pyrimidinones and Ventricular-Fibrillation

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Topics: Amiodarone; Anti-Arrhythmia Agents; Emergency Medical Services; Humans; Intensive Care Units; Lidocaine; Out-of-Hospital Cardiac Arrest; Placebos; Pyrimidinones; Ventricular Fibrillation

Amiodarone (AMD) and nifekalant (NIF) are used in the treatment of ventricular fibrillation or tachycardia; however, only few studies have been conducted on their efficacies. Therefore, a meta-analysis was conducted. Relevant sources were identified from PubMed, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi. The outcomes were short-term and long-term survival in patients with shock-resistant ventricular fibrillation /pulseless ventricular tachycardia. Thirty-three studies were analysed. The results showed that, compared to the control treatment, AMD did not improve short-term survival (odds ratio (OR): 1.25, 95% confidence interval (CI): 0.91-1.71) or long-term survival (OR: 1.00, 95% CI: 0.63-1.57). However, compared to the control treatment, NIF significantly improved short-term survival (OR: 3.23, 95% CI: 2.21-4.72) and long-term survival (OR: 1.88, 95% CI: 1.36-2.59). No significant difference was observed in short-term survival (OR: 0.85, 95% CI: 0.63-1.15) or long-term survival (OR: 1.25, 95% CI: 0.67-2.31) between AMD- and NIF-treated patients. The results suggest that NIF is beneficial for short-term and long-term survival in shock-resistant ventricular fibrillation/pulseless ventricular tachycardia; however, the efficacy of AMD in either outcome is not clear.

Topics: Amiodarone; Humans; Publication Bias; Pulse; Pyrimidinones; Randomized Controlled Trials as Topic; Survival Analysis; Tachycardia, Ventricular; Treatment Outcome; Ventricular Fibrillation

Early direct current (DC) shock is the most important therapy for ventricular fibrillation. Following the increased availability of automated external defibrillators (AED), the survival rate of cardiopulmonary arrest patients with ventricular fibrillation has improved. Although patients with shock-resistant ventricular fibrillation require additional antiarrhythmic drug therapy, the optimal protocol has not been established. Nifekalant is a pure potassium channel blocker with a pyrimidinedione structure. Nifekalant was approved in Japan for the treatment of life-threatening ventricular tachyarrhythmias in 1999, and is widely used as a class III antiarrhythmic intravenous drug. Intravenous amiodarone was approved in Japan in 2007, and exhibits various effects on ion channels, receptors, sympathetic activity, and thyroid function. Nifekalant and amiodarone also exhibit many pharmacological and pharmacodynamic differences. As nifekalant has no negative inotropic effect and a rapid action and clearance with a short half-life, it has some advantages over amiodarone for use in cardiopulmonary resuscitation. Indeed, data from clinical and animal studies suggest that nifekalant is superior to amiodarone for resuscitation of cardiopulmonary arrest resulting from shock-resistant ventricular fibrillation. A 300-mg bolus intravenous injection of amiodarone is considered an overdose for resuscitation of shock-resistant ventricular fibrillation. Further clinical studies are required to evaluate the effects of nifekalant compared with amiodarone, and to determine the optimal dose of amiodaone, for resuscitation of shock-resistant ventricular fibrillation.

Topics: Amiodarone; Anti-Asthmatic Agents; Defibrillators; Humans; Injections, Intravenous; Potassium Channel Blockers; Pyrimidinones; Ventricular Fibrillation

Acute coronary syndrome causes several types of arrhythmia because of its electrical instability and ischemia. The most important arrhythmia is ventricular tachycardia which degenerates to ventricular fibrillation. Prompt direct current cardioversion will be needed and prevention of ventricular tachyarrhythmia by potassium channel blocker became more popular in Japan. Nifekalant or amiodarone should be selected. Atrial fibrillation also occurred in the patients with acute coronary syndrome, and it may deteriorate hemodynamics condition. Therefore, termination and prevention of atrial fibrillation is another important issue in acute coronary syndrome. Aprindine, amiodarone, or bepridil will be the choice to prevent recurrent atrial fibrillation after direct current cardioversion.

