Lidocaine and Shock Proarrhythmia. Introduction: Lidocaine increases monophasic shock defibrillation energy requirement (DER) values but does not alter biphasic shock DER values. However, the mechanism of this drug/shock waveform interaction is unknown. It may be that lidocaine increases the proarrhythmic actions of monophasic shocks but not biphasic shocks. Thus, lidocaine may increase monophasic shock DER values by increasing myocardial vulnerability to shock‐induced ventricular fibrillation. Methods and Results: Area of myocardial vulnerability (AOV), defined by a two‐dimensional grid according to shock strength (y‐axis) and shock coupling interval (x‐axis), was assessed for biphasic shocks ( n = 11 ) and monophasic shocks ( n = 13 ) in intact swine hearts. Shocks were randomly delivered during right ventricular pacing at 10 shock strengths (50 to 500 V) and five coupling intervals (160 to 240 msec). AOV was defined as the number of points within the test grid that induced ventricular fibrillation. AOV, upper limit of vulnerability (ULV), and DER values were determined at baseline and during systemic infusion of lidocaine (10 mg/kg/hour). Lidocaine increased AOV, ULV, and DER values by 35%, 23%, and 36%, respectively, for monophasic shocks. However, lidocaine did not alter AOV, ULV, or DER values for biphasic shocks. Conclusion: Lidocaine increases the AOV to monophasic shocks, which is directly related to changes in ULV and DER values. This implies that lidocaine increases the proarrhythmic activity of monophasic shocks but not biphasic shocks. This may explain why lidocaine increases monophasic shock DER values.
Pericardial Procainamide Delivery. Introduction: Procainamide delivery into the pericardial space may produce a greater and more prolonged electrophysiologic effect, particularly in thin superficial atrial tissue, compared with intravenous delivery. Methods and Results: Swine were randomized to sequential procainamide doses delivered intravenously ( n = 6 ) or into the pericardial space ( n = 7 ). The cumulative pericardial doses were 0.5, 1.5, and 3.5 mg/kg, and the intravenous doses were 2, 10, and 26 mg/kg. Pericardial procainamide prolonged right atrial effective refractory period from baseline by 22% ( P < 0.01 ) but only at the 3.5 mg/kg cumulative dose. This dose slowed interatrial conduction time by 14% ( P < 0.05 ) and raised atrial fibrillation threshold by 70 mA ( P < 0.05 ). Pericardial procainamide had minimal effect on ventricular electrophysiology. Similar results occurred with a single 2 mg/kg pericardial dose in a closed chest model. Intravenous 10 and 26 mg/kg cumulative doses prolonged atrial effective refractory period from baseline by 24% and 18% ( P < 0.01 ), respectively. The 26 mg/kg cumulative intravenous dose slowed interatrial and atrial‐ventricular conduction times by 27% and 17%, respectively ( P < 0.05 ), raised atrial fibrillation threshold, and slowed ventricular conduction time by 29% ( P < 0.05 ). Pericardial procainamide produced pericardial fluid concentrations ranging from 250 to 1,500 μ g/mL, but plasma concentrations were < 1 μ g/mL. Intravenous procainamide doses produced pericardial fluid concentrations similar to plasma trough concentrations 0 to 12 μ g/mL. Conclusion: The single 2 mg/kg and 3.5 mg/kg cumulative pericardial procainamide doses prolonged atrial refractoriness and raised atrial fibrillation threshold similar to the 26 mg/kg cumulative intravenous dose, but the duration of effect was similar between delivery methods. Pericardial procainamide did not affect global or endocardial ventricular electrophysiology nor was it associated with ventricular proarrhythmia.
<i>Objective:</i> The insulin resistance syndrome is associated with atherosclerosis and cardiovascular events; however, the underlying mechanism of vascular dysfunction is unknown. The purpose of the current study was to assess endothelium- and smooth-muscle-mediated vasodilation in isolated coronary arteries from insulin-resistant rats and to determine whether insulin resistance alters the activity of the specific endothelium-derived relaxing factors. <i>Methods:</i> Male Sprague-Dawley rats were randomized to insulin resistance or control. Insulin resistance was induced by a fructose-rich diet. After 4 weeks of diet, coronary arteries were removed and vascular function was assessed in vitro using videomicroscopy. Acetylcholine (10<sup>–9</sup>–3 × 10<sup>–5</sup> <i>M</i>)- or sodium-nitroprusside (10<sup>–9</sup>–3 × 10<sup>–4</sup> <i>M</i>)-induced relaxations were determined. To evaluate the role of the specific endothelium-derived relaxing factors, several inhibitors were used, including N-nitro-<i>L</i>-arginine (LNNA), charybdotoxin/apamin (CTX/apamin), and indomethacin. <i>Results:</i> Studies with nitroprusside showed that smooth-muscle-dependent relaxation did not differ between insulin resistance and control groups. In contrast, maximal relaxation (E<sub>max</sub>) to acetylcholine was decreased in the insulin resistance group (56 ± 7%) versus control (93 ± 3%). LNNA pretreatment further impaired E<sub>max</sub> in the IR group from 56 ± 7 to 17 ± 2% (p < 0.01). In control, E<sub>max</sub> was only slightly impaired by LNNA (93 ± 3 to 63 ± 6%; p < 0.05). The addition of CTX/apamin also decreased relaxation in the control group (93 ± 3 to 47 ± 7%; p < 0.05), whereas relaxation in insulin-resistant rats was not affected (45 ± 5% with CTX/apamin vs. 56 ± 7% with acetylcholine alone, NS). Pretreatment with indomethacin did not affect relaxation in either group, while pretreatment with the combination of LNNA and CTX/ apamin completely abolished relaxation in both groups. <i>Conclusions:</i> Endothelium-dependent relaxation is impaired in small coronary arteries from insulin-resistant rats. The mechanism of this defect is related to a decrease in an endothelium-dependent, nitric oxide/prostanoid-independent relaxing factor or endothelium-derived hyperpolarizing factor.
