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Suppression of ventricular fibrillation and positive inotropic action of bethanidine sulfate, a chemical analog of bretylium tosylate that is well absorbed orally.

Bethanidine sulfate is a closely related chemical analog of bretylium that has virtually identical pharmacologic and antifibrillatory actions on the ventricle. Unlike bretylium, which is very poorly absorbed from the gut, bethanidine is rapidly and effectively absorbed after oral administration. Bethanidine increased ventricular fibrillation threshold in the normal dog heart from an average control value of 28.5 mA to an average peak value of 66.5 mA, an increase of 150 percent. In the infarcted heart, bethanidine increased ventricular fibrillation threshold from an average postinfarction level of 14.4 mA to an average peak value of 55.3 mA, an increase of 327 percent. Like bretylium, the antifibrillatory action of bethanidine was manifested by the appearance of nonsustained ventricular fibrillation when superthreshold shocks induced episodes of ventricular fibrillation lasting from 2 to 120 seconds and converting spontaneously to sinus rhythm. In contrast, the untreated dog heart must always be defibrillated electrically. The onset of antifibrillatory action began as early as 2 minutes after intravenous administration and 15 to 30 minutes after oral administration; peak action occurred in approximately 60 minutes. Bethanidine had prolonged positive inotropic action in the isolated heart as reflected by an increase in cardiac output and blood pressure lasting up to 60 minutes. Bethanidine lowered coronary vascular resistance and increased coronary blood flow. The oral efficacy and rapid onset of action gives bethanidine a potential role in the prevention of out-of-hospital ventricular fibrillation.

Administration, Oral↗

Ventricular fibrillation in patients without significant structural heart disease: a multicenter experience with implantable cardioverter-defibrillator therapy.

OBJECTIVES: This study was undertaken to characterize the outcome of survivors of ventricular fibrillation with no or minimal structural heart disease who received an implantable cardioverter-defibrillator. BACKGROUND: The prognosis among survivors of ventricular fibrillation with minimal or no structural cardiac abnormalities remains unclear. Since the advent of implantable cardioverter-defibrillators, this question takes on added importance. METHODS: This 10-center retrospective study provided information on 28 survivors of ventricular fibrillation (mean age 42 years) with minimal or no structural abnormalities who were treated with an implantable cardioverter-defibrillator. RESULTS: Ventricular tachyarrhythmias (polymorphic in all but one patient) were induced during baseline programmed stimulation in 39% of patients. During a median 30.6-month follow-up period after implantable cardioverter-defibrillator implantation, there were no cardiac deaths and two noncardiac deaths. Sixteen patients experienced 36 shock episodes (total 88 shocks). The majority of shocks were classified as "indeterminate"; one patient received 47 "spurious" shocks during one shock episode and each of four patients received one "appropriate" shock. Ventricular arrhythmias were not inducible in any of these latter four patients. CONCLUSIONS: Survivors of ventricular fibrillation with minimal or no structural cardiac abnormalities receiving an implantable cardioverter-defibrillator have an excellent 3-year survival rate. The occurrence, albeit infrequent, of appropriate implantable cardioverter-defibrillator shocks in this group suggests that these patients have a potential risk of recurrent cardiac arrest whose fatal outcome may be avoided by implantable cardioverter-defibrillator therapy.

Actuarial Analysis↗

Comparison of four techniques for recognition of ventricular fibrillation from the surface ECG.

Four ventricular fibrillation (VF) detection techniques were assessed using recordings of VF to evaluate sensitivity and VF-like recordings to evaluate specificity. The recordings were obtained from Coronary Care Unit patients. The techniques were: threshold crossing intervals (TCI); peaks in the autocorrelation function (ACF); signal content outside the mean frequency (VF-filter); and signal spectrum shape (spectrum). Using 70 extracts, each 4 s long, from VF recordings, the VF filter achieved a sensitivity of 77 per cent; the ACF, TCI and spectrum algorithms had sensitivities of 67, 53 and 46 per cent, respectively. Susceptibility to false alarms was assessed using 40 extracts from VF-like recordings. The TCI algorithm was the most specific (93 per cent), while the spectrum, VF filter and ACF algorithms had specificities of 72, 55 and 38 per cent, respectively. The TCI algorithm achieved overall sensitivity of 93 per cent and specificity of 60 per cent. The spectrum, VF filter and ACF algorithms had overall sensitivities of 80, 93 and 87 per cent, and overall specificities of 60, 20 and 0 per cent, respectively.

Algorithms↗

Model-based analysis of the ECG during early stages of ventricular fibrillation.

During the early stages of ventricular fibrillation (VF), identification of the changes in electrocardiographic (ECG) characteristics may be helpful in the determination of defibrillation energy for implantable defibrillators. The hypothesis that the ECG can be quantified by using autoregressive (AR) modeling during VF was tested. Electrocardiograms were recorded for durations of up to 60 seconds of VF in five isolated rabbit hearts. Fourth-order AR parameters of successive 2-second epochs with 50% overlapping of data segments were estimated. At the beginning of VF, mean values of frequency of the first and second poles were 12.5 +/- 1.2 Hz and 24.7 +/- 1.9 Hz, respectively. During VF, frequencies of these poles decreased. At the end of 60 seconds, pole frequencies were 8.7 +/- 1.1 Hz and 21.4 +/- 0.8 Hz. Intersubject variability of the frequencies of the poles was found to be low. Maximum standard deviations for the frequencies of the first and second poles were determined to be 1.9 and 2, respectively. Results of this study show that the VF ECG can be modeled by using the AR modeling technique, and it is possible to quantify the changes in the frequency content of the ECG during VF by using this modeling method.

Action Potentials↗

Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart.

BACKGROUND: Ventricular fibrillation (VF) leads to global ischemia of the heart. After 1 to 2 minutes of onset, the VF rate decreases and appears more organized. The objectives of this study were to determine the effects of no-flow global ischemia on nonlinear wave dynamics and establish the mechanism of ischemia-induced slowing of the VF rate. METHODS AND RESULTS: Activation patterns of VF in the Langendorff-perfused rabbit heart were studied with the use of 2 protocols: (1) 15 minutes of no-flow global ischemia followed by reperfusion (n=7) and (2) decreased excitability induced by perfusion with 5 micromol/L of tetrodotoxin (TTX) followed by washout (n=3). Video imaging ( approximately 7500 pixels per frame; 240 frames per second) with a voltage-sensitive dye, ECG, and signal processing (fast Fourier transform) were used for analysis. The dominant frequency of VF decreased from 13.5+/-1.3 during control to 9.3+/-1.4 Hz at 5 minutes of global ischemia (P<0.02). The dominant frequency decreased from 13.9+/-1.1 during control to 7.0+/-0.3 Hz at 2 minutes of TTX infusion (P<0.001). The rotation period of rotors on the epicardial surface (n=27) strongly correlated with the inverse dominant frequency of the corresponding episode of VF (R2=0. 93). The core area, measured for 27 transiently appearing rotors, was 5.3+/-0.7 mm2 during control. A remarkable increase in core area was observed both during global ischemia (13.6+/-1.7 mm2; P<0.001) and TTX perfusion (16.8+/-3.6 mm2; P<0.001). Density of wave fronts decreased during both global ischemia (P<0.002) and TTX perfusion (P<0.002) compared with control. CONCLUSIONS: This study suggests that rotating spiral waves are most likely the underlying mechanism of VF and contribute to its frequency content. Ischemia-induced decrease in the VF rate results from an increase in the rotation period of spiral waves that occurs secondary to an increase in their core area. Remarkably, similar findings in the TTX protocol suggest that reduced excitability during ischemia is an important underlying mechanism for the changes seen.

Animals↗

Factors related to the induction of ventricular fibrillation in the normal canine heart by programmed electrical stimulation.

