CB2 receptors antagonist SR144528 (5 mg kg −1 ); or placebo. Thirty min after injection, animals received continuous intravenous infusion of WIN55, 212-2 (1.0 mg kg −1 h −1 ) for 4 h while control animals received placebo. The identical temperature environment was maintained in all animals. Results In animals treated with WIN55, 212-2, blood temperatures decreased progressively from 37 °C to 34 °C within 4 h. This hypothermic effect was completely blocked by CB1 but not CB2 antagonist. Accordingly, significantly better cardiac output, ejection fraction and myocardial performance index, reduced neurological deficit scores, improved microcirculation and longer duration of survival were observed in WIN55, 212-2-treated animals, which were also completely abolished by pretreatment with CB1 antagonist. Conclusions Pharmacologically induced hypothermia with WIN55, 212-2 improved post-resuscitation myocardial and cerebral function, associated with a significantly increased duration of survival in a rat post-cardiac arrest model. The hypothermic and resulted beneficial effects of WIN55, 212-2 were mediated through CB1 receptors.

Objectives Though there is evidence to implicate that the mitochondrion may play an important role in the development of postresuscitation myocardial dysfunction, limited data are available regarding the ultrastructural alterations of the mitochondria, mitochondrial energy-producing ability, and their relationship to postresuscitation myocardial dysfunction. This study was designed to determine whether mitochondrial abnormalities contribute to the development of postresuscitation myocardial dysfunction. Methods Fifteen anesthetized male Sprague-Dawley rats were randomized to: (1) global myocardial ischemia/reperfusion, in which 8 min of ventricular fibrillation was induced and successful defibrillation was achieved after 6 min of cardiopulmonary resuscitation (CPR); (2) global myocardial ischemia, in which ventricular fibrillation and CPR were performed without defibrillation attempt; and (3) sham control. Results Myocardial function was significantly impaired after resuscitation. Mitochondria were massively swollen in global ischemic hearts and mildly swollen in the resuscitated hearts. Concomitantly, ATP levels abruptly declined during global ischemia and partially recovered after resuscitation. Furthermore, mitochondrial abnormalities were supported by the incapability of utilizing energy substrates manifested by the accumulations of intramyocellular lipid droplets and glycogen deposits. Conclusions In this model of cardiac arrest and CPR, the presence of ultrastructural mitochondrial abnormalities, further evidenced by the incapability of utilizing energy substrates and impairment of energy-production, might, in part, contribute to the development of postresuscitation myocardial dysfunction.

To investigate left ventricular function by the Langendorff method after successful cardiac resuscitation in rats.Prospective, randomized, controlled animal study.University research laboratory.Adult, male Sprague-Dawley rats.Myocardial function was investigated in three subsets of isolated, perfused rat hearts that were harvested either before inducing ventricular fibrillation (controls) or at defined intervals after successful resuscitation from ventricular fibrillation. Ventricular fibrillation was induced with an electrode catheter advanced into the right ventricle of 15 mature, mechanically ventilated Sprague-Dawley rats. After an interval of 4 mins of untreated ventricular fibrillation and an additional 5 mins of precordial compression, spontaneous circulation was restored by a direct current, transthoracic countershock. The heart of each animal was then harvested at either 2 or 20 mins after successful cardiac resuscitation. The same model was utilized for harvesting the controls. Animals were randomized to each of the three subsets immediately before induction of cardiac arrest.There was a progressive decrease in myocardial contractility of the isolated, perfused hearts. Mean left ventricular systolic pressure was 128 +/- 8 mm Hg in control animals. In hearts harvested at 2 mins after successful resuscitation, the maximal generated pressure was reduced to 106 +/- 9 mm Hg. When harvested at 20 mins after successful resuscitation, it was reduced to 81 +/- 11 mm Hg. There were corresponding decreases in the mean maximal rate of left ventricular pressure increase (dP/dtmax) from 2880 +/- 110 to 2470 +/- 120 mm Hg/sec at 2 mins and to 1810 +/- 135 mm Hg/sec at 20 mins. These decreases in contractility were associated with striking decreases in myocardial relaxation and compliance.These studies, therefore, document progressive systolic and diastolic myocardial dysfunction immediately after successful cardiac resuscitation with restoration of spontaneous circulation.

Aim of study In the present study, we investigated trans-nasal cooling in settings of pulseless electrical activity (PEA). We hypothesized that early trans-nasal cooling during CPR improves outcomes when cardiac arrest is associated with PEA. Methods Ventricular fibrillation (VF) was electrically induced in 16 domestic male pigs weighing 40±3kg. After 14min of untreated VF, PEA was induced following delivery of one or more electrical shocks. One min after onset of PEA, CPR was started, including chest compression and ventilation. Each animal received 5min of CPR prior to defibrillation attempt. CPR and resuscitation efforts were discontinued at 15min unless return to spontaneous circulation was achieved. In 8 animals, selective trans-nasal cooling was begun coincident with start of CPR and 8 randomized controls were identically treated except for trans-nasal cooling. Mean aortic pressure was continuously measured together with aortic and right atrial pressure and nasal, body and right jugular vein temperatures. Coronary perfusion pressure (CPP) was computed from measured data. Results Six of eight animals were resuscitated after early trans-nasal cooling, while only one untreated control was resuscitated ( p =0.012). Nasal, body and jugular vein temperatures decreased after cooling. At PC (precordial compression) 5min, the cooled group recorded a higher CPP (25±5mmHg) than the non-cooled group (15±4mmHg, p =0.001). Conclusion When selective trans-nasal cooling was initiated during CPR in the animal model of prolonged cardiac arrest with PEA, CPP was higher and the likelihood of return of spontaneous circulation was improved.

Objective: To compare resuscitation outcomes and myocardial function among intra-arrest head cooling, delayed surface cooling, and uncooled controls. Design: Prospective animal study. Setting: University-affiliated animal research laboratory. Subjects: Twenty-four male domestic pigs. Interventions: Ventricular fibrillation remained untreated for 10 mins after which animals were assigned into three groups: 1) intra-arrest head cooling, 2) postresuscitation surface cooling, and 3) uncooled controls. Head cooling by evaporative perfluorochemical began coincident with the start of cardiopulmonary resuscitation and continued for a total of 4 hrs. Surface cooling using a cooling blanket began at 2 hrs after return of spontaneous circulation and continued for 8 hrs. Control animals were treated identically with the exception for cooling. Measurements and Main Results: Return of spontaneous circulation was achieved in eight of eight head-cooled animals, in seven of eight surface-cooled animals, and in seven of eight of controls. Myocardial functions measured by transthoracic echocardiography were significantly better in the head-cooled animals than in surface-cooled and controls. All head-cooled animals survived for more than 96 hrs. This contrasted with six of eight survivors after surface cooling, and only two of eight among controls. Conclusions: Both intra-arrest head cooling and delayed surface cooling improved postresuscitation myocardial dysfunction. The beneficial effects were greatest with head cooling initiated with cardiopulmonary resuscitation.

Objective: Employing transnasal head-cooling in a pig model of prolonged ventricular fibrillation, we compared the effects of 4 hrs of head-cooling started during cardiopulmonary resuscitation with those of 8 hrs of surface-cooling started at 2 hrs after resuscitation on 96-hr survival and neurologic outcomes. Design: Prospective controlled animal study. Setting: University-affiliated research laboratory. Subjects: Domestic pigs. Interventions: Twenty-four male pigs were subjected to 10 min of untreated ventricular fibrillation followed by 5 min of cardiopulmonary resuscitation. In the head-cooling group, hypothermia was started with cardiopulmonary resuscitation and continued for 4 hrs after resuscitation. In the surface-cooling group, systemic hypothermia with a cooling blanket was started, in accord with current clinical practices, at 2 hrs after resuscitation and continued for 8 hrs. Methods in the control animal studies were identical except for temperature interventions. Measurements and Main Results: All animals were resuscitated except for one animal in each of the surface-cooling and control groups. After 5 min of cardiopulmonary resuscitation, jugular vein temperature was significantly decreased in the head-cooled animals. However, there were no differences in pulmonary artery temperatures among the three groups at that time. Nevertheless, both head-cooled and surface-cooled animals had an improved 96-hr survival after resuscitation. Significantly better neurologic outcomes were observed in early head-cooled animals in the first 3 days after resuscitation. Conclusion: Early head-cooling during cardiopulmonary resuscitation continuing for 4 hrs after resuscitation produced favorable survival and neurologic outcomes in comparison with delayed surface-cooling of 8 hrs duration.

OBJECTIVE To investigate the presence of apoptosis after the global myocardial ischemia of cardiopulmonary resuscitation and the regional myocardial ischemia after left anterior descending coronary artery occlusion and relate it to the severity of postresuscitation myocardial dysfunction. DESIGN Prospective animal study. SETTING University-affiliated animal research laboratory. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Fifteen male Sprague-Dawley rats weighing 450-550 g were randomized to: (1) 8 mins of untreated cardiac arrest followed by 6 mins of cardiopulmonary resuscitation; (2)left anterior descending coronary artery occlusion for 45 mins followed by 4 hrs of reperfusion; and (3) left anterior descending coronary artery sham group. Cardiac functions, including ejection fraction, analog differentiation of left ventricular pressure at 40 mm Hg, and rate of maximal left ventricular pressure decline were continuously measured for 4 hrs. The hearts were then harvested for the terminal transferase-mediated 2'-deoxyuridine, 5'-triphosphate nick end-labeling assay analysis. MEASUREMENTS AND MAIN RESULTS Myocardial function was significantly impaired after resuscitation from cardiac arrest and reperfusion from left anterior descending coronary artery occlusion(p < .01). There was no difference in the percentage of apoptotic cells between the cardiopulmonary resuscitation animals and sham-operated animals. Fewer apoptotic cells were observed in cardiac arrest/cardiopulmonary resuscitation animals in comparison to left anterior descending coronary artery occlusion animals (p < .05), even though myocardial function was more severely impaired after resuscitation (p < .01). CONCLUSIONS Myocardial function was significantly impaired after cardiac arrest/cardiopulmonary resuscitation and ischemia/reperfusion. However, apoptosis was not involved in the mechanism of postresuscitation myocardial dysfunction in this setting.

OBJECTIVE We have previously demonstrated that nasopharyngeal cooling initiated during cardiopulmonary resuscitation improves the success of resuscitation. In this study, we compared the effects of nasopharyngeal cooling with cold saline infusion initiated during cardiopulmonary resuscitation on resuscitation outcome in a porcine model of prolonged cardiac arrest. We hypothesized that nasopharyngeal cooling initiated during cardiopulmonary resuscitation would yield better resuscitation outcome when compared with cold saline infusion. DESIGN Randomized, prospective animal study. SETTING University-affiliated research laboratory. SUBJECTS Yorkshire-X domestic pigs (Sus scrofa). INTERVENTIONS Ventricular fibrillation was induced in 14 pigs weighing 38 +/- 2 kg. After 15 mins of untreated ventricular fibrillation, cardiopulmonary resuscitation was performed for 5 mins before defibrillation. Coincident with the start of cardiopulmonary resuscitation, animals were randomly assigned to receive nasopharyngeal cooling with the aid of the RhinoChill Device (BeneChill, San Diego, CA) or cold saline infusion with 30 mL/kg 4 degrees C saline. One hour after restoration of spontaneous circulation, surface cooling was begun with the aid of a water blanket in both groups and maintained for 4 hrs. MEASUREMENTS AND MAIN RESULTS Jugular vein temperature significantly decreased in animals subjected to nasopharyngeal cooling in comparison with those receiving cold saline infusion (p < .01). Core temperature, however, decreased only in animals receiving cold saline infusion (p < .01). Coronary perfusion pressure was significantly higher in the animals treated with nasopharyngeal cooling (p = .02). All seven animals treated with nasopharyngeal cooling were successfully resuscitated in contrast to only two animals resuscitated in the cold saline infusion group (p = .02). CONCLUSION In this model, nasopharyngeal cooling initiated during cardiopulmonary resuscitation improved the success of resuscitation compared to cooling with cold saline infusion.

Both clinical and experimental studies have demonstrated substantial impairment of ventricular function after resuscitation from cardiac arrest. Indeed, postresuscitation myocardial dysfunction has been implicated as a potentially important mechanism, accounting for fatal outcomes after successful resuscitation in 70% of victims within the first 72 hrs. Recent experimental studies implicated the total electrical energy delivered during defibrillation as an important correlate with the severity of postresuscitation myocardial dysfunction and postresuscitation survival. This prompted us to investigate the option of using lower electrical energy biphasic waveform defibrillation. We compared the effects of low-energy biphasic waveform defibrillation with conventional monophasic waveform defibrillation after a short (4 mins), intermediate (7 mins), or prolonged (10 mins) interval of untreated ventricular fibrillation. Biphasic waveform defibrillation with a fixed energy of 150 joules proved to be as effective as conventional monophasic damped sine waveform defibrillation for restoration of spontaneous circulation, with significantly lower delivered energy. This was associated with significantly less severity of postresuscitation myocardial dysfunction. The low-energy biphasic waveform defibrillation is, therefore, likely to be the future direction of transthoracic defibrillation in settings of cardiopulmonary resuscitation.

Summary Objectives Coincident with "agonal" gasping during cardiac arrest, there are prominent increases in stroke volumes even in the absence of chest compression. In the present study, we tested the hypothesis that gasps also increase carotid blood flow (CBF) during untreated cardiac arrest. Materials and methods The tracheas of nine domestic male pigs, weighing 39±2kg, were intubated and animals were ventilated mechanically. Ventricular fibrillation (VF) was induced electrically and untreated for 5min. Coincident with the onset of VF, mechanical ventilation was discontinued. The right femoral artery and vein were cannulated. Intrathoracic pressure (ITP) was measured with the aid of a balloon tipped catheter advanced into the esophagus for a distance of 35cm. A transonic flowprobe was placed around the right common carotid artery for measurement of CBF. Results Gasps increased in frequency during the first 4min of untreated VF together with increases in CBF. The CBF produced by gasping averaged 220±102mL/min, which represented approximately 59% of a pre-cardiac arrest CBF. Significant increases in CBF were highly correlated with the decreases in ITP during the inspiratory phase of the gaspings ( r =0.78) and with the increases in aortic pressure during the expiratory phase of the gaspings ( r =0.76). Conclusions Spontaneous gasps produce significant increases in CBF during untreated cardiac arrest. The present study therefore confirmed beneficial effects of gasping during cardiac arrest.

Interruptions in cardiopulmonary resuscitation (CPR), particularly as guided by automated external defibrillators, have been implicated in poor survival from cardiac arrest. Interruptions of CPR may be reduced by eliminating repetition of shocks between periods of CPR, elimination of the interval for patient assessment before CPR, and extension of the periods of CPR.The effects of exclusion of a 30s post-shock assessment interval prior to CPR and use of a longer interval (180s versus 90s) of CPR on resuscitation and post-resuscitation function were assessed in a factorial design using an established swine model of cardiac arrest. Repetitive shocks were excluded. Ventricular fibrillation was induced ischemically and maintained untreated for 5min.All subjects were resuscitated, 95% survived 3 days, and 97% of survivors had full neurological recovery. Exclusion of the assessment interval reduced the delay to first return of spontaneous circulation by 33.1s (P=0.004) and the delay to sustained resuscitation by 99.2s (P=0.004), reduced post-resuscitation ECG ST elevation by 0.12mV (P=0.03), and alleviated transient post-resuscitation ejection fraction reduction (P0.0001). Extension of the CPR interval reduced transient post-resuscitation fractional area change impairment (P=0.003).Exclusion of an interval for assessment of airway, breathing and signs of circulation mitigates post-resuscitation dysfunction in a swine model of cardiac arrest. Extension of the period of CPR independently provides measurable, though less comprehensive, mitigation as well.

Objectives: 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 δ-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 δ-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. Design: Prospective, controlled laboratory study. Setting: University-affiliated research laboratory. Interventions: In the series of studies performed in the established rat and pig model of cardiac arrest and cardiopulmonary resuscitation, the δ-opioid receptor agonist, pentazocine, was administered during ventricular fibrillation. Measurements and Main Results: The myocardial metabolism reflected by the concentration of lactate, or myocardial tissue Pco 2 and Po 2 cardiopulmonary resuscitation. These are associated with less severe postresuscitation myocardial dysfunction and longer duration of postresuscitation survival. Conclusions: δ-Opioid-induced pharmacologic myocardial hibernation is an option to minimize the myocardial ischemia and reperfusion injury during cardiac arrest and cardiopulmonary resuscitation. (Crit Care Med 2006; 34[Suppl.]:S486-S489)

Summary Aim of study After cardiac arrest, uninterrupted chest compressions with restoration of myocardial blood flow facilitates restoration of spontaneous circulation. We recognized that this may best be accomplished with a mechanical device and especially so during transport. We therefore sought to develop a lightweight, portable chest compressor which may be carried on the belt or attached to the oxygen tank typically carried on the back of the first response rescuer. A miniaturized pneumatic chest compressor (MCC) weighing less than 2kg was developed and compared with a currently marketed "Michigan Thumper ® ", which weighed 19kg. We hypothesized that the 2kg, low profile, portable device will be as effective as the standard pneumatic Thumper ® for restoring circulation during CPR. Material and methods Ventricular fibrillation was electrically induced in 10 domestic male pigs weighing 39±2kg, and untreated for 5min. Animals were then randomized to receive chest compressions with either the MCC or the Thumper ® . After 5min of mechanical chest compression, defibrillation was attempted with a 150J biphasic shock. Coronary perfusion pressure (CPP) and end tidal PCO 2 (EtPCO 2 ) were measured by conventional techniques together with right carotid artery blood flow (CBF). Results Four of five animals compressed with the Thumper ® and each animal compressed with the MCC were successfully resuscitated. No significant differences in CPP, EtPCO 2 , CBF and post-resuscitation myocardial function were observed between groups. Resuscitated animals survived for more than 72h without neurological impairment. Conclusion The low profile, 2kg miniaturized chest compressor is as effective as the conventional Thumper ® in an experimental model of CPR.

Background— The success of resuscitation with a 1-shock versus the conventional 3-shock defibrillation protocol was investigated subject to the range of treatment variation imposed by automated external defibrillators (AEDs). Methods and Results— Ventricular fibrillation was induced in 44 domestic pigs. After 7 minutes of untreated VF, animals were randomized among 4 groups representing all combinations of the 1- versus 3-shock protocol and 2 different AED regimens (AED1, AED2). Because few AEDs support a 1-shock protocol, manual defibrillators were used to replicate the AED treatment regimen: electrical waveform, dose sequence, and cardiopulmonary resuscitation (CPR) interruption intervals. Initial shock(s) were delivered, followed by 60 seconds of CPR, and the treatment was repeated until resuscitation was successful or for 15 minutes. The 1-shock protocol was associated with improved outcome, reducing CPR interruptions from 45% to 34% of total resuscitation time ( P =0.019) and increasing survival from 64% to 100% ( P =0.004). Survival was 91% for AED1 versus 36% for AED2 ( P =0.024) with a 3-shock protocol but was increased to 100% for both by adoption of a 1-shock protocol. Improvements in postresuscitation left ventricular ejection fraction and stroke volume were observed with AED1 compared with AED2 (difference of means, 15% and 28% of baseline respectively, P Conclusions— Adoption of a 1-shock versus a 3-shock resuscitation protocol improved survival and minimized outcome differences imposed by variations in AED design and implementation. When a conventional 3-shock defibrillation protocol was used, however, the choice of AED had a significant impact on resuscitation outcome.

