Severity Of Postresuscitation Myocardial Dysfunction Research Articles

IVABRADINE-INDUCED HEART RATE REDUCTION INCREASES THE SEVERITY OF POSTRESUSCITATION MYOCARDIAL DYSFUNCTION IN A RAT MODEL OF CARDIOPULMONARY RESUSCITATION.

Aims: A rapid heart rate (HR) that occurs after cardiopulmonary resuscitation (CPR) is a short-term compensatory mechanism preserving cardiac output. However, if of long duration, it is unfavorable for myocardial function postresuscitation because of disrupted balance between myocardial oxygen supply and demand. This raises the assumption that such a sustained fast HR should be regulated. The present study aimed to investigate the follow-on effect of ivabradine (a specific inhibitor of the I f current of the sinoatrial node)-induced HR reduction (HRR) on postresuscitation myocardial function in a rat model of CPR. Methods and results: Six minutes of ventricular fibrillation and 8 min of CPR were performed on Sprague-Dawley rats. All 32 resuscitated animals were then randomized into saline and ivabradine groups, each group having nonsurvival and survival subgroups (n = 8 each). Saline or ivabradine (0.5 mL/kg) was administered at 1 h postresuscitation. Heart rate, myocardial function as expressed by cardiac output, ejection fraction, and myocardial performance index were assessed at baseline and hourly from 1 to 5 h postresuscitation. Heart rate variability was analyzed at baseline and at 1, 3, and 5 h postresuscitation. Serum epinephrine and cardiac troponin I at baseline and at 1, 3, and 5 h postresuscitation in nonsurvival subgroup were measured. Survival duration in the survival subgroup was observed. The baseline HR was approximately 390 beats/min (bpm). After resuscitation, an average increase of Δ ≈ +15 bpm (relative ratio ≈ +3.8%) with a resultant HR of 405 bpm lasting more than 5 h occurred. Ivabradine group achieved a steady HRR of Δ ≈ -30 bpm (relative ratio ≈ -7.4%) as compared with saline group ( P < 0.01). Postresuscitation myocardial function was significantly worse in the ivabradine group (all P < 0.01). Heart rate variability was significantly impaired in the ivabradine group (all P < 0.05). Serum cardiac troponin I and epinephrine concentration were significantly higher in the ivabradine group (all P < ?0.01). Survival duration was significantly shortened in the ivabradine group as compared with the saline group (388 vs. 526 min, P < ?0.01). Conclusions: Ivabradine-induced HRR increases the severity of postresuscitation myocardial dysfunction and shortens survival duration in a rat model of CPR.

Abstract 120: Artesunate Reduces the Severity of Post-Resuscitation Myocardial and Cerebral Dysfunction

Introduction: Artesunate (ART) possesses anti-inflammatory activity, which can mitigate the systemic inflammatory response in poor outcomes of cardiac arrest (CA). We investigated the effects of ART on myocardial and cerebral function, duration of survival, and inflammation in a rat model of CA and cardiopulmonary resuscitation (CPR). Hypothesis: ART reduces the severity of post resuscitation myocardial and cerebral dysfunction by alleviating inflammation in a rat model of CA and CPR. Methods: 30 male Sprague-Dawley rats weighing between 450g-550g were randomized into 3 groups: Sham (S), Control (C), and Artesunate (A). C and A were divided into subgroups: survival and non-survival (n=6). Ventricular fibrillation (VF) was induced and untreated for 6 min. A 4J defibrillation was attempted after 8 min of CPR. Phosphate buffer (1ml/kg, pH 7.9-8.1) or ART (2.4mg/kg), was administered at return of spontaneous circulation (ROSC). Myocardial function was measured at baseline and every hour for 4h post ROSC. Plasma levels of IL-6, TNF-α and cTnI were detected at baseline and 4h after ROSC. Survival animals were observed for an additional 72h. Neurologic deficit scores were recorded daily. Results: ART reduced the severity of post-resuscitation myocardial dysfunction compared to C. It attenuated IL-6, TNF-α and cTnI plasma levels 4h after ROSC (p&lt;0.05) (Fig. 1). Post-resuscitation cerebral function and survival rate also improved significantly (p&lt;0.05) (Fig. 2). Conclusion: ART reduces the severity of post-resuscitation myocardial and cerebral dysfunction, improves survival rate and attenuates inflammation in a rat of model of CA and CPR.

