pyrimidinones and Heart-Arrest

In Japan, intravenous nifekalant (NIF) was often used for direct current cardioversion-resistant ventricular fibrillation (VF), until the use of intravenous amiodarone (AMD) was approved in 2007. The defibrillatory efficacy of NIF and AMD has thus far not been compared for resuscitation.. Between August 2007 and April 2009, 403 consecutive out-of-hospital patients with cardiopulmonary arrest were transferred to the Emergency Medical Service of Tokai University. Of these, 30 patients with first defibrillation failure or VF recurrence were enrolled for this NIF/AMD study. The final defibrillation success (and hospital survival rate) was 67% (10/15) in the AMD and 47% (7/15) in the NIF group. The discharge survival rate was 53% (8/15) in the AMD and 21% (4/15) in the NIF group (P = 0.06). Notably, all 4 survivors in the NIF group could take up normal daily life again, whereas this was restricted to only 2 patients from the 11 survivors in the AMD group. The difference is probably partly attributable to longer time from AMD administration to defibrillation success compared with NIF. In the cases of defibrillation failure, VF continued in 4/8 by NIF, however, asystole or pulseless electrical activity occurred in 4/5 patients by AMD.. AMD may be borderline superior over NIF to facilitate defibrillation in out-of-hospital patients with cardiopulmonary arrest. However, from the view point of preservation of brain function, NIF is not inferior to AMD for CPR.

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Drug Therapy, Combination; Electric Countershock; Emergency Service, Hospital; Female; Heart Arrest; Heart Diseases; Humans; Male; Middle Aged; Prognosis; Pyrimidinones; Survival Analysis; Treatment Outcome; Ventricular Fibrillation

Early defibrillation of ventricular tachycardia and fibrillation (VT/VF) is an urgent and most important method of resuscitation for survival in cardiopulmonary arrest (CPA). We have previously reported that nifekalant (NIF), a specific I(Kr) blocker developed in Japan, is effective for lidocaine (LID) resistant VT/VF in out-of-hospital CPA (OHCPA). However, little is known about the differences in the effect of NIF on OHCPA with acidosis and in-hospital CPA (IHCPA) without acidosis.. The present study enrolled 91 cases of DC shock resistant VT/VF among 892 cases of CPA that occurred between June 2000 and May 2003. NIF was used (0.15-0.3 mg/kg) after LID according to the cardiopulmonary resuscitation (CPR) algorithm of Tokai University. The defibrillation rate was higher in the NIF group for both OHCPA and IHCPA than for LID alone, and the VT/VF rate reduction effect could be maintained even with acidosis. However, sinus bradycardia in OHCPA, and torsades de pointes in IHCPA were occasionally observed. These differences in adverse effects might be related to the amount of epinephrine, serum potassium levels, serum pH, and interaction with LID.. NIF had a favorable defibrillating effect in both CPA groups, and it shows promise of becoming a first-line drug for CPR.

Topics: Acidosis; Aged; Anti-Arrhythmia Agents; Electric Countershock; Epinephrine; Female; Heart Arrest; Humans; Hydrogen-Ion Concentration; Inpatients; Male; Middle Aged; Outpatients; Potassium; Pyrimidinones; Resuscitation; Retrospective Studies; Tachycardia, Ventricular

We report a 55-year-old man who was resuscitated from out-of-hospital cardiac arrest and subsequently developed three episodes of ventricular fibrillation (VF) on the same day. Early repolarization (ER) pattern was not significant (<0.1 mV) on postresuscitation ECG. However, ER pattern became evident (0.25 mV) before the onset of VF and then completely disappeared. The unusual dynamics of ER pattern observed in the present case could be called "masked" ER syndrome.

