Michael R. Ujhelyi

Pharmacokinetic aspects of digoxin-specific Fab therapy in the management of digitalis toxicity.

SummaryDigoxin intoxication occurs frequently and may require treatment with digoxin-specific Fab therapy. Little is known, however, regarding the biological fate of this compound. Pharmacokinetic studies have not been performed in healthy volunteers, but there are limited kinetic data from patients who have received therapy for the treatment of digoxin toxicity. Digoxin-specific Fab is eliminated via renal and nonrenal routes, having a volume of distribution slightly exceeding extracellular volume (0.40 L/kg) and an elimination half-life of 16 to 20 hours. Patients with renal impairment and end-stage renal disease have elimination half-life values that are prolonged up to 10-fold in magnitude, while volume of distribution is unaffected. Systemic clearance of digoxin-specific Fab is approximately 0.32 ml/min/kg in digoxin-toxic patients with preserved renal function. Renal failure also decreases Fab clearance by up to 75%. Therefore, Fab may reside in the serum of anephric patients for 2 to 3 weeks after administration.More important is the effect of Fab on the disposition of digoxin. Because digoxin-specific Fab has a stronger digoxin-binding affinity than do biological membranes, it can sequester tissue-bound and intracellular digoxin into the extracellular spaces. This results in a rapid increase in digoxin serum concentrations in the central compartment. Since the majority of digoxin is bound by Fab, it cannot interact with its biological receptor and thus reverses digoxin toxicity.The pharmacokinetic fate of total digoxin after administration of digoxin-specific Fab follows that of Fab. However, it appears that the elimination half-life of Fab is slightly shorter than that of total digoxin in patients with end-stage renal disease, suggesting that the clearance of Fab is slightly faster than that of total digoxin. Free digoxin concentrations fall rapidly after Fab administration and then rebound upwards within 12 to 24 hours. This rebound in free digoxin concentrations, however, is delayed by 12 to 130 hours in patients with renal dysfunction and end-stage renal disease. Rebound in free digoxin concentrations occurs during the initial phase of the biexponential decline of the serum concentration-time profile for digoxin-specific Fab, suggesting that distribution from the vascular spaces is the likely cause. Following the increase, free digoxin concentrations decline in a manner that is dependent on renal and nonrenