Thesis (Ph. D.)--University of Washington, 1990. / Vita. Includes bibliographical references (leaves [270]-296).

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Thesis (Ph.D.)--Boston University

The endotracheal (ET) route for the administration of selected drugs has been proposed as an effective alternate route of drug administration during emergency situations when an intravenous (IV) line cannot be established. Lidocaine may be beneficial in the treatment of ventricular fibrillation (VF) resulting from acute myocardial infarction, although this hypothesis has not been confirmed in the literature. The efficacy of lidocaine in the treatment of ventricular fibrillation due to acute coronary artery ligation was examined, as well as the use of the endotracheal route as an alternative to IV injection. Rabbits were anesthetized with sodium pentobarbital or halothane, intubated with an endotracheal tube, and animals receiving pentobarbital were mechanically respired. Ventricular fibrillation was produced by occlusion of the left circumflex coronary artery, or by subsequent reperfusion of ischemic myocardium. Endotracheal administration of 2mg/Kg lidocaine (2mg/ml in normal saline) resulted in lower peak plasma lidocaine concentrations initially compared with IV injection, but more sustained levels in the therapeutic range for lidocaine (p<0.05). Administration of lidocaine either IV or ET during ventricular fibrillation resulted in a significant increase (p<0.05) in plasma lidocaine concentrations during the first minute compared with controls. During ventricular fibrillation there was no significant difference between plasma lidocaine levels following IV or ET administration. Administration of lidocaine 2mg/Kg endotracheally (in normal saline) during VF resulted in a significant decrease in the duration of fibrillation compared with untreated and normal saline controls (p <0.001). / Pharmaceutical Sciences, Faculty of / Graduate

Ventricular arrhythmias are difficult to study in man. The current experimental models are arrhythmias induced by electrical stimulation, coronary artery ligation or by subsequent reperfusion. An electrophysiological model will be useful for exploring the cellular mechanism of arrhythmias and for studying the mechanism of action of new anti-arrhythmic drugs. This project seeks to establish automaticity as a model for studying ventricular arrhythmias. Objectives 1. To review the literature on the mechanism of ventricular arrhythmias. 2. To explore ventricular automaticity induced by "reperfusion" after O₂ and substrate deprivation. 3 . To explore beta-adrenoceptor mediated ventricular automaticity. 4 . To evaluate possible new anti-arrhythmic drugs, carminomycin and ketanserin.

Background: The incidence of ventricular fibrillation (VF) out-of-hospital cardiac arrest (OHCA) treated by first responders has declined over the past decade. Since VF OHCA occurs primarily in the setting of severe coronary artery disease, primary and secondary prevention strategies may in part account for the decline. However, such strategies may not have a similar impact on non-ischemic arrest. Methods: All Rochester Minnesota residents who presented with a VF OHCA from 1991 to 2004, treated by emergency medical services (EMS), were included in the study. Incidence rates were calculated based on the population for Rochester during the time period. Changes over time were tested using Poisson regression models. The significance of the trends was estimated according to the Mantel-Haenszel test for association, and two-tailed p-values reported. Results: The overall incidence of EMS-treated VF OHCA in Rochester during the study period was 10.6 per 100,000 (95% CI 9.1-11.8). The incidence decreased significantly (p < 0.001) over the study period [1991-1994: 18.2/100,000 (95% CI 13.4-21.9); 1995-1999: 11.8/100,000 (95% CI 10.4-17.9); 2000-2004: 8.7/100,000 (95% CI 6.0-13.0)]. The incidence of VF OHCA with ischemic heart disease also declined [1991-1994: 13.4/100,000 (95% CI 8.9-16.9); 1995-1999: 11.1/100,000 (95% CI 8.2-15.9); 2000-2004: 5.5/100,000 (95% CI 3.8-8.2), p < 0.001]. In contrast, the incidence VF OHCA with non-ischemic heart disease increased [1991-1994: 2.1/100,000 (95% CI 1.13-3.1); 1995-1999: 2.3/100,000 (95% CI 1.9-3.7); 2000-2004: 2.9/100,000 (95% CI 2.0-3.4), p < 0.001]. Conclusion: The incidence of VF OHCA is declining. The decline is attributable to the reduction of VF cardiac arrest with ischemic heart disease; suggesting an impact of treatment strategies targeted at coronary artery disease. The relative increasing incidence of non-ischemic VF OHCA suggests that more efforts are required to minimize mortality in this cohort population.

Background: Ventricular fibrillation (VF) is associated with dysfunctional cardiac calcium cycling and poor survival. We hypothesized dantrolene improves survival following VF by stabilizing calcium dysregulation. Methods: VF was induced in 26 healthy Yorkshire pigs and left untreated for 4 min followed by 3 min of CPR and defibrillation. Dantrolene was infused during CPR. Rabbit hearts (n=14) were studied to evaluate the effect of dantrolene on VF-induced calcium cycling dysfunction. Results: Survival was higher in the dantrolene group. (85% vs. 39%, P=0.01) Dantrolene-treated pigs required significantly lower defibrillation energy level. (150J vs. 650J, P<0.05) Systolic pressure was significantly higher during the post-defibrillation period in the dantrolene group. (P=0.001) In rabbit hearts, dantrolene significantly mitigated the amplitude of VF-induced diastolic calcium elevations and increased the calcium alternans threshold. (P<0.05) Conclusion: Our findings suggest dantrolene facilitates successful defibrillation, prevents myocardial stunning and improves survival following VF. The effects are mediated through normalizing the VF-induced dysfunctional calcium cycling.

Background: Ventricular fibrillation (VF) is associated with dysfunctional cardiac calcium cycling and poor survival. We hypothesized dantrolene improves survival following VF by stabilizing calcium dysregulation. Methods: VF was induced in 26 healthy Yorkshire pigs and left untreated for 4 min followed by 3 min of CPR and defibrillation. Dantrolene was infused during CPR. Rabbit hearts (n=14) were studied to evaluate the effect of dantrolene on VF-induced calcium cycling dysfunction. Results: Survival was higher in the dantrolene group. (85% vs. 39%, P=0.01) Dantrolene-treated pigs required significantly lower defibrillation energy level. (150J vs. 650J, P<0.05) Systolic pressure was significantly higher during the post-defibrillation period in the dantrolene group. (P=0.001) In rabbit hearts, dantrolene significantly mitigated the amplitude of VF-induced diastolic calcium elevations and increased the calcium alternans threshold. (P<0.05) Conclusion: Our findings suggest dantrolene facilitates successful defibrillation, prevents myocardial stunning and improves survival following VF. The effects are mediated through normalizing the VF-induced dysfunctional calcium cycling.

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Thesis (Ph. D.)--University of Washington, 1994. / Vita. Includes bibliographical references (leaves [159]-165).