Topics: Amiodarone; Angina, Unstable; Anti-Asthmatic Agents; Aprindine; Atrial Fibrillation; Bepridil; Electric Countershock; Humans; Myocardial Infarction; Potassium Channel Blockers; Pyrimidinones; Recurrence; Syndrome; Tachycardia, Ventricular; Ventricular Fibrillation

Arrhythmias are commonly occur after cardiac surgery. Recurrent sustained ventricular tachycardia and ventricular fibrillation in the acute phase after cardiac surgery is the most lethal arrhythmia and may warrant acute intervention and aggressive treatment. Although class I agents are usually ineffective and exacerbate the heart failure in cases with a low ejection fraction, nifekalant(a newer class III agent) and amiodarone can be effective. Hemodynamically tolerable sustained monomorphic ventricular tachycardia can be successfully terminated with ramp or burst pacing via an epicardial ventricular pacing lead. Initiation of intra-aortic balloon pumping and emergency percutaneous cardiopulmonary bypass and emergency catheter ablation can be considered for those patients not responding to the conventional resuscitative measures.

Topics: Amiodarone; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Catheter Ablation; Humans; Intra-Aortic Balloon Pumping; Postoperative Complications; Pyrimidinones; Recurrence; Tachycardia, Ventricular; Ventricular Fibrillation

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

Intravenous amiodarone (AMD) has been used for the treatment of ventricular tachycardia/fibrillation (VT/VF) in emergency care medicine. However, AMD acts slowly and is occasionally accompanied by hypotension and bradycardia. The antiarrhythmic effect of intravenous nifekalant (NIF) was assessed in patients with VT/VF complicating acute coronary syndrome (ACS) according to our study protocol.. Among a series of 1,143 ACS patients, 41 patients who suffered sustained VT/VF were enrolled; 19 failed to respond to a preceding lidocaine (LID) injection. NIF was given first as an intravenous bolus injection (0.2 mg/kg) and then as a continuous intravenous infusion at a relatively low dose level (0.2 mg x kg(-1) x h(-1)). Sustained VT/VF was successfully inhibited by NIF in 34 patients (83%). In subgroup analysis, NIF achieved VT/VF inhibition in 79% of patients who received preceding LID and in 86% of patients who received direct NIF. There were no significant changes in systolic blood pressure or heart rate following NIF therapy. A corrected QT interval was significantly prolonged (P<0.01), whereas torsade de pointes developed in only 1 patient (2%).. An intravenous bolus injection and subsequent continuous infusion of NIF at a relatively low dosage were effective in treating severe ventricular tachyarrhythmias complicating ACS, reducing the potential risk of proarrhythmia.

Topics: Acute Coronary Syndrome; Aged; Amiodarone; Anti-Arrhythmia Agents; Blood Pressure; Electrocardiography; Emergency Medical Services; Female; Heart Rate; Humans; Infusions, Intravenous; Injections, Intravenous; Lidocaine; Male; Middle Aged; Pyrimidinones; Tachycardia, Ventricular; Torsades de Pointes; Ventricular Fibrillation

Although nifekalant hydrochloride (NIFE) has been demonstrated to suppress ventricular tachyarrhythmia, especially electrical storm, the mechanism by which it does so is still unclear. We examined its effects on the spatial dispersion of repolarization (SDR) after implantable cardioverter-defibrillator (ICD) shock.. In twenty five patients with an ICD, we recorded the 87-lead ECG during sinus rhythm (the CONTROL group) under general anesthesia, after NIFE administration alone, and just after termination of induced ventricular fibrillation (VF) by ICD shock with or without NIFE administration. In all recordings, the corrected QT interval (QTc) was measured in each lead. The dispersion of QTc (QTc-D; maximum QTc minus minimum QTc) was also measured. Compared with the CONTROL, the QTc-D exhibited significant deterioration after ICD shock (61 +/- 12, 91 +/- 24 ms(1/2), respectively, p < 0.001). However, the QTc-D after NIFE administration either with or without ICD shock did not differ from the CONTROL group (65 +/- 20, 61 +/- 18, and 61 +/- 12 ms(1/2), respectively, p = 0.99).. NIFE suppressed the deterioration of SDR by ICD shock. This might be a mechanism by which NIFE suppresses recurrence of ventricular tachyarrhythmia after ICD shock.

Topics: Adrenergic beta-Antagonists; Aged; Amiodarone; Anti-Arrhythmia Agents; Defibrillators, Implantable; Electrocardiography; Female; Humans; Male; Middle Aged; Pyrimidinones; Sotalol; Tachycardia, Ventricular; Ventricular Fibrillation; Ventricular Function, Left

Nifekalant hydrochloride (NIF) is a novel intravenous class-III antiarrhythmic agent with a pirimidinedione structure that purely blocks the K+ channel without inhibiting beta-adrenergic receptors. The authors investigated the efficacy of NIF for refractory ventricular tachycardia/fibrillation (VT/VF). They studied 30 patients treated with an intravenous infusion of NIF [ 26 men, 4 women; age: 63 +/- 17 (mean +/- SD) years] at a dose of 0.19 +/- 0.14 mg/kg body weight per hour. Sixteen were patients with acute coronary syndrome (ACS), and 14 were patients with chronic structural heart disease (Chr-HD). Amiodarone and sotalol had already been administered to 9 patients with Chr-HD before the administration of NIF. The QT and T peak-end (Tp-e) intervals were measured and corrected by Bazett's method (QTc, cTp-e). The left ventricular ejection fraction was depressed (28 +/- 9%). NIF was effective for preventing VT/VF without proarrhythmia and hemodynamic deterioration in 21 patients (70%; 12 with ACS; 9 with Chr-HD), but ineffective in 4 patients (all with Chr-HD). The QTc prolongation in the responders was more pronounced than in the nonresponders (25% +/- 15% versus 5% +/- 7% increase; P < 0.05). Proarrhythmic torsade de pointes (TdP) developed transiently in the remaining 5 patients in whom the cTp-e was markedly increased compared with that in the responders (93% +/- 49% versus 37% +/- 41% increase; P < 0.05). In conclusion, these findings indicate that the intravenous administration of NIF is useful in the emergent treatment of inhibiting drug-refractory VT/VF, although proarrhythmic TdP owing to an enhancement of transmural dispersion of repolarization needs to be taken into account.

Topics: Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Diseases; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrimidinones; Risk Factors; Treatment Outcome; Ventricular Fibrillation

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

We evaluated the association between nifekalant or amiodarone on hospital admission and in-hospital mortality for cardiac arrest patients with persistent ventricular fibrillation on hospital arrival.. This was a retrospective cohort study using the Japanese Diagnosis Procedure Combination inpatient database. We identified 2961 patients who suffered cardiogenic out-of-hospital cardiac arrest and who had ventricular fibrillation on hospital arrival between July 2007 and March 2013. Patients were categorized into amiodarone (n=2353) and nifekalant (n=608) groups, from which 525 propensity score-matched pairs were generated.. We found a significant difference in the admission rate between the nifekalant and amiodarone groups in propensity score-matched groups (75.6% vs. 69.3%, respectively; difference, 6.3%; 95% confidence interval (CI), 0.9-11.7). An analysis using the hospital nifekalant/amiodarone rate as an instrumental variable found that receiving nifekalant was associated with an improved admission rate (22.2%, 95% CI, 11.9-32.4). We found no significant difference in in-hospital mortality between the nifekalant and amiodarone groups (81.5% vs. 82.1%, respectively; difference, -0.6%; 95% CI, -5.2 to 4.1). Instrumental variable analysis showed that receiving nifekalant was not associated with reduced in-hospital mortality (6.2%, 95% CI, -2.4 to 14.8).. This nationwide study suggested no significant in-hospital mortality association between nifekalant and amiodarone for cardiogenic out-of-hospital cardiac arrest patients with ventricular fibrillation/persistent ventricular tachycardia on hospital arrival. Although nifekalant may potentially improve hospital admission rates compared with amiodarone for these patients, further studies are required to confirm our results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Emergency Medical Services; Female; Hospital Mortality; Hospitalization; Humans; Male; Middle Aged; Out-of-Hospital Cardiac Arrest; Pyrimidinones; Retrospective Studies; Ventricular Fibrillation; Young Adult

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

Nifekalant is a pure potassium channel blocker that has been used to treat ventricular tachyarrhythmias since 1999 in Japan. Intravenous amiodarone was approved later than nifekalant in Japan, and it is still unclear which of the two agents is superior. The aim of this study was to compare the efficacy of nifekalant and amiodarone for resuscitation of out-of-hospital cardiopulmonary arrest caused by shock-resistant ventricular fibrillation.. From December 2005 to January 2011, ambulance services transported 283 out-of-hospital cardiopulmonary arrest patients to our hospital. Of these, 25 patients were treated with nifekalant or amiodarone in response to ventricular fibrillation that was resistant to two or more shocks. We undertook a retrospective analysis of these 25 patients.. We enrolled 20 men and 5 women with a mean age (± standard deviation) of 61.1 ± 16.4 years. All 25 patients were treated with tracheal intubation and intravenous epinephrine. Fourteen patients received nifekalant and 11 patients received amiodarone. The rates of return of spontaneous circulation (ROSC) (nifekalant, 5/14, versus amiodarone, 4/11; P = 0.97) and survival to discharge (nifekalant, 4/14, versus amiodarone, 2/11; P = 0.89) were not significantly different between the two groups. The time from nifekalant or amiodarone administration to ROSC was 6.0 ± 6.6 and 20.3 ± 10.0 min, respectively, which was significantly different (P < 0.05).. In this small sample size study, nifekalant, compared with amiodarone, is equally effective for ROSC and survival to discharge after shock-resistant ventricular fibrillation and can achieve ROSC more quickly. Further prospective studies are needed to confirm our results.