Topics: Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Defibrillators, Implantable; Electric Countershock; Electrocardiography; Heart Arrest; Humans; Isosorbide Dinitrate; Magnesium; Male; Middle Aged; Potassium Chloride; Pyrimidinones; Vasodilator Agents; Ventricular Fibrillation

The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR).. Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR. GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045).. CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

Topics: Aldehyde Oxidoreductases; Animals; Benzoates; Disease Models, Animal; Heart; Heart Arrest; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Oxidation-Reduction; Pyrimidinones; Resuscitation; Treatment Outcome

The purpose of the experiment was to compare the effects of nifekalant and amiodarone on the return of spontaneous circulation (ROSC), survival, as well as on the hemodynamic parameters in a swine model of prolonged ventricular fibrillation (VF).. After 8 min of untreated VF, bolus doses of epinephrine (adrenaline) and either nifekalant, or amiodarone, or saline (n = 10 per group), were administered after randomization. Cardiopulmonary resuscitation (CPR) was commenced immediately after drug administration and defibrillation was attempted 2 min later. CPR was resumed for another 2 min after each defibrillation attempt and the same dose of adrenaline was given every 4th minute during CPR.. Forty-eight hour survival was significantly higher with nifekalant compared to amiodarone (p < 0.001) and saline (p = 0.02), (9/10 vs. 0/10 vs. 3/10, respectively). Systolic aortic pressure, diastolic aortic pressure and coronary perfusion pressure were significantly higher with nifekalant during CPR and immediate post-resuscitation period (p < 0.05). The animals in the amiodarone group had a slower heart rate at the 1st and 45th min post-ROSC (p < 0.001 and p = 0.006, respectively). The number of electric shocks required for terminating VF, time to ROSC and adrenaline dose were significantly higher with amiodarone compared to nifekalant (p < 0.001).. Nifekalant showed a more favorable hemodynamic profile and improved survival compared to amiodarone and saline in this swine model.

Topics: Amiodarone; Animals; Blood Pressure; Cardiopulmonary Resuscitation; Disease Models, Animal; Electric Countershock; Epinephrine; Female; Heart Arrest; Heart Rate; Pyrimidinones; Survival Analysis; Swine; Ventricular Fibrillation

To compare the efficacy of nifekalant and amiodarone in the treatment of cardiac arrest in a porcine model.. After 4min of untreated ventricular fibrillation, animals were randomly treated with nifekalant (2mgkg(-1)), amiodarone (5mgkg(-1)) or saline placebo (n=12 pigs per group). Precordial compression and ventilation were initiated after drug administration and defibrillation was attempted 2min later. Hemodynamics were continuously measured for 6h after successful resuscitation.. Compared with saline, nifekalant and amiodarone equally decreased the number of electric shocks, defibrillation energy, epinephrine dose, and duration of cardiopulmonary resuscitation required for successful resuscitation (P<0.01). The incidence of restoration of spontaneous circulation (ROSC) and the 24-h survival rate were higher in both antiarrhythmic drug groups (P<0.05) vs. the saline group. Furthermore, post-resuscitation myocardial dysfunction at 4-6h after successful resuscitation was improved in animals given antiarrhythmic drugs as compared with the saline group (P<0.05). There were no differences between nifekalant and amiodarone for any of these parameters.. The effect of nifekalant was similar to that of amiodarone for improving defibrillation efficacy and for the treatment of cardiac arrest. Administration of either nifekalant or amiodarone before defibrillation increased the ROSC and 24-h survival rates and improved post-resuscitation cardiac function in this porcine model.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Arrest; Heart Rate; Male; Pyrimidinones; Swine; Treatment Outcome; Ventricular Fibrillation; Ventricular Function

Although nifekalant is a class III antiarrhythmic agent without negative inotropic activity, its effect in patients with shock-refractory ventricular fibrillation remains unclear.. Patients who had an out-of-hospital cardiac arrest with ventricular fibrillation that persisted after 3 shocks from an external defibrillator, intravenous epinephrine, and another shock were retrospectively studied. The patients received lidocaine from January 1997 through June 2001 and nifekalant from July 2001 through December 2004. Short-term survival rates (survival to hospital admission and 24-h survival) were compared between the groups. The study group comprised 120 patients (mean age: 62+/-16 years): 55 received nifekalant and 65 received lidocaine. Age, sex, history of ischemic heart disease, whether arrest was witnessed or not and time to arrival at the hospital did not differ significantly between the groups. As compared with lidocaine, nifekalant was associated with significantly higher rates of survival to hospital admission (67% vs 37%, p<0.001) and 24-h survival (53% vs 31%, p=0.01). Multivariate analysis showed that treatment with nifekalant and early initiation of cardiopulmonary resuscitation were independent predictors of 24-h survival.. As compared with lidocaine, nifekalant may improve short-term survival in patients with out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation.