Abstract 211: UAMC-3203 Reduces the Severity of Post-resuscitation Myocardial Dysfunction in a Rat Model of Cardiac Arrest and Cardiopulmonary Resuscitation

Introduction: Previous studies have demonstrated that ferroptosis, a newly defined iron-dependent cell death, mediates ischemia/reperfusion induced cardiomyopathy. However, it is unclear whether ferroptosis plays a role in post-resuscitation myocardial dysfunction (PRMD). This study investigated the effects of UAMC-3203, a novel analog of ferroptosis specific inhibitors, on myocardial function after cardiopulmonary resuscitation (CPR). Hypothesis: Administration of UAMC-3203 during CPR alleviates PRMD in a rat model of cardiac arrest (CA) and CPR. Methods: 18 male Sprague-Dawley rats weighing between 450-550g were randomized into 3 groups: 1) Sham, 2) Control, and 3) UAMC-3203 (5mg/kg, IP at start of precordial compression). Ventricular fibrillation (VF) was induced and continued for 6min. CPR was then initiated for 8min, after which defibrillation was attempted. Ejection fraction (EF), cardiac output (CO) and myocardial performance index (MPI) were measured by echocardiography at baseline, 15min, 1h, 3h and 6h respectively after return of spontaneous circulation (ROSC). Results: A significant reduction in cardiac function was observed after resuscitation. At 15 minutes after ROSC, ultrasound showed no difference in cardiac function between UAMC and control. However, at 1, 3, and 6 h after ROSC, UAMC significantly improved myocardial function (p&lt;0.05) (Fig. 1). Conclusion: A ferroptosis-specific inhibitor, UAMC-3203, alleviated PRMD significantly in a rat of model of CA and CPR. Further study is needed to determine the benefit of this agent in larger animals and potential safety in humans before it can be tested in clinical resuscitation.

Effects of ω-3 PUFA and ascorbic acid combination on post-resuscitation myocardial function

Accumulating evidence demonstrated that administration of ω-3 polyunsaturated fatty acid (ω-3 PUFA) or ascorbic acid (AA) following cardiac arrest (CA) improves survival. Therefore, we investigate the effects of ω-3 PUFA combined with AA on myocardial function after CA and cardiopulmonary resuscitation (CPR) in a rat model.Thirty male rats were randomized into 5 groups: (1) sham; (2) control; (3) ω-3 PUFA; (4) AA; (5) ω-3 PUFA + AA. Ventricular fibrillation (VF) was induced and untreated for 6 min followed by defibrillation after 8 min of CPR. Infusion of drug or vehicle occurred at the start of CPR. Myocardial function and sublingual microcirculation were measured at baseline and after return of spontaneous circulation (ROSC). Heart tissues and blood were collected 6 h after ROSC. Myocardial function and sublingual microcirculation improvements were seen with ω-3 PUFA or AA compared to control after ROSC (p < 0.05). ω-3 PUFA + AA shows a better myocardial function than ω-3 PUFA or AA (p < 0.05). ω-3 PUFA or AA decreases pro-inflammatory cytokines, cTnI, myocardium malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) modified proteins compared to control (p < 0.05). ω-3 PUFA and AA combined have lower MDA and 4-HNE modified proteins than alone (p < 0.05). ω-3 PUFA or AA treatment reduces the severity of post-resuscitation myocardial dysfunction, improves sublingual microcirculation, decreases lipid peroxidation and systemic inflammation in the early phase of recovery following CA and resuscitation. A combination of ω-3 PUFA and AA treatment confers an additive effect in suppressing lipid peroxidation and improving myocardial function.