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Cardiopulmonary Resuscitation; Dose-Response Relationship, Drug; Electric Countershock; Female; Humans; Male; Middle Aged; Out-of-Hospital Cardiac Arrest; Prospective Studies; Pyrimidinones; Retrospective Studies; Ventricular Fibrillation

To compare the efficacy and safety of nifekalant, a pure class III anti-arrhythmic drug, and lidocaine in patients with shock-resistant in-hospital ventricular fibrillation (VF) or ventricular tachycardia (VT).. Between August 2005 and March 2008, we conducted a prospective, two-arm, cluster observational study, in which participating hospitals were pre-registered either to the nifekalant arm or the lidocaine arm. Patients were enrolled if they had in-hospital VF or VT resistant to at least two defibrillation shocks. Congenital or drug-induced long QT syndrome was excluded. The primary end-point was termination of VF or VT with/without additional shock. The secondary end-points were return of spontaneous circulation (ROSC), 1-month survival and survival to hospital discharge. We also assessed the frequency of adverse events, including asystole, pulseless electrical activity and torsade de pointes.. In total, 55 patients were enrolled. After nifekalant, 22 of 27 patients showed termination of VF or VT, as compared with 15 of 28 patients treated with lidocaine with/without additional shock (odds ratio (OR): 3.8; 95% confidence interval (CI): 1.1-13.0; P=0.03). Twenty-three of 27 patients given nifekalant showed ROSC, as compared with 15 of 28 patients given lidocaine (OR: 5.0; 95% CI: 1.4-18.2; P=0.01). There was no difference in 1-month survival or survival to hospital discharge between the nifekalant and lidocaine arms. There was a higher incidence of asystole with lidocaine (7 of 28 patients) than with nifekalant (0 of 27 patients) (P=0.005). Torsade de pointes was not observed.. Nifekalant was more effective than lidocaine for termination of arrhythmia and for ROSC in patients with shock-resistant in-hospital VF or VT (umin-CTR No. UMIN 000001781).

Topics: Aged; Anti-Arrhythmia Agents; Chi-Square Distribution; Female; Humans; Lidocaine; Male; Middle Aged; Prospective Studies; Pyrimidinones; Statistics, Nonparametric; Survival Rate; Tachycardia, Ventricular; Treatment Outcome; 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

Nifekalant hydrochloride (NIF) is an intravenous class-III antiarrhythmic agent that purely blocks the K(+)-channel without inhibiting β-adrenergic receptors. The present study was designed to investigate the feasibility of NIF as a life-saving therapy for out-of-hospital ventricular fibrillation (VF).. The Japanese Population-based Utstein-style study with basic and advanced Life Support Education study was a multi-center registry study with 4 participating institutes located at the northern urban area of Osaka, Japan. Eligible patients were those treated with NIF because of out-of-hospital VF refractory to 3 or more precordial shocks and intravenous epinephrine. Between February 2006 and February 2007, 17 patients were enrolled for the study. The time from a call for emergency medical service to the first shock was 12(6-26)min. The time from the first shock to the NIF administration was 25.5(9-264)min and the usage dose of NIF was 25(15-210)mg. When excluding 3 patients in whom percutaneous extracorporeal membrane oxygenation was applied before NIF administration, the rate of return of spontaneous circulation was 86% and the rate of admission alive to the hospital was 79%. One patient developed torsade de pointes.. Intravenous administration of NIF seems to be feasible as a potential therapy for advanced cardiac life-support in patients with out-of-hospital VF, and therefore further study is warranted.

Topics: Aged; Anti-Arrhythmia Agents; Defibrillators; Electric Countershock; Electrocardiography; Feasibility Studies; Female; Humans; Japan; Male; Middle Aged; Out-of-Hospital Cardiac Arrest; Patient Admission; Pilot Projects; Prospective Studies; Pyrimidinones; Registries; Survival Analysis; Survival Rate; Time Factors; Torsades de Pointes; Treatment Failure; Ventricular Fibrillation

Topics: Anti-Arrhythmia Agents; Defibrillators; Electric Countershock; Humans; Out-of-Hospital Cardiac Arrest; Patient Admission; Pyrimidinones; Survival Rate; Tachycardia, Ventricular; Time Factors; Torsades de Pointes; Treatment Failure; Ventricular Fibrillation

Multicomponent dietary supplement containing ephedra and caffeine (DSEC) was widely used for weight loss and energy enhancement. The Food and Drug Administration (FDA) banned the sale of DSEC in 2004 because of side effects such as cardiotoxity. We report a rare case of intractable ventricular fibrillation, requiring frequent defibrillation, by DSEC overdose. The direct cardiotoxity of ephedra, synergistic effect of caffeine and ephedra, and hypokalemia may cause refractory ventricular arrhythmia.

Topics: Adult; Caffeine; Dietary Supplements; Drug Overdose; Drug Synergism; Electric Countershock; Ephedra; Female; Humans; Hypokalemia; Lidocaine; Magnesium; Pyrimidinones; Ventricular Fibrillation

Ventricular tachycardia (VT), ventricular fibrillation (VF), and atrial flutter (AFL) are potentially fatal or serious complications arising after cardiac surgery. Generally, we treat these complications with class I antiarrhythmic agents and/or direct counter shock (DC). However, sometimes these complications do not respond to antiarrhythmic agents and require frequent DC. Moreover, these class I agents induce heart failure due to their negative inotropic effect. Nifekalant hydrochloride (NIF) is a class III antiarrhythmic agent that prolongs the refractory period of the atrial and ventricular myocardium without any negative inotropic action. From July 2003 to September 2004, we treated 11 patients with NIF for perioperative arrhythmias (VT 5, VF 2, and AFL 4). NIF was administered by continuous intravenous infusion (0.3 to 0.4 mg/ kg/h) to prevent the recurrence of VT/VF and AFL. NIF prevented the recurrence of VT in 3 of the 5 cases. No recurrence was observed in 2 cases with VF. Furthermore, NIF prevented the recurrence of AFL in all the 4 patients. None of the patients exhibited changes in heart rate, cardiac output, and QTc interval. Additionally, no occurrence of Torsades de pointes was observed in any of the cases. In conclusion, NIF is an effective and safe antiarrhythmic agent for the treatment of perioperative arrhythmias under continuous monitoring of the QTc interval.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Flutter; Cardiac Surgical Procedures; Female; Humans; Male; Middle Aged; Postoperative Complications; Pyrimidinones; Tachycardia, Ventricular; Ventricular Fibrillation

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

Nifekalant (NF), a pure K(+) channel blocker developed in Japan, has been reported to be effective in the treatment of life-threatening ventricular arrhythmias. We studied its efficacy in 18 men and 4 women with out-of-hospital ventricular fibrillation (VF) admitted to our emergency department between August 2001 and March 2004. The number of DC shocks delivered for out-of-hospital VF, serum Na(+) and K(+), arterial blood pH, and base excess were compared in 8 patients treated with NF, 0.3 mg/kg i.v. followed by a continuous intravenous (group N) versus 14 patients treated with lidocaine, 2 mg/kg, i.v. (group C). The two groups were similar with respect to their baseline characteristics. Sinus rhythm returned in 5 of 8 patients in group N versus 2 of 14 patients in group C (P < 0.05). These seven patients were admitted to the intensive care unit, though all died within 1 month. The results of this study suggest that NF may be effective in defibrillation of out-of-hospital VF, though controlled studies are needed to confirm our observations.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Electric Countershock; Emergency Treatment; Female; Humans; Injections, Intravenous; Male; Middle Aged; Pyrimidinones; Ventricular Fibrillation