Topics: Aged; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Epinephrine; Female; Heart Arrest; Humans; Lidocaine; Male; Middle Aged; Multivariate Analysis; Pyrimidinones; Retrospective Studies; Survival Rate; Time Factors; Ventricular Fibrillation

Because nifekalant hydrochloride (NIF) displayed a superior defibrillating effect on ventricular tachycardia/fibrillation (VT/VF) in cardiopulmonary arrest (CPA) patients, despite some QT prolongation, its effect on transmural dispersion of repolarization (TDR) in the left ventricle (LV) in an animal model of CPA was investigated.. Eight beagle dogs were created with a myocardial infarction under anesthesia, and then VT/VF induction by continuous stimulation and cardiopulmonary resuscitation (CPR) were repeated. NIF (0.3 mg/kg) was administered under acidotic conditions (pH 7.26). The QTc interval measured by Y-lead ECG showed no significant prolongation before and after NIF. The activation recovery interval (ARI) measured by 64-lead LV surface mapping showed minimum ARI prolongation (40%) by NIF without maximum ARI prolongation, and as a result the ARI dispersion decreased by 67%. The repolarization time (RPT) with the plunge electrode showed 13-19% prolongation in the subendocardium and subepicardium with CPR, but NIF prolonged the RPT in the middle layer alone (17%), and as a result Plunge-TDR decreased by 82% (n=8, p<0.05).. Administration of NIF during CPR decreased the TDR by RPT prolongation selectively in the middle layer. Because the subendocardial and subepicardial RPTs after CPR were already prolonged before NIF administration, it may have been the reason why the QT-prolonging effect of NIF was not reflected in the body surface ECG.

Topics: Animals; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Disease Models, Animal; Dogs; Heart Arrest; Heart Conduction System; Humans; Pyrimidinones; Tachycardia, Ventricular; Ventricular Fibrillation

Class I antiarrhythmic agents are not always effective in the treatment of life-threatening ventricular tachycardia/ventricular fibrillation (VT/VF) especially in patients with cardiopulmonary arrest. Nifekalant hydrochloride(NIF) is a novel class III antiarrhythmic agent for malignant VT/VF. This study prospectively evaluated NIF efficacy for life-threatening VT/VF observed after cardiopulmonary arrest.. Thirty-two of 145 patients who were transferred to the emergency room in Tokai University Hospital showed VT/VF after resuscitation from cardiopulmonary arrest from June 2000 to March 2001. These 32 patients were treated with 12 mg (mean) epinephrine and 1.0-2.0 mg/kg lidocaine following direct current application(200 to 360J), and then classified into two groups. Eleven patients received intravenous 0.15 to 0.3 mg/kg NIF followed by intravenous infusion of 0.3 to 0.4 mg/kg/hr NIF(NIF group). The other 21 patients received 1.0 to 2.0 mg/kg of lidocaine(non-NIF group).. Sinus rhythm was restored in the nine patients(82%) in the NIF group but only four patients (19%) in the non-NIF group. QTc was not prolonged(0.45 +/- 0.04 sec, n = 9) and no torsades de pointes was observed in the NIF group. Two patients survived but the remaining nine patients died in the NIF group. Five patients died of cardiac standstill following sinus bradycardia and repeated sinus arrest within 2 to 27 hr after admission, two patients died of sudden cardiac arrest from sinus rhythm, and two patients died of persistent VT/VF. In contrast, all 21 patients in the non-NIF group died. Seventeen patients died of persistent VT/VF before hospitalization, one patient died of recurrent VT/VF, and three patients died of cardiac standstill following sinus bradycardia.. NIF effectively suppresses VT/VF which is refractory to direct current shock in patients with cardiopulmonary arrest. However, NIF may rather worsen electrophysiological function in the sinus node after administration of high doses of epinephrine, and may induce sinus bradycardia and/or sinus arrest. Careful observation, such as monitoring of electrocardiography and blood pressure and temporary cardiac pacemaker use, is needed to prevent death in patients surviving after cardiopulmonary arrest if NIF is administered following high dose epinephrine infusion.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Drug Resistance; Emergency Medical Services; Epinephrine; Female; Heart Arrest; Humans; Lidocaine; Male; Middle Aged; Prospective Studies; Pyrimidinones; Tachycardia, Ventricular; Ventricular Fibrillation