The science and technology of CPR is only just emerging from its infancy. However, substantial improvements are anticipated, including the ability of lay rescuers to identify cardiac arrest promptly, the availability of additional measurements, and expanded intelligence provided by expanded AEDs with which to more effectively prompt the rescuer through the resuscitation procedure. Most important in our view is the ability to maintain uninterrupted precordial compression. Better timing and better waveforms for defibrillation are emerging. The recognition of the importance of postresuscitation myocardial dysfunction and the selection of better vasopressor agents to minimize the adverse inotropic and chronotropic actions of adrenergic drugs are also likely to improve outcomes of CPR.

Introduction: Earlier studies have implicated the adverse effects of β- and α1-adrenergic receptors during cardiopulmonary resuscitation (CPR). Because carvedilol is both a nonselective β- and α1-selective adrenergic receptor-blocking agent, we hypothesized that pre-treatment with carvedilol would convert the actions of epinephrine to that of a selective a2-agonist. Methods: Ventricular fibrillation (VF) was induced in Sprague-Dawley rats weighing approximately 500 g. Animals were randomized to 4 groups of 5 animals each: (1) placebo pretreatment and epinephrine treatment, (2) carvedilol pretreatment and placebo treatment, (3) carvedilol pretreatment and epinephrine treatment, and (4) placebo pretreatment and placebo treatment. Carvedilol (50 µg/kg) was injected as a bolus into the right atrium 15 minutes before VF was induced. VF was untreated for 8 minutes, after which CPR (chest compression and mechanical ventilation) was begun. Epinephrine (30 µg/kg) was injected into the right atrium 2 minutes after the start of CPR. Electrical defibrillation was attempted after 14 minutes of VF. Results: All but 2 animals were successfully resuscitated. Approximately equivalent increases in coronary perfusion pressure from 23 ± 1 mm Hg to 30 ± 3 mm Hg were observed after the injection of epinephrine independently of carvedilol pretreatment. Carvedilol pretreatment followed by epinephrine treatment reduced early postresuscitation ventricular ectopy (116 ± 147 vs 834 ± 380, P < .01) and minimized increases in arterial blood lactate at 5 minutes after resuscitation (10.9 ± 2.1 mmol/L vs 17.4 ± 3.5 mmol/L, P < .01). The postresuscitation cardiac index measured 4 hours later was increased (307 ± 43 mL • min-1• kg-1 vs 210 ±6 mL • min-1• kg-1, P Conclusion: After β- and α1-adrenergic blockade with carvedilol before inducing cardiac arrest, epinephrine administered during CPR yielded better postresuscitation myocardial and neurologic functions and significantly increased postresuscitation survival.

Objective: To investigate the effects of levosimendan, a nonadrenergic inotropic calcium sensitizer, in comparison with adrenergic dobutamine for the management of postresuscitation myocardial dysfunction following resuscitation from prolonged cardiac arrest. Design: Randomized prospective animal study. Setting: Animal research laboratory. Subjects: Male Yorkshire-cross domestic pigs Interventions: Ventricular fibrillation was induced in male domestic pigs weighing between 35 and 40 kg. Cardiopulmonary resuscitation, including precordial compression and mechanical ventilation, was started after 7 mins of untreated cardiac arrest Electrical defibrillation was attempted after 5 mins of cardiopulmonary resuscitation. Each animal was successfully resuscitated without pharmacologic intervention. Resuscitated animals were randomized to treatment with levosimendan, dobutamine, or saline placebo. The inotropic agents or an equivalent volume of placebo diluents was administered 10 mins after restoration of spontaneous circulation. Levosimendan was administered in a loading dose of 20 μg.kg -1 over 10 mins followed by a 220-min infusion of 0.4 μg.kg -1 .min -1 . Dobutamine was infused into the right atrium in an amount of 5 μg.kg -1 .min -1 . Treatment was continued for a total of 230 mins. Measurements and Main Results: Levosimendan and dobutamine produced comparable increases in cardiac output. However, levosimendan produced significantly greater left ventricular ejection fraction and fractional area changes compared with dobutamine and saline placebo. Conclusions: Levosimendan has the potential of improving postresuscitation myocardial function. It is likely to serve as an alternative to dobutamine as an inotropic agent for management of postresuscitation myocardial dysfunction.