Ventricular tachycardia (VT), which causes hemodynamic instability, and ventricular fibrillation (VF) sometimes occur in patients with severe underlying cardiovascular disease such as myocardial ischemia or infarction, and are associated with high mortality. This report presents the efficacy of nifekalant hydrochloride (nifekalant), a pure class III antiarrhythmic agent, in treating life-threatening ventricular arrhythmia in such patients. From June 2000, when nifekalant became commercially available in Japan, to May 2003, 30 ischemic heart disease (IHD) patients with VT/VF resistant to direct-current (DC) countershock received nifekalant in our hospital. These 30 patients served as the nifekalant group in this study. As a control group, we also included 33 IHD patients with VT/VF that had been resistant to DC countershock upon or during hospitalization between January 1996 and May 2000 before nifekalant became commercially available. No significant differences were observed in patient background factors and treatments between the two groups. The rates of death within 48 hours of occurrence of VT/VF were significantly lower in the nifekalant group (7%, 2/30) than in the control group (27%, 9/33; P < 0.03). The rates of cardiac death during hospitalization were also significantly lower in the nifekalant group (40%, 12/30) than in the control group (67%, 22/33; P < 0.03). The rates of survival until hospital discharge were significantly higher in the nifekalant group (57%, 17/30) than in the control group (30%, 10/33; P < 0.03). Multivariate analysis of all 63 patients revealed nifekalant administration was the factor that significantly improved the mortality (odds ratio for cardiac death, 0.26; 95% confidence interval (CI), 0.07 to 0.95; P = 0.041). Nifekalant improves the prognosis for life-threatening ventricular arrhythmia in IHD patients.

Topics: Aged; Anti-Arrhythmia Agents; Drug Administration Schedule; Electrocardiography; Female; Humans; Male; Multivariate Analysis; Myocardial Ischemia; Prognosis; Pyrimidinones; Survival Rate; Tachycardia, Ventricular; Ventricular Fibrillation

Because class I anti-arrhythmic drugs sometimes suppress cardiac function caused by their negative inotropic effects, they are not adequate for use in patients with severe heart failure, even as emergency treatment for life-threatening ventricular tachyarrhythmias (ventricular tachycardia (VT)/ventricular fibrillation (VF)).. An objective evaluation committee re-evaluated the effect of nifekalant in 191 patients with refractory VT/VF. The attack termination was achieved in 45 out of 93 patients (48.4%). Nifekalant was administered to 39 patients with direct-current (DC) shock-resistant VT/VF and directly terminated VT/VF in 9 patients. In 15 of the remaining 29 patients (51.7%), VT/VF was successfully cardioverted by additional DC shock after nifekalant administration. Prevention of recurrence was achieved in 60 out of 99 patients (60.6%). Corrected QT interval (QTc) was significantly prolonged after initial administration of nifekalant (0.463+/-0.056 to 0.504 +/-0.072), and during maintenance infusion (0.470 +/-0.056 to 0.547+/-0.070). As an adverse reaction, excess prolongation of QTc was noted in 11 patients including 3 patients with torsades de pointes. Hemodynamic parameters tended to improve after maintenance infusion of nifekalant.. Nifekalant is effective and useful for life-threatening refractory ventricular tachyarrhythmias, although careful observation of the QT interval is required.

Topics: Aged; Anti-Arrhythmia Agents; Emergency Medical Services; Female; Humans; Male; Marketing; Middle Aged; Pyrimidinones; Torsades de Pointes; 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

Topics: Angioplasty, Balloon, Coronary; Anti-Arrhythmia Agents; Coronary Angiography; Electric Countershock; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Pyrimidinones; Stents; Ventricular Fibrillation

Antiarrhythmic agents with a Class III action are known to increase defibrillation efficacy. We investigated whether a Class III drug simply shifts the dose-response curve for defibrillation or more extensively alters the curve. Forty-five dogs were divided into four groups according to the shock waveform and the presence or absence of treatment with a novel Class III drug, MS-551 (2 mg/kg bolus + 0.02 mg/kg per min). In addition to the conventional transcardiac DFT, dose-response curves were obtained by fitting the results of 40 fibrillation-defibrillation sequences at five shock strengths to a logistic model. MS-551 significantly decreased DFT regardless of the shock waveform (control vs MS-551 = 306 +/- 79 V vs 229 +/- 72 V [monophasic shock, P < 0.05], or 227 +/- 42 V vs 176 +/- 26 V [biphasic shock, P < 0.005]). The dose-response curves in dogs treated with MS-551 had a gentler slope than those without treatment, and the ratio of the voltages corresponding to 50% and 90% defibrillation success (V90/V50) was significantly greater in the MS-551 group (monophasic: 1.21 +/- 0.06 vs. 1.62 +/- 0.42 [P < 0.005], biphasic: 1.20 +/- 0.05 vs 1.37 +/- 0.18 [P < 0.01]). The V90/DFT ratio was also significantly larger in the MS-551 group (monophasic: 1.22 +/- 0.12 vs 1.66 +/- 0.37 [P < 0.001]; biphasic: 1.19 +/- 0.11 vs 1.44 +/- 0.79 [P < 0.005]). Thus, this Class III drug decreased the shock strength corresponding to relatively higher success rate (approximately 90%) less markedly than that for moderate success rate (approximately 50%). These results suggest that a Class III drug does not simply shift the dose response curve in proportion to the change in DFT, but more extensively alters its configuration.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Dogs; Electric Countershock; Electrocardiography; Electrophysiology; Pyrimidinones; Ventricular Fibrillation