Programmed electrical stimulation was performed in eight normal dogs using a stimulator and endocardial electrode catheters identical to those used in human studies. The right and left ventricular apex were paced at a drive cycle length of 400 ms and, in some cases, 500 ms, with a pacing sequence of single (S1S2), double (S1S2S3) and triple (S1S2S3S4) premature impulses introduced after eight paced complexes. Pacing sequences were performed using combinations of pulse width (1, 2 and 4 ms) and current strengths of 2, 5 and 10 times diastolic threshold, and in three dogs, 15 times diastolic threshold. Twenty-two episodes of ventricular fibrillation were initiated in five dogs in 170 pacing sequences using current strengths up to 10 times diastolic threshold, and six episodes of ventricular fibrillation in the two of three remaining dogs tested at 15 times diastolic threshold. Ventricular fibrillation was reproducible on seven of nine occasions. Ventricular fibrillation was never induced by S1S2 at up to 15 times diastolic threshold; it was induced by S1S2S3 in 3 (1.8%) of 170 sequences, but only at 10 times diastolic threshold. It was induced by S1S2S3S4 in 19 (11.4%) of 167 sequences using 2 to 10 times diastolic threshold, although 20 of 28 episodes only occurred with S1S2S3S4 at 10 or more times diastolic threshold.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Simultaneous recording of atrial and ventricular monophasic action potentials: monophasic action potential duration during atrial pacing, ventricular pacing, and ventricular fibrillation.

A newly developed transvenous suction electrode was used in dogs to record monophasic action potentials (MAPs) from the right atrium and right ventricle simultaneously. Continuous MAP recordings could be made from the same endocardial site for test periods of 1.5 hours. Left ventricular pacing at increasing heart rates resulted in a statistically significant decrease of right ventricular MAP duration. A high degree of correlation was found between right ventricular MAP duration at 90% of repolarization and the QT interval during both right atrial and left ventricular pacing. At the onset of ventricular fibrillation (VF), right ventricular MAP duration shortened to 25% of the value obtained during left ventricular pacing at a cycle length of 250 ms. A cyclic alternation in amplitude of the right ventricular MAPs was observed during VF. Fast Fourier Transform Analysis of right ventricular MAPs during VF showed a significant dominant frequency at 12 Hz, with no levels of interest beyond this frequency. This observation might prove to be useful in elaborating a new algorithm for the automatic detection of ventricular fibrillation.

Action Potentials↗

Carbon monoxide and ventricular fibrillation threshold in normal dogs.

In a blind, randomized study, the effect of breathing 100 ppm of carbon monoxide versus compressed, purified air for 2 hr on ventricular fibrillation threshold was investigated in twenty anesthetized normal open-chested dogs. The mean arterial carboxyhemoglobin level was 1.12% in the air control period, 0.99% after air, 1.10% in the carbon monoxide control period, and 6.48% after carbon monoxide. Carbon monoxide increased the mean arterial carboxyhemoglobin (P less than .001). Mean ventricular fibrillation thresholds were 19.9 +/- 6.5 mA in the carbon monoxide control period, 15.7 +/- 5.6 mA after carbon monoxide 20.8 +/- 6.3 mA in the air control period, and 24.5 +/- 9.5 mA after air. Carbon monoxide decreased the ventricular fibrillation threshold (P less than .005). These data show that breathing 100 ppm of carbon monoxide for 2 hr reduces the ventricular fibrillation threshold in anesthetized normal open-chested dogs.

Air↗

Mode of onset of malignant ventricular arrhythmias in idiopathic ventricular fibrillation.

INTRODUCTION: The mode of onset of malignant ventricular arrhythmias (ventricular tachycardia [VT] or ventricular fibrillation [VF]) has been well described in patients with organic heart disease and in patients with the long QT syndromes. Less is known about the mode of onset of VF in patients with out-of-hospital VF who have no evidence of organic heart disease or identifiable etiology. METHODS AND RESULTS: We reviewed the ECGs of all our patients with idiopathic VF. Documentation of the onset of spontaneous arrhythmias was available for 22 VF episodes in 9 patients (6 men and 3 women; age 41 +/- 16 years). In all instances, spontaneous VF followed a rapid polymorphic VT, which was initiated by premature ventricular complexes (PVCs) with very short coupling intervals. The PVC initiating VF had a coupling interval of 302 +/- 52 msec and a prematurity index of 0.4 +/- 0.07. These PVCs occurred within 40 msec of the peak of the preceding T wave. Pause-dependent arrhythmias were never observed. CONCLUSION: Cardiac arrest among patients with idiopathic VF has a very distinctive mode of onset. Documentation of a polymorphic VT that is not pause dependent is of diagnostic value.

