Can a class III antiarrhythmic drug improve electrical defibrillation efficacy during ventricular fibrillation?

OBJECTIVES: 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. BACKGROUND: Pretreatment with class III antiarrhythmic agents is known to enhance electrical defibrillation efficacy. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Do the effects of antiarrhythmic drugs on defibrillation efficacy vary among different shock waveforms?

This study was designed to extend our knowledge on how pharmacological modification of defibrillation efficacy is associated with shock waveform. In 35 anesthetized dogs, the baseline transcardiac DFT was determined using 12-ms monophasic and three biphasic waveforms (10 ms-2 ms, 8 ms-4 ms, and 6 ms-6 ms). Twenty-eight dogs were then treated with either lidocaine (n = 7), mexiletine (n = 7), dofetilide (n = 7), or MS-551 (n = 7), while 7 dogs were left untreated to confirm the reproducibility of DFT data. Subsequently, DFT measurements were repeated in all dogs. Waveform related differences of the baseline DFT were significant, and the monophasic DFT was higher than any of the biphasic DFTs. Lidocaine increased DFT by 11% +/- 12% (12-ms monophasic), 20% +/- 20% (10 ms-2 ms, P < 0.05), 13% +/- 20% (8 ms-4 ms), and 12% +/- 10% (6 ms-6 ms, P < 0.05). With infusion of mexiletine, the DFT increased by 17% +/- 16% (P < 0.05), 9% +/- 12%, 10% +/- 10% (P < 0.05), and 4% +/- 15%, respectively. Both dofetilide and MS-551 significantly decreased the DFT regardless of the pulse waveform (dofetilide: from -18% +/- 19% to -24% +/- 19%, MS-551; from -18% +/- 11% to -32% +/- 6%). In all drug groups, waveform related differences in DFT remained significant. These results support the view that the advantages of biphasic shock waveforms are not lessened by treatment with antiarrhythmic drugs.

Effect of atrial natriuretic peptide on electrical defibrillation efficacy.

INTRODUCTION: In vitro studies have suggested that human atrial natriuretic peptide (ANP) modulates the electrophysiologic properties of myocardial cells. This study assessed whether ANP could influence defibrillation efficacy. METHODS AND RESULTS: In 35 anesthetized dogs, the transcardiac defibrillation threshold (DFT) as well as hemodynamic and electrophysiologic variables were determined before and during treatment with ANP (n = 11), hydralazine (n = 11), or saline (n = 13). ANP (1.5 microg/kg + 0.2 microg/kg per min) increased the plasma concentration of cyclic GMP (a second messenger for ANP) and significantly decreased aortic blood pressure (mean 100+/-11 mmHg to 83+/-15 mmHg). ANP also prolonged ventricular repolarization (effective refractory period 157+/-7 msec to 165+/-11 msec) and markedly reduced DFT (5.4+/-1.2 J to 3.8+/-0.7 J [P < 0.01]) without changing pulmonary artery pressure or sinus cycle length. Neither saline nor hydralazine (1.5 mg/kg) had a significant effect on DFT (saline 4.7+/-2.1 J to 4.6+/-2.4 J; hydralazine 4.3+/-2.0 J to 4.2+/-1.9 J), although hydralazine caused pronounced hypotension (mean aortic pressure 103+/-9 mmHg to 74+/-13 mmHg). CONCLUSION: These results suggest that ANP increases defibrillation efficacy, and that this effect is not necessarily shared by other vasodilating agents.

Effect of a class III antiarrhythmic drug on the configuration of dose response curve for defibrillation.

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.

Electrophysiological background of individual variability in electrical defibrillation efficacy.

This study was performed to test whether heart-to-heart variability of defibrillation efficacy is attributable to differences in postshock refractory state of nondepolarized myocardium. In 30 anesthetized dogs, a localized potential gradient was created using 1-16 V of stimulus across a pair of platinum plate electrodes on the right ventricle (5-mm interelectrode distance). The postshock recovery interval (PSRI) of the relatively refractory myocardium directly adjacent to the excited area was estimated by measuring the recovery interval after an appropriately timed field stimulus. The transcardiac defibrillation threshold (DFT) was also determined. The results showed that DFT normalized by the weight of the heart was inversely correlated with the PSRI measured with a field stimulus of 6 V (local shock intensity approximately 5 V/cm) or more (6 V: r = -0.502, P < 0.005; 16 V: r = -0.635, P < 0.0005). This observation suggests that variability of defibrillation efficacy in intact hearts is largely due to differences in the postshock refractory state of the nondepolarized myocardium.