Objective: Postresuscitation myocardial dysfunction has been recognized as a leading cause of early death after initial successful resuscitation. Recent experimental and clinical studies have indicated that the β-adrenergic effect of epinephrine significantly increases the severity of postresuscitation myocardial dysfunction. The fact that β-adrenergic stimulation increases myocardial oxygen consumption during ventricular fibrillation is an important implication with respect to both the exogenous in terms of pharmacologic interventions during cardiopulmonary resuscitation and the endogenous as the result of intense sympathetic activation of cardiovascular collapse. Earlier experimental evidence has indicated that oxygenation improved by β-blockade and β 1 -blocking agent did offset the adverse effect of epinephrine. This prompted us to investigate the effect of β-blockade on both exogenous and endogenous β stimulation in an established rat model. Design: Prospective, randomized, controlled study. Setting: Animal research laboratory. Subjects: Male Sprague-Dawley rats. Interventions: In this series of studies, propranolol was administrated before ventricular fibrillation as a pretreatment combined with epinephrine treatment during precordial compression and then alone in a prolonged cardiac arrest setting. Measurements and Main Results: Improved postresuscitation myocardial dysfunction (cardiac index, dP/dt 40 , -dP/dt) was observed with propranolol, a nonselective β-adrenergic blocker, in pretreated animals such that the beneficial effects were associated with better postresuscitation survival. Conclusion: Nonselective β-blockade improved the outcome of cardiopulmonary resuscitation in a rat model and deserves further evaluation in settings of cardiopulmonary resuscitation.

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.

Background— Both α 1 - and β-adrenergic agonists increase the severity of global myocardial ischemic injury. We hypothesized that combined β- and α 1 -adrenergic blockade would improve initial resuscitation and postresuscitation myocardial and neurological functions. We further hypothesized that the resulting α 2 -actions of relatively brief duration would favor improved functions compared with the more prolonged effect of nonadrenergic vasopressin. Methods and Results— Three groups of 5 male domestic pigs weighing 37±3 kg were investigated. Ventricular fibrillation was untreated for 7 minutes before the start of precordial compression, mechanical ventilation, and attempted defibrillation. Animals were randomized to receive central venous injections of equipressor doses of (1) epinephrine, (2) epinephrine in which both α 1 - and β-adrenergic effects were blocked by previous administration of prazosin and propranolol, and (3) vasopressin during CPR. All but 1 animal were successfully resuscitated. After injection of epinephrine, significantly better cardiac output and fractional area change, together with lesser increases in troponin I, were observed after α 1 - and β-adrenergic blockade. Postresuscitation neurological function was also improved after α 1 - and β-block in comparison with unblocked epinephrine and after vasopressin. Conclusions— Equipressor doses of epinephrine, epinephrine after α 1 - and β-adrenergic blockade, and vasopressin were equally effective in restoring spontaneous circulation after prolonged ventricular fibrillation. However, combined α 1 - and β-adrenergic blockade, which represented a predominantly selective α 2 -vasopressor effect, resulted in improved postresuscitation cardiac and neurological recovery.

The primary goal of cardiopulmonary resuscitation is to reestablish blood flow to vital organs until spontaneous circulation is restored. Adrenergic vasopressor agents produce systemic vasoconstriction. This increases aortic diastolic pressure, and consequently, coronary and cerebral perfusion pressures. The pharmacologic responses to the adrenergic agents are mediated by a group of receptors that are classified as alpha (α), including α1, and α2, and beta (β), including β1 and β2. Epinephrine, which has each of these adrenergic actions, has been the preferred adrenergic agent for the management of cardiac arrest for almost 40 years. Its primary efficacy is due to its ca-adrenergic vasopressor effects. This contrasts with its β-adrenergic actions, which are inotropic, chronotropic, and vasodilator. Accordingly,,B-adrenergic actions prompt increases in myocardial oxygen consumption, ectopic ventricular arrhythmias, and transient hypoxemia due to pulmonary arteriovenous shunting. This may account for the failure to demonstrate that epinephrine improves ultimate outcomes in human victims of cardiac arrest. Major interest has more recently been focused on selective α-adrenergic agonists. Both α1,-agonists and α2-agonists are peripheral vasopressors. However, rapid desensitization of α-adrenergic receptors occurs during cardiopulmonary resuscitation. Moreover, ax-adrenergic receptors are present in the myocardium, and α1-agonists, like β-adrenergic agonists, increase myocardial oxygen consumption. If they cross the blood-brain barrier, α2-adrenoceptor agonists also have centrally acting vasodilator effects. In the absence of central nervous system access, α2-adrenergic agonists have selective peripheral vasoconstrictor effects. Under experimental conditions of cardiopulmonary resuscitation, selective α2-agonists, which do not gain entrance into the brain, produce only systemic vasoconstriction. Experimentally, these selective Ut2-agonists are as effective as epinephrine for initial cardiac resuscitation and have the additional advantage of minimizing myocardial oxygen consumption during the global myocardial ischemia of cardiac arrest. Accordingly, myocardial ischemic injury during cardiopulmonary resuscitation is minimized, and postresuscitation myocardial function is preserved with improved survival.