Adult↗

Ventricular fibrillation induced by ischemia-reperfusion is not prevented by the NPY Y2 receptor antagonist BIIE0246.

Neuropeptide Y is released together with norepinephrine from sympathetic nerve terminals during conditions of increased sympathetic activity. Neuropeptide Y is known to inhibit vagal activity, and accordingly, it might increase the risk for ventricular fibrillation during myocardial ischemia-reperfusion, with concomitant sympathetic stimulation. Counteracting the inhibiting effect of neuropeptide Y by the specific neuropeptide Y2 antagonist, BIIE0246, we expected occurrence of ventricular fibrillation in association with repeated periods of myocardial ischemia-reperfusion to decrease. The midleft anterior descending coronary artery was repeatedly occluded in 16 open-chest pigs. Eight pigs received BIIE0246, and the controls received the vehicle only. Ventricular fibrillation developed in 2 animals of the control group, but in 4 pigs receiving BIIE0246. Occurrence of ventricular fibrillation and ventricular tachycardia did not differ significantly between the 2 groups, and in association with repeated periods of regional myocardial ischemia, did not decline in pigs treated by the specific neuropeptide Y2-receptor antagonist BIIE0246.

Animals↗

Comparison of bretylium and lidocaine in the prevention of ventricular fibrillation after aortic cross-clamp release in coronary artery bypass surgery.

The authors compared bretylium and lidocaine for reducing the incidence and persistence of ventricular fibrillation following aortic cross-clamp release performed during coronary artery bypass surgery. Thirty-three adult patients scheduled for elective bypass surgery were randomly assigned in a double-blind fashion to receive a bolus of bretylium, 10 mg/kg, lidocaine, 2 mg/kg, or saline, in equal volumes prior to the release of the aortic cross-clamp. Coronary artery bypass surgery was conducted using standard cardiopulmonary bypass (CPB) procedures with systemic cooling to 24 degrees to 28 degrees C. Temperature, arterial blood gases, and electrolytes were recorded. After clamp release, the first electrical rhythm was noted. Abnormal rhythms (ventricular fibrillation) were allowed to persist for 1 to 2 minutes, and if spontaneous conversion to a supraventricular rhythm did not occur, defibrillation with internal DC countershocks was applied. Patients were compared with respect to occurrence of ventricular fibrillation, need for DC countershocks, antiarrhythmic drugs, and inotropic support. There was no significant difference among the groups with respect to age, sex, preoperative medications, past medical histories, ejection fractions, average number of bypasses, cross-clamp times, or temperatures during bypass. The incidence of ventricular fibrillation after aortic cross-clamp removal was: saline 91%, lidocaine 64% (P less than 0.01), and bretylium 36% (P less than 0.01). The number of countershocks required to defibrillate, while lower in the bretylium group, did not reach statistical significance. After cardiopulmonary bypass, cardiac output and systemic vascular resistance were comparable. Bretylium warrants further study in this setting.

Aged↗

Analysis of the ventricular fibrillation ECG signal amplitude and frequency parameters as predictors of countershock success in humans.