Abstract 11: Beneficial Effects of Hcn Inhibitor on Post-Resuscitation Myocardial Dysfunction in a Porcine Model of Cardiac Arrest

Introduction: Previous studies have demonstrated that β-adrenergic blocking agents improved neurologic function and the rate of survival. However, its negative inotrope effects that increased the severity of PRMD (post-resuscitation myocardial dysfunction). We studied whether ivabradine (IVA) improves PRMD in a cardiac arrest model. Hypothesis: we hypothesized that the rational use of IVA would improve severity of PRMD and prognosis in a porcine model of CA. Methods: Ventricular fibrillation was induced and untreated for 8 minutes in anesthetized domestic swine while defibrillation was attempted after 6 minutes of cardiopulmonary resuscitation. Hemodynamic parameters were monitored continuously after ROSC. Mitral E/A ratio and E/e′ velocity ratio were assessed by echocardiography at Baseline, PR 1, 2, 4, 8 and 24hours after ROSC. The levels of cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured by ELISA method at Baseline, PR 1, 4 and 24hours. The animals were euthanized 24h after ROSC, and the cardiac tissue was removed for histopathological analysis. Results: Heart rate in the IVA group reduced significantly compared with the control group (all P &lt; 0.05) at PR 1, 2, 4, 8hours. Animals subjected to IVA groups presented significantly better post-resuscitation relaxation function (E/A, E/e′) than those in the Placebo groups (all P &lt; 0.05) (Figure1). IVA group had a lower cTnI and NT-proBNP levels than Placebo group at PR 1, 4 and 24hours (all P &lt; 0.05) (Figure1). Biopsy score in the IVA group was significantly lower at PR 24hours when compared with the Placebo group (all P &lt; 0.05) (Figure2). Conclusions: Heart rate reduction with IVA, improved left ventricular diastolic function and reduced myocardial injury.

Abstract 11162: Hypothermia Attenuates Postresuscitation Myocardial Dysfunction by Inhibiting Beta Adrenergic Signaling

Introduction: Therapeutic hypothermia reduce the severity of post-resuscitation myocardial dysfunction caused by epinephrine administered during cardiopulmonary resuscitation (CPR) , and the mechanism remains unclear. Hypothesis: hypothermia may reduce the concentration of cyclic adenosine monophosphate (cAMP), a second messenger of beta-adrenergic receptor activity. Methods: Thirty two male Sprague-Dawley rats were randomized to four groups: 1) normothermic placebo control; 2) normothermic epinephrine; 3) hypothermic placebo control; and 4) hypothermic epinephrine. Ventricular fibrillation was induced electrically and untreated for 8 mins. Hypothermia was initiated coincident with the start of CPR and maintained at 33 ± 0.2°C for 4 hrs after resuscitation and animals were then euthanized. Either placebo or epinephrine was administered 5 mins after the start of CPR and 3 mins before defibrillation. Post-resuscitation ejection fraction was measured hourly for 4 hrs. The hearts were then harvested for cAMP and Inositol 1,4,5-trisphosphate (IP3) assay analysis. Results: All animals were successfully resuscitated except one in normothermic placebo group. Epinephrine significantly increased coronary perfusion pressure during CPR (26.5±6.23mmHg vs 21.14±1.95 mmHg P&lt;0.05). Post-resuscitation myocardial function was significantly impaired in normothermic epinephrine group compared with other three groups (figure 1). The concentration of myocardial cAMP was double in normothermic epinephrine group (655.06±447.63 umol/L) when compared to that in hypothermic epinephrine group (302.51±97.98 umol/L P&lt;0.05). However, there was no difference in the concentration of IP3 in all four groups. Conclusions: The potential mechanism of myocardial protective effect of hypothermia may involve the reduced activities of β-receptors.

CHANGES IN SUBLINGUAL MICROCIRCULATION IS CLOSELY RELATED WITH THAT OF BULBAR CONJUNCTIVAL MICROCIRCULATION IN A RAT MODEL OF CARDIAC ARREST.

Following successful resuscitation, a significantly impaired microcirculation has been identified. The severity of the impairment of microcirculation is closely related to that of vital organ dysfunction. Sublingual microcirculation is a traditional site for the measurement of tissue perfusion. In the present study, we investigated the bulbar conjunctival microcirculatory alterations following CPR and its relationship with the changes of sublingual microcirculation in a rat model of cardiac arrest.Male Sprague-Dawley rats (450-550 g) were utilized. Ventricular fibrillation was induced and untreated for 8 min followed by 8 min of CPR. Sublingual and bulbar conjunctival microcirculatory blood flow was visualized by a sidestream dark-field imaging device at baseline, 30 min, 1, 2, 4, and 8 h post-resuscitation. Both perfused vessel density (PVD) and microcirculatory flow index (MFI) were recorded.The post-resuscitation PVD and MFI were significantly decreased in both sublingual and bulbar conjunctival sites. Sublingual PVD decreased from baseline of 5.9 ± 0.3 to 3.1 ± 0.4 n/mm at 30 min post-resuscitation and MFI from 3.0 ± 0.0 to 1.5 ± 0.3 (both P < 0.05 vs. baseline). Bulbar conjunctival PVD was significantly reduced from baseline of 6.5 ± 0.6 to 3.9 ± 0.5 n/mm at 30 min post-resuscitation and MFI from 3.0 ± 0.0 to 1.2 ± 0.4 (both P < 0.05 vs. baseline). PVD, MFI, and cardiac function did not change significantly from the 30-min measurements in the surviving rats throughout the remainder of the study (both P > 0.05 vs. 30-min post-resuscitation). The decreases in sublingual microcirculatory blood flow were closely correlated with the reductions of bulbar conjunctival microcirculatory blood flow (PVD: r = 0.87, P < 0.05; MFI: r = 0.92, P < 0.05). Myocardial function was significantly impaired in all animals after resuscitation when compared with baseline values (P < 0.05). The impairments of both sublingual and bulbar conjunctival microcirculation were significantly correlated with the impairment of myocardial function.In the rat model of cardiac arrest, the changes in sublingual microcirculatory blood flow are closely correlated with that of bulbar conjunctival microcirculatory blood flow after successful resuscitation. The changes are correlated with the severity of post-resuscitation myocardial dysfunction. Our study testified sublingual site could be substituted by bulbar conjunctival at least in the rat model of cardiac arrest. The measurement of conjunctival microcirculation may provide an accessible and convenient option as sublingual site for monitoring microcirculation in humans.

Abstract 10770: Curcumin Mitigates the Severity of Post-Resuscitation Myocardial Dysfunction Caused by Epinephrine in a Rat Cardiac Arrest Model

Introduction: Epinephrine significantly increases the severity of post-resuscitation myocardial dysfunction (PRMD) and reduces the duration of survival. The cardioprotective effect of curcumin against catecholamine-induced cardiotoxicity has been established. In the present study, we investigated the effects of curcumin on PRMD caused by epinephrine in a rat model of cardiac arrest. Hypothesis: Curcumin reduces the severity of PRMD caused by epinephrine. Methods: Twenty-four male Sprague-Dawley rats weighing between 450-550g were randomized into three groups: 1) Placebo group; 2) Epinephrine (20ug/kg) group; 3) Curcumin (100 mg/kg) pretreatment + epinephrine (20ug/kg) group. Ventricular fibrillation (VF) was then induced. After 8 mins of VF, CPR was initiated for 8 mins, and defibrillation was then attempted. Myocardial function was measured by echocardiography at baseline and hourly for 4 hours following successful resuscitation. Results: All animals except for two in the placebo group were resuscitated. Post-resuscitation myocardial function was significantly impaired in all animals. Significantly worse myocardial function was observed in the Epinephrine group in comparison with the two other groups (Figure). However, myocardial function was significantly better in the animals treated with curcumin when compared with those in the two other groups (Figure). Conclusion: In a rat cardiac arrest model, curcumin reduced the severity of PRMD caused by epinephrine.

Combining Epinephrine and Esmolol Attenuates Excessive Autophagy and Mitophagy in Rat Cardiomyocytes After Cardiac Arrest.

Recent experimental and clinical studies have indicated that the β-adrenergic effect of epinephrine significantly increases the severity of postresuscitation myocardial dysfunction. The aim of this study was to investigate whether the short-acting β1-selective adrenergic blocking agent, esmolol, would impact postresuscitation autophagy and mitophagy in cardiomyocytes in a rat cardiac arrest (CA) model. CA was induced in Sprague Dawley rats by epicardial ventricular fibrillation for 5 minutes. After successful resuscitation, the surviving rats were randomly divided into 2 groups that received femoral venous injections of epinephrine combined with either esmolol (EE group) or epinephrine (E group). Arterial blood samples were obtained at times 0, 30, and 180 minutes after return of spontaneous circulation. Surviving rats were euthanatized at 12 or 24 hours after return of spontaneous circulation, and the hearts were removed for histochemical analysis, electron microscopy, Western blotting, and TUNEL experiment. Relative to the E group, the EE group had reduced N-Methyl-D-Aspartate receptors expression and reduced arterial lactate levels (P < 0.05), suggesting that epinephrine/esmolol can attenuate postresuscitation antioxidation and apoptosis. This protective effect also correlated with a reduction of excessive autophagy and mitophagy in the cardiomyocytes, as evidenced by a reduction in Beclin-1 and Parkin expression (P < 0.05). Esmolol significantly alleviates postresuscitational autophagy, including mitophagy, and cardiomyocyte apoptosis in a rat CA model.

The protective effects of a phosphodiesterase 5 inhibitor, sildenafil, on postresuscitation cardiac dysfunction of cardiac arrest: metabolic evidence from microdialysis.

IntroductionRecent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion injury. The aim of this study was to determine, by obtaining metabolic evidence from microdialysis, if sildenafil could reduce the severity of postresuscitation myocardial dysfunction and lead to cardioprotection through beneficial effects on energy metabolism.MethodsTwenty-four male piglets were randomly divided into three groups: sildenafil (n = 8), saline (SA; n = 8) and sham operation (n = 8). Sildenafil pretreatment consisted of 0.5 mg/kg sildenafil administered once intraperitoneally 30 minutes prior to ventricular fibrillation (VF). The myocardial interstitial fluid (ISF) concentrations of glucose, lactate, pyruvate, glutamate and glycerol were determined by microdialysis before VF. Afterward, the piglets were subjected to 8 minutes of untreated VF followed by 15 minutes of open-chest cardiopulmonary resuscitation. ISF was collected continuously, and the experiment was terminated 24 hours after resuscitation.ResultsAfter 8 minutes of untreated VF, the sildenafil group exhibited higher glucose and pyruvate concentrations of ISF and lower lactate and glutamate levels in comparison with the SA group, and these data reached statistical significance (P < 0.05). Advanced cardiac life support was delivered to both groups, with a 24-hour survival rate showing a promising trend in the sildenafil group (7 of 8 versus 3 of 8 survivors, P < 0.05). Compared with the SA group, the sildenafil group had a better outcome in terms of hemodynamic and oxygen metabolism parameters (P < 0.05). Myocardial tissue analysis revealed a dramatic increase in the contents of ATP, ADP and phosphocreatine in the sildenafil group versus the SA group at 24 hours after return of spontaneous circulation (ROSC; P = 0.03, P = 0.02 and P = 0.02, respectively). Furthermore, 24 hours after ROSC, the sildenafil group had marked elevations in activity of left ventricular Na+-K+-ATPase and Ca2+-ATPase compared with the SA group (P = 0.03, P = 0.04, respectively).ConclusionsSildenafil could reduce the severity of postresuscitation myocardial dysfunction, and it produced better clearance of metabolic waste in the ISF. This work might provide insights into the development of a novel strategy to treat postresuscitation myocardial dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0641-7) contains supplementary material, which is available to authorized users.