We tested whether a new class III drug (MS-551) administered during ventricular fibrillation (VF) could decrease the defibrillation threshold (DFT) in anesthetized canine hearts.. Pretreatment with class III antiarrhythmic agents is known to enhance electrical defibrillation efficacy.. In a preliminary study (n = 10), we ascertained the validity of DFT determination by a sequence of incremental defibrillation shocks in a single fibrillation/defibrillation episode. We then compared the DFTs after 130 s of VF with and without administration of MS-551 (2 mg/kg body weight) at 10 s after the onset of VF in 12 open chest dogs and 8 closed chest dogs.. MS-551 decreased the DFT in both experimental models (open chest [mean +/- SD]: from 416 +/- 106 to 318 +/- 92 V, p < 0.05; closed chest: from 714 +/- 75 to 615 +/- 112 V, p < 0.05). The change (delta) in DFT in each heart was inversely correlated with the drug-induced prolongation of VF cycle length before the defibrillation attempt (delta DFT vs. delta VF cycle length 10 s before the first discharge: r = -0.58 and -0.81, p < 0.05).. MS-551 given after the induction of VF improved defibrillation efficacy. Class III antiarrhythmic agents deserve consideration when VF is resistant to electrical defibrillation during cardiopulmonary resuscitation.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Dogs; Electric Countershock; Heart; Pyrimidinones; Treatment Outcome; Ventricular Fibrillation

The antiarrhythmic effects of a new class III antiarrhythmic agent, MS-551 [1,3-dimethyl-6-(2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl) propylamino]ethylamino)-2,4(1H,3H)-pyrimidinedione hydrochloride], were investigated using canine coronary ligation-reperfusion arrhythmia models under slow and fast heart rate conditions and compared with those of d-sotalol. Slow and fast heart rate conditions were produced by using different anesthetics; i.e., halothane anesthesia for the slow heart rate condition and pentobarbital Na anesthesia for the fast heart rate condition. MS-551 prolonged QTc and suppressed the occurrence of fatal ventricular fibrillation (VF) on coronary reperfusion under either halothane or pentobarbital anesthesia. However, it also showed proarrhythmic effects, i.e., induction of torsades de pointes-like arrhythmia in 1 of 6 halothane anesthetized dogs before coronary ligation. d-Sotalol did not suppress the reperfusion VF in halothane anesthetized animals, nor did it show proarrhythmic effects. However, in the pentobarbital anesthetized animals, d-sotalol suppressed reperfusion VF accompanied by proarrhythmic effects in 1 of 7 dogs. d-Sotalol did not show reverse rate dependent QT prolongation. These results indicate that although both these class III drugs have similar electrophysiological properties, such as QTc prolongation, they have different antiarrhythmic effects. Also, antifibrillatory effects of class III drugs on coronary reperfusion apparently can not be explained solely by their QT prolonging effects.

Topics: Animals; Anti-Arrhythmia Agents; Dogs; Female; Halothane; Ligation; Male; Myocardial Reperfusion; Pentobarbital; Pyrimidinones; Sotalol; Ventricular Fibrillation