OBJECTIVE: The purpose of this study was to assess from the ventricular fibrillation ECG signal whether certain amplitude parameters, or frequency parameters derived using fast Fourier transform analysis, are predictive of countershock success (defined as a stable supraventricular rhythm following countershock). DESIGN: Retrospective, descriptive study. SETTING: Emergency medical service at a university hospital. PATIENTS: Twenty-six patients with out-of-hospital cardiac arrest, whose initial ECG rhythm was identified as ventricular fibrillation. METHODS AND RESULTS: In all patients, advanced cardiac life support was performed in the out-of-hospital setting and a semiautomatic defibrillator was used for countershock therapy and simultaneous on-line ECG recording. For each patient, ECG data were stored in modules in digitized form over a period of 20 min and analyzed retrospectively. Using fast Fourier transform analysis of the ventricular fibrillation ECG signal in the frequency range of 0.3 to 30 Hz (mean +/- SD), median frequency, dominant frequency, edge frequency, and amplitude were as follows: 5.17 +/- 1.05 Hz, 4.56 +/- 0.99 Hz, 10.74 +/- 3.46 Hz, and 1.33 +/- 0.44 mV before successful countershock (n = 20); and 4.21 +/- 1.17 Hz (p = 0.0034), 3.31 +/- 1.57 Hz (p = 0.0004), 9.46 +/- 2.93 Hz (p = 0.5390), and 1.15 +/- 0.69 mV (p = 0.0134) before unsuccessful countershock (n = 134). Using software filters to completely eliminate interference due to manual cardiopulmonary resuscitation from the ventricular fibrillation power spectrum, only amplitude remained statistically different (p < or = 0.03) in predicting countershock success. CONCLUSIONS: We conclude that in patients, median frequency, dominant frequency, and amplitude are predictive of countershock success in humans.

Electric Countershock↗

Changes in canine ventricular fibrillation threshold induced by verapamil, flecainide and bretylium.

The changes produced by verapamil, bretylium and flecainide in both ventricular fibrillation threshold (VFT) and ventricular repetitive response threshold (VRRT) were studied in 20 closed-chest dogs anaesthetized with pentobarbital. Right ventricle endocardium thresholds were determined using bipolar electrode catheters. Increasing intensity stimulus trains (200 ms, 4 ms, 100 Hz, 1 mA steps) were delivered 50 ms after QRS; VRRT and VFT were calculated before and after drug administration. Three study groups were considered according to the drug assayed: (1) verapamil 0.15 mg.kg-1 n = 6; (2) flecainide 2.0 mg.kg-1 n = 7, and (3) bretylium 10.0 mg.kg-1 n = 7. Flecainide significantly increased VRRT (4.8 +/- 1.4 vs 9.4 +/- 1.5 mA, P < 0.05), but the latter failed to change in the other two groups. VFT remained unchanged with verapamil, increased slightly post-flecainide (10.3 +/- 4.6 vs 12.4 +/- 4.1, P < 0.05 mA) and markedly post-bretylium (10.3 +/- 4.6 vs 17.3 +/- 7.5, P < 0.05). VFT changes were significantly correlated (r = 0.77, P < 0.05) with the effective refractory period changes in the bretylium group. Thus, of the three drugs tested, bretylium induced the greatest VFT increases without modifying VRRT, whereas flecainide affected both parameters. Only in the bretylium series were ERP changes significantly correlated to the corresponding VFT changes. This suggests that ventricular fibrillation threshold increase is not a non-specific property of antiarrhythmic drugs. Changes in ventricular repetitive response threshold may provide additional information.

Animals↗

Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes.

BACKGROUND: The long-QT and Brugada syndromes are important substrates of malignant ventricular arrhythmia. The feasibility of mapping and ablation of ventricular arrhythmias in these conditions has not been reported. METHODS AND RESULTS: Seven patients (4 men; age, 38+/-7 years; 4 with long-QT and 3 with Brugada syndrome) with episodes of ventricular fibrillation or polymorphic ventricular tachycardia and frequent isolated or repetitive premature beats were studied. These premature beats were observed to trigger ventricular arrhythmias and were localized by mapping the earliest endocardial activity. In 4 patients, premature beats originated from the peripheral right (1 Brugada) or left (3 long-QT) Purkinje conducting system and were associated with variable Purkinje-to-muscle conduction times (30 to 110 ms). In the remaining 3 patients, premature beats originated from the right ventricular outflow tract, being 25 to 40 ms ahead of the QRS. The accuracy of mapping was confirmed by acute elimination of premature beats after 12+/-6 minutes of radiofrequency applications. During a follow-up of 17+/-17 months using ambulatory monitoring and defibrillator memory interrogation, no patients had recurrence of symptomatic ventricular arrhythmia but 1 had persistent premature beats. CONCLUSIONS: Triggers from the Purkinje arborization or the right ventricular outflow tract have a crucial role in initiating ventricular fibrillation associated with the long-QT and Brugada syndromes. These can be eliminated by focal radiofrequency ablation.