We describe a series of investigations that used transesophageal echo-Doppler observations during cardiac arrest and cardiopulmonary resuscitation. Regular contractions of the left atrium persisted during the initial 7 mins of untreated ventricular fibrillation. Ventricular chamber deformation and mitral valve closing and opening followed precordial compression and relaxation. Stroke volumes computed from differences between diastolic and systolic areas of the left ventricle were predictive of the success of the resuscitation. Progressive decreases in left ventricular compliance were associated with decreases in left ventricular diastolic and stroke volumes and progressed to a stone heart.

Objectives To report observations on preserved regular atrial electrical and mechanical systole during ventricular fibrillation (VF) and to quantitate blood flow generated by atrial contractions in this setting. Methods In 10 rats, right atrial pressure pulses were continuously recorded before and for an interval of 8 min after inducing VF. In 3 isolated, perfused rat hearts, epicardial right atrial electrograms were recorded after inducing VF. In 15 pigs, transesophageal echo-Doppler measurements were obtained with pulsed and color-Doppler visualization of flow across the mitral valve after onset of VF. Results In each rat, regular right atrial pressure pulses were documented during VF. These persisted over an average interval of 7.5 min. In isolated, perfused hearts, right atrial contractions were accompanied by regular atrial depolarizations. In pigs, regular atrial contractions generated atrial stroke volumes of approximately 12 mL, or 25% of prearrest values during the first minute after onset of VF, but those declined to approximately 6 mL after 10 min of untreated cardiac arrest. Blood flow from the left atrium into the left ventricle failed to advance significantly into the systemic circuit. During atrial diastole, we observed reversal of flow into the left atrium. Conclusions Atrial contractions are preserved during the initial 8 min or more after cardiac arrest due to VF. Substantial forward flow into the left ventricle failed to advance through the outflow tract but regurgitated into the atrium during atrial diastole.

Background The fatal outcome of victims after initially successful resuscitation from cardiac arrest has been attributed both to global myocardial ischemia during the interval of cardiac arrest and to the adverse effects of reperfusion. The present study was prompted by earlier experimental observation that the magnitude of myocardial dysfunction was in part related to the energy delivered during electrical defibrillation. Methods and Results Ventricular fibrillation (VF) was induced in 15 Sprague-Dawley rats. Precordial compression was begun together with mechanical ventilation after 4 minutes of untreated VF and continued for 6 minutes. Spontaneous circulation was restored in each animal after external defibrillation with a single stored 2-, 10-, or 20-J countershock. Cardiac index and the rate of left ventricular pressure rise at left ventricular pressure of 40 mm Hg (dP/dt 40 ) and fall (negative dP/dt) during the 240-minute interval after successful resuscitation were decreased, and left ventricular diastolic pressure was increased. These decreases in myocardial function were closely related to the energy of electrical defibrillation. After a 20-J shock, animals survived for only 5±3 hours; after a 10-J shock, animals survived for 15±4 hours; and after a 2-J shock, all animals survived for >24 hours. Conclusions The severity of postresuscitation myocardial dysfunction is related, at least in part, to the magnitude of the electrical energy of the delivered shock.