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Introduction: The detrimental effects of epinephrine are closely related to its β- and a1- action, which significantly increases the severity of post-resuscitation (PR) myocardial dysfunction. In the present study, we investigated the effects of β- and β- plus α1- adrenergic blocking agents on post-resuscitation myocardial dysfunction and myocardial injury biomarkers. Methods: Twenty-four male Sprague-Dawley rats weighing between 450 - 550g were randomized into 4 groups: 1) placebo; 2) epinephrine; 3) epinephrine with β- blocker (propranolol) and; 4) epinephrine with β- plus α1- blockers (propranolol and prazosin). Ventricular fibrillation (VF) was electrically induced. CPR was initiated after 8 mins of untreated VF and continued for 8 mins. Defibrillation was then attempted. Ejection fraction (EF) and myocardial performance index (MPI) were measured at baseline and at hourly intervals for 4 hrs after resuscitation. Troponin I (Tn I) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were measured at baseline and at 1 and 4 hrs after resuscitation by the ELISA kits. Results: The β- and β- plus α1- blockers significantly reduced the severity of PR myocardial dysfunction. EF and MPI were 60.23 ± 1.23 and 1.01 ± 0.06 in the β- blocker group and 63.63 ± 1.51 and 0.89 ± 0.03 in the β- plus α1- blockers treated group compared to 39.90 ± 2.60 and 1.34 ± 0.10 in the epinephrine treated group and 44.58 ± 4.57 and 1.25 ± 0.10 in the placebo group at PR 4 hrs (p<0.05). The β- and β- plus α1- blockers pretreatment also reduced the releases of Tn I and NT-pro BNP compared with the placebo and epinephrine groups at PR 4 hrs (2.4 ± 1.0 and 1.8 ± 0.6 vs. 8.2 ± 5.2 and 9.5 ± 6.9 ng/L, p<0.05; 153.7 ± 44.9 and 151.7 ± 24.3 vs. 241.8 ± 16.9 and 298.9 ± 118.5 ng/L, p<0.05). The β- and β- plus α1-blockers significantly improved the duration of survival (67.8 ± 10.2 and 72.0 ± 0 vs. 34.4 ± 34.6 and 22.8 ± 26.4 hrs, p<0.05). Conclusions: The β- and β- plus α1-blockers reduced the severity of PR myocardial dysfunction and attenuated release of myocardial injury biomarkers with improved duration of survival in a rat model of CPR.