Adult↗

Pentobarbital versus medetomidine-ketamine-fentanyl anaesthesia: effects on haemodynamics and the incidence of ischaemia-induced ventricular fibrillation in swine.

The present study was performed to compare haemodynamic variables at baseline and the incidence of ventricular fibrillation during the early phase of ischaemia in swine during pentobarbital or medetomidine-ketamine-fentanyl anaesthesia. Twenty-two swine (mean +/- SD: 29+/- 3 kg) were anaesthetized with sodium pentobarbital (induction with 36 mg/kg intraperitoneally, and maintenance with 5-20 mg/kg/h intravenously [i.v.]) and 6 swine (27+/- 3 kg) were anaesthetized with ketamine and fentanyl (premedicated with medetomidine 0.1 mg/kg and ketamine 10 mg/kg intramuscularly, induction with ketamine 20 mg/kg and fentanyl 0.025 mg/kg i.v., and maintenance with ketamine 20 mg/kg/h and fentanyl 0.025 mg/kg/h i.v.). After a stabilization period of 30 min, the left anterior descending coronary artery (LAD) was occluded for 10 min. Haemodynamic data and occurrence of ventricular fibrillation were recorded. The ischaemic area was measured by fluorescing microspheres. Swine anaesthetized with medetomidine-ketamine-fentanyl had significantly lower heart rate, myocardial contractility, peak left ventricular pressure, arterial blood pressure, aortic blood flow, myocardial blood flow and cardiac index at baseline, than swine anaesthetized with pentobarbital. Whereas none of the swine anaesthetized with pentobarbital fibrillated during the LAD occlusion, ventricular fibrillation occurred in 83% of the animals anaesthetized with medetomidine-ketamine-fentanyl (P< 0.001). No significant difference was found in size of ischaemic area between the two groups. Thus, we show a depression in haemodynamic variables at baseline and a higher incidence of ventricular fibrillation during the early phase of ischaemia in swine anaesthetized with medetomidine-ketamine-fentanyl compared to swine anaesthetized with pentobarbital.

Anesthesia↗

High-dose fentanyl reduces intraoperative ventricular fibrillation in neonates with hypoplastic left heart syndrome.

STUDY OBJECTIVE: To determine retrospectively the effect of high-dose opiate-oxygen (O2) anesthetic technique on intraoperative ventricular fibrillation in high-risk neonates. DESIGN: Retrospective chart review of different anesthetic techniques in a partially contemporaneous patient group (1981 to 1983). SETTING: Cardiac anesthesia service at a university pediatric hospital. PATIENTS: Forty neonates undergoing Norwood Stage I repair of hypoplastic left heart syndrome. INTERVENTIONS: High-dose fentanyl-O2 anesthesia in 30 neonates and low-dose morphine sulfate 50%-nitrous oxide (N2O) in 10 neonates. MEASUREMENTS AND MAIN RESULTS: Clinical condition assessed by preoperative and intraoperative arterial blood gases, requirements for sodium bicarbonate (NaHCO3), need for inotropic and pressor support, and vital signs. Outcome assessments by intraoperative ventricular fibrillation (frequency before and after bypass) and hospital mortality. Clinical condition and hospital mortality were no different. The frequency of intraoperative ventricular fibrillation was significantly different: 3% with high-dose fentanyl and 50% with morphine-N2O (p less than 0.005). CONCLUSIONS: High-dose opiate-O2 anesthesia in these patients markedly decreased intraoperative ventricular fibrillation. Other clinical reports and recent experimental work suggest that this finding is due to high-dose opiates rather than the avoidance of N2O.

Anesthesia, Inhalation↗