Three-dimensional activation sequence of cesium-induced ventricular arrhythmias.

To investigate the electrophysiological and electrocardiographic characteristics of ventricular arrhythmia due to abnormal repolarization, we studied the three-dimensional activation sequence of cesium-induced ventricular tachycardia (VT) in 10 anesthetized dogs using a 384-channel recording system. Seventeen monomorphic VT (mVT) and eight polymorphic VT (pVT) episodes induced by cesium chloride (2 or 3 mM/kg) were analyzed. Only a single arrhythmogenic focus was detected in most beats of VT, whereas two competing foci were temporarily observed in two episodes of pVT. The site of arrhythmogenic focus of mVT was the endocardium (5 of 17), the midmyocardium (4 of 17), or undetermined (8 of 17). Both endocardial and midmyocardial arrhythmogenic foci were also found in pVT, and most pVT (6 of 8) were associated with the transition of the site of arrhythmogenic focus. These results are consistent with the view that both myocardial muscle fibers and Purkinje cells can cause ventricular arrhythmia due to abnormal repolarization and that changing the site of arrhythmogenic focus is the main mechanism of pVT.

Postshock recovery interval of relatively refractory myocardium as a possible explanation for disparate defibrillation efficacy between monophasic and biphasic waveforms.

We investigated the electrophysiological background for the waveform related variability of defibrillation efficacy. In 22 open-chest dogs, a localized potential gradient was created using an 8-V or 16-V field stimulus across a pair of plate electrodes separated by 5 mm. The post shock recovery interval of the nondepolarized myocardium adjacent to the excited area was estimated by the residual refractory period after an appropriately timed field stimulus. The postshock recovery interval and the defibrillation threshold were compared among six different waveforms but with the same total duration of 12 ms (n = 11) or 16 ms (n = 11). Six defibrillation thresholds in individual hearts showed a significant inverse correlation with postshock recovery intervals in most dogs (8/11) tested with a total pulse duration of 12 ms (8 V stimulus: r = -0.80 +/- 0.20 [n = 11]). In contrast, waveforms with a total duration of 16 ms failed to reveal this distinct relationship. We conclude that the waveform related variability of defibrillation efficacy is associated with the refractoriness of relatively refractory myocardium when the total pulse duration is within a certain range. However, the mechanisms responsible for waveform performance may vary as the total pulse duration changes.

Is ventricular fibrillation interval an indicator of electrical defibrillation threshold?

To clarify whether peak-to-peak interval of the fibrillation wave (VF interval) during VF is an independent indicator of defibrillation efficacy, we measured the transcardiac DFT, VF intervals of the surface and local ECGs (lead II and the right ventricle), and the ERP in 82 open-chest dogs. Both VF intervals showed a negative correlation with heart weight (surface: r = -0.358 [P < 0.005]; local; r = -0.349 [P < 0.005]). DFT was 2.0 +/- 0.7 A and positively correlated with heart weight (r = 0.453 [P < 0.0001]). ERP did not show a significant correlation with heart weight. DFT was negatively correlated with VF interval (vs surface VF interval: r = -0.568 [P < 0.0001]; vs local VF interval: r = -0.504 [P < 0.0001]), but showed only a weak negative correlation with ERP (r = -0.314 [P < 0.005]). Even after allowing for the dependency of DFT and VF intervals on heart weight (normalized to a 100-g heart), the correlation between VF interval and DFT was still significant (vs surface VF interval: r = -0.487 [P < 0.0001]; vs local VF interval: r = -0.414 [P < 0.0002]). These results suggest that VF interval is an indicator of DFT in intact hearts that have not received pharmacological intervention.