Objective: To characterize the disposition of total and free serum digoxin following the administration of digoxin Fab antibody in patients with varying degrees of renal function. Design: Observational study of pharmacokinetics and pharmacodynamics. Setting: Critical care and telemetry units of two university-affiliated teaching institutions, Hartford Hospital and Henry Ford Hospital. Patients: Fourteen digoxin-intoxicated patients (baseline total digoxin > 3.2 nmol/mL) with mean (SD) serum creatinine of 380.1 212.2 mol/L who received digoxin Fab antibody therapy. Measurements: Serum was drawn every 12 to 24 hours for 80 to 327 hours after Fab administration. Total and free digoxin were assayed in serum by fluorescence polarization immunoassay or modified immunofluorometric assay. Results: Before Fab was administered, total digoxin ranged from 3.5 to 10.5 nmol/mL. After treatment with Fab, total digoxin increased rapidly to a mean (SD) maximum of 51.8 22.7 nmol/mL and decreased to 7.2 4.7 nmol/mL at the last measurement. Total digoxin was eliminated in a two-phase fashion. The half-life of the initial phase of total digoxin decline was 11.6 4.1 hours, and the half-life of the second or terminal elimination phase was 118 57 hours. Free digoxin levels decreased rapidly following Fab therapy, to a mean nadir of 0.6 1.1 nmol/mL, but rebounded to a mean maximum free digoxin concentration of 1.7 1.3 nmol/mL in 77 46 hours. The time to maximum free digoxin rebound occurred later in patients with end-stage renal disease (n = 4) compared with other patients (127 40 hours compared with 55 28 hours). Conclusion: Elimination of digoxin following Fab therapy is prolonged in digoxin-toxic patients with renal dysfunction. In addition, rebound of free digoxin is delayed in anephric patients. Monitoring free digoxin following the administration of Fab may be of value in selected patients to guide additional Fab dosing, confirm possible rebound toxicity, or guide the reinitiation of digoxin therapy.
Acceptability of the atrial defibrillator is partly limited by concerns about shock related anxiety and discomfort. Sedation and/or automatic cardioversion therapy during sleep may ease shock discomfort and improve patient acceptability. Three atrial cardioversion techniques were compared: patient‐activated cardioversion with sedation, automatic night cardioversion with sedation, and automatic night cardioversion without sedation. Sedation was oral midazolam (15 mg). Fifteen patients aged 60 ± 13 years were assigned each strategy randomly for three consecutive episodes of persistent atrial fibrillation requiring cardioversion. Patients completed questionnaires for multiple parameters immediately and again at 24 hours postcardioversion. Atrial cardioversion strategies with oral sedation (patient‐activated and automatic) significantly reduced shock recall by 77% (P < 0.005), therapy dissatisfaction by 57%‐71% (P < 0.03), shock discomfort by 61%‐73% (P < 0.01), shock pain by 79%‐83% (P < 0.001), and shock intensity by 73%‐77% (P < 0.03), compared to automatic night cardioversion without sedation (P < 0.02). Atrial shock pain was short‐lived and caused little disruption to the patients' daily routines. Automatic night cardioversion without sedation, resulted in sleep disturbances not seen with the other strategies (42% vs 0%, P < 0.001) as well as concerns about future pain or discomfort. Twelve patients (80%) chose patient‐activated cardioversion with sedation as their preferred treatment, and three (20%) remainder chose automatic night cardioversion with sedation. Ninety percent of patients chose automatic night cardioversion without sedation as the least acceptable therapy. Sedation significantly increases atrial shock acceptability regardless of cardioversion method. Shocks without sedation are significantly less acceptable to patients using the atrial defibrillators. (PACE 2004; 27:910–917)
An experimental model of conduction velocity (CV) and refractory period dispersion was established to determine which variable is a determinant of myocardial vulnerability. Anesthetized swine were instrumented with a left anterior descending coronary artery catheter for regional infusion of lidocaine (n = 6), low-dose d-sotalol (n = 4), high-dose d-sotalol (n = 6), or saline (n = 6), to create dispersion in CV (lidocaine), refractoriness (d-sotalol), or neither (saline). Ventricular fibrillation thresholds (VFTs) and refractory periods were determined at five sites (one drug perfused, four non-drug perfused). CV was determined in one drug-perfused area (left ventricular epicardial apex) and one non-drug perfused area (right ventricular epicardial base). Lidocaine and low- and high-dose d-sotalol increased VFT when stimuli were delivered in the drug-perfused area. However, lidocaine decreased VFT when stimuli were delivered at non-drug perfused areas by an average of 52%. Neither d-sotalol dose affected VFT when stimuli were delivered in non-drug perfused areas. Lidocaine increased CV dispersion by 18-26 cm/s but did not alter refractoriness. Both d-sotalol doses increased dispersion in refractoriness by 15-27 ms but did not alter CV. Saline did not affect either variable. Regional lidocaine had profibrillatory effects when stimuli were delivered in non-drug perfused areas, whereas regional d-sotalol did not. Hence, CV dispersion is a more likely determinant of myocardial vulnerability than refractoriness.