We studied the electrophysiologic and antifibrillatory properties of MS-551 (1,3-dimethyl-6-((2-[N-hydroxy-ethyl)-3-(4-nitrophenyl) propylamino] ethylamino) 2,4(1H,3H) pyrimidinedione hydrochloride) in a conscious canine model of sudden cardiac death. Three to 5 days after surgically induced myocardial infarction (MI: 2-h occlusion of the left anterior descending coronary artery, LAD), animals were subjected to programmed electrical stimulation (PES) to identify those at risk for sudden cardiac death. MS-551 was administered (2.0, 3.0, or 4 x 2.0 mg/kg intravenously, i.v.). Vehicle-treated animals received 0.9% sodium chloride solution for injection. MS-551 (multiple-dose regimen) increased ventricular effective refractory period (VERP) from 112 +/- 4 to 137 +/- 4 ms (p < 0.05) as compared with vehicle treatment, which did not alter VERP (125 +/- 6 to 121 +/- 5 ms). MS-551 prolonged QTc interval from a predrug value of 293 +/- 8 to 333 +/- 18 ms postdrug. The size of surgically induced MI did not differ among groups: 2.0 mg/kg, 23 +/- 4%; 3.0 mg/kg, 28 +/- 2%; 4 x 2.0 mg/kg, 25 +/- 3%; and vehicle, 28 +/- 3% of the left ventricle. Single bolus administration of MS-551 (2.0 or 3.0 mg/kg i.v.) did not confer significant protection against sudden cardiac death. However, repeated administration of MS-551 protected against sudden cardiac death in 8 of 10 dogs as compared with 2 of 12 in the vehicle-treated group (p < 0.05). The data indicate that a multiple-dose regimen of MS-551 provides protection against ischemia-induced ventricular fibrillation (VF) in the postinfarcted heart. The mechanism by which MS-551 achieves its antifibrillatory effect most likely depends on its ability to prolong VERP of myocardium without altering ventricular conduction velocity.

Topics: Animals; Anti-Arrhythmia Agents; Chromatography, High Pressure Liquid; Death, Sudden, Cardiac; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Electrocardiography; Electrophysiology; Male; Myocardial Infarction; Pyrimidinones; Random Allocation; Ventricular Fibrillation

We studied the electrophysiologic and antifibrillatory effects of the class III agent MS-551 in a rabbit isolated heart model in which ventricular fibrillation (VF) occurs reproducibly under conditions of hypoxia/reoxygenation in the presence of the ATP-dependent potassium channel opener, pinacidil. Ten minutes after MS-551 or vehicle administration, addition of pinacidil (1.25 microM) to the buffer was followed by a 12-min hypoxic period and 40-min reoxygenation. At a low concentration of MS-551 (1.0 microM), VF occurred in 5 of 6 hearts, the same incidence as in the control group (5 of 6). In contrast 0 of 6 hearts treated with 15 microM MS-551 developed VF (p < 0.05 vs. vehicle). Ventricular effective refractory period (VERP) was determined in a separate group of isolated hearts (n = 13). Pinacidil alone, during normoxic perfusion, decreased VERP 48 +/- 11% (p < 0.05) 15 min after exposure. Five minutes of hypoxia alone also decreased VERP (57 +/- 8%, p < 0.05). Under normoxic conditions, MS-551 increased ERP 31 +/- 10% (p < 0.05 vs. baseline). VERP prolongation by MS-551 was reduced in the presence of pinacidil but remained 22 +/- 6% (p < 0.05) above baseline. The results suggest that VERP shortening owing to pinacidil-mediated ATP-dependent K+ channel opening is associated with development of VF in isolated heart. MS-551 attenuates the pinacidil-mediated decrease in VERP and prevents pinacidil+hypoxia-reoxygenation-induced VF. Because pinacidil and hypoxia open myocardial KATP channels, putatively decreasing VERP, MS-551 may exert its antifibrillatory effect through partial blockade of KATP channels.

Topics: Animals; Anti-Arrhythmia Agents; Disease Models, Animal; Dogs; Guanidines; Heart; Heart Atria; Hypoxia; In Vitro Techniques; Pinacidil; Pyrimidinones; Rabbits; Vasodilator Agents; Ventricular Fibrillation

The effects of SK&F 93479, a potent histamine H2-receptor antagonist, on ventricular arrhythmias induced by coronary artery ligation in dogs and rats, and by aconitine infusion in mice were investigated. It was found that SK&F 93479 in large doses, significantly prevented the occurrence of spontaneous ventricular fibrillation and the changes in ventricular fibrillation threshold following coronary artery ligation in dogs. In rats subjected to ligation of the main left coronary artery, it significantly reduced the incidence of ventricular fibrillation, and significantly prolonged the time of onset of ventricular tachycardia and ventricular fibrillation. On the contrary, SK&F 93479 did not significantly alter the incidence or the time of onset of cardiac dysrhythmias caused by aconitine infusion in mice. These findings suggest that SK&F 93479 lacks non-specific antiarrhythmic activity and that its protective effects against coronary artery ligation may be mediated by its histamine H2-receptor antagonizing action. They also support the hypothesis that histamine may contribute to the genesis of ventricular arrhythmias resulting from acute myocardial ischaemia.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Dogs; Electrocardiography; Histamine H2 Antagonists; Male; Mice; Mice, Inbred ICR; Pyrimidinones; Rats; Rats, Inbred Strains; Ventricular Fibrillation