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Introduction: Post-resuscitation myocardial dysfunction is one of leading causes of death after resuscitation from cardiac arrest. It is generally considered as a reversible myocardial stunning. However, its mechanism and especially whether there is myocardial tissue damage after global ischemia of cardiac arrest remain unclear. In the present study, we investigated the relationship between the severity of post-resuscitation myocardial dysfunction and myocardial injury biomarkers. Methods: Thirty-six male Sprague-Dawley rats weighing between 450-550g were randomized into 6 groups: 1) placebo; 2) epinephrine; 3) epinephrine with α1- blocker; 4) epinephrine with α2- blocker; 5) epinephrine with β- blocker and; 6) epinephrine with β- and α1- blocker. Ventricular fibrillation (VF) was electrically induced. CPR was initiated after 8 mins of untreated VF and continued for 8 mins. Defibrillation was then attempted. Ejection fraction (EF) and myocardial performance index (MPI) were measured by echocardiography at baseline and hourly interval for 4 hrs after resuscitation. The serum concentrations of Troponin I (Tn I) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were measured at baseline, 1 and 4 hrs after resuscitation by the ELISA kits. Results: All animals except for one in the placebo group were resuscitated. The post-resuscitation myocardial function measured by EF and MPI were significantly impaired after resuscitation in all animals. The most severe impairment was observed in epinephrine with α2- blocker and epinephrine treated animals. The impairment of myocardial mechanical function was parallel with myocardial injury biomarkers measured by Tn I and NT-pro BNP (EF and Tn I: r = -0.639, p < 0.01, EF and NT-pro BNP: r = -0.729, p < 0.01 and MPI and Tn I: r =-0.604, p < 0.01, MPI and NT-pro BNP: r = -0.649, p < 0.01, respectively). Conclusions: The severity of post-resuscitation myocardial dysfunction was closely related to myocardial injury biomarkers which indicate that post-resuscitation myocardial dysfunction is associated with myocardial tissue injury.

CDP-CHOLINE IMPROVES THE OUTCOME OF CARDIAC ARREST VERSUS EPINEPHRINE IN RATS

ObjectivesCDP-Choline is a cholinergic agent which can both stimulate the cholinergic pathway and increase blood pressure. We aimed to investigate the effects of CDP-Choline on the outcome of cardiac arrest...

The effects of epinephrine on outcomes of normothermic and therapeutic hypothermic cardiopulmonary resuscitation*

To investigate the effects of epinephrine when administered during either normothermic or therapeutic hypothermic cardiopulmonary resuscitation on postresuscitation myocardial and cerebral function and survival. Prospective, randomized, placebo-controlled experimental study. University-affiliated animal research laboratory. Thirty-two healthy male Sprague-Dawley rats. Ventricular fibrillation was induced and untreated for 8 mins. The animals were then randomly assigned to one of four groups: normothermic placebo control; normothermic epinephrine; hypothermic placebo control; and hypothermic epinephrine. Hypothermia was initiated coincident with the start of cardiopulmonary resuscitation. The blood temperature was reduced and maintained at 32 ± 0.2°C and continued for 4 hrs after resuscitation. Normothermic animals were maintained at 37 ± 0.2°C. Either placebo or epinephrine (20 μg/kg) was administered 5 mins after the start of cardiopulmonary resuscitation and 3 mins before defibrillation. Postresuscitation cardiac output, ejection fraction, and myocardial performance index were measured hourly for 4 hrs after resuscitation; neurologic deficit scores were measured daily for 7 days, and durations of survival were observed for up to 3 mos. Except for three normothermic control animals, all animals were resuscitated. When epinephrine was administered during normothermic cardiopulmonary resuscitation, postresuscitation myocardial function was severely impaired when compared with the normothermic control group. However, postresuscitation myocardial function was significantly better in animals treated with epinephrine during hypothermic cardiopulmonary resuscitation when compared with hypothermic controls. This was associated with significantly fewer postresuscitation ventricular arrhythmias, less ST-segment elevation, better postresuscitation neurologic deficit scores, and longer duration of survival. Epinephrine, when administered during normothermic cardiopulmonary resuscitation, significantly increases the severity of postresuscitation myocardial dysfunction and decreases the duration of survival. These detrimental effects of epinephrine, however, no longer exist when it is administered during therapeutic hypothermic cardiopulmonary resuscitation.

Minimal interruption of cardiopulmonary resuscitation for a single shock as mandated by automated external defibrillations does not compromise outcomes in a porcine model of cardiac arrest and resuscitation

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. Randomized prospective animal study. University affiliated research laboratory. Domestic pigs. 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. 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.

Outcomes of CPR in the presence of partial occlusion of left anterior descending coronary artery

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. Ventricular fibrillation (VF) was induced by LAD occlusion with a balloon tipped catheter in 16 domestic male pigs weighing 41+/-2kg. After a 7min 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 2min before a defibrillation attempt. Thirty minutes following successful resuscitation the LAD catheter was withdrawn in the animals with partial occlusion of the LAD. In the animals that had the LAD totally unoccluded before to starting CPR, each animal was resuscitated successfully and survived for more than 72h with better neurological recovery during the initial 24h 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 72h. 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. 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.

Simultaneous blockade of α1- and β-actions of epinephrine during cardiopulmonary resuscitation

Experimental and clinical studies have implicated that alpha1- and beta-adrenergic effects of epinephrine significantly increased the severity of postresuscitation myocardial dysfunction by increasing myocardial oxygen consumption during ventricular fibrillation. This prompted experimental studies to investigate the effect of simultaneous blockade of alpha1- and beta-actions of epinephrine during cardiopulmonary resuscitation. Literature review. Improved postresuscitation myocardial dysfunction was observed in epinephrine-treated animals after its alpha1- and beta-actions were blocked, which were associated with less postresuscitation arrhythmia, lower blood lactate level, better neurologic recovery, and longer duration of survival. After simultaneous alpha1- and beta-adrenergic blockade, epinephrine administered during cardiopulmonary resuscitation yielded improved postresuscitation myocardial functions and significantly better postresuscitation outcomes.

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.

Nonselective β-blocking agent improves the outcome of cardiopulmonary resuscitation in a rat model

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 beta-adrenergic effect of epinephrine significantly increases the severity of postresuscitation myocardial dysfunction. The fact that beta-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 beta-blockade and beta1-blocking agent did offset the adverse effect of epinephrine. This prompted us to investigate the effect of beta-blockade on both exogenous and endogenous beta stimulation in an established rat model. Prospective, randomized, controlled study. Animal research laboratory. Male Sprague-Dawley rats. 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. Improved postresuscitation myocardial dysfunction (cardiac index, dP/dt40, -dP/dt) was observed with propranolol, a nonselective beta-adrenergic blocker, in pretreated animals such that the beneficial effects were associated with better postresuscitation survival. Nonselective beta-blockade improved the outcome of cardiopulmonary resuscitation in a rat model and deserves further evaluation in settings of cardiopulmonary resuscitation.

Delta-opioid receptor agonist reduces severity of postresuscitation myocardial dysfunction.

Postresuscitation myocardial dysfunction is recognized as a leading cause of early death after initially successful cardiopulmonary resuscitation (CPR). In the present study, we hypothesized that a delta-opioid receptor agonist would decrease the severity of postresuscitation myocardial dysfunction and improve survival. Fifteen Sprague-Dawley rats, fasted overnight with access to water, were anesthetized by an injection of 45 mg/kg ip pentobarbital sodium. Additional doses of 10 mg/kg were administered at hourly intervals but not within 30 min before induced ventricular fibrillation (VF). Either the delta-opioid receptor agonist pentazocine (300 microg/kg), pentazocine pretreated with the opioid receptor-blocking agent naloxone (1 mg/kg), or saline placebo was injected into the right atrium after 5 min of untreated VF and 3 min before initiation of CPR. After an additional 8 min of CPR administration, defibrillation was attempted. All animals were successfully resuscitated. Left ventricular rate of pressure increase at 40 mmHg and cardiac index values were significantly improved in pentazocine-treated animals, which also had significantly longer survival times (60 +/- 11 vs. 16 +/- 7 h; P < 0.01). Except for ease of defibrillation, the beneficial effects of pentazocine were completely abolished by pretreatment with naloxone. The concept of pharmacological hibernation employing a delta-opioid receptor agonist is a novel and promising intervention for minimizing global ischemic injury during CPR and postresuscitation myocardial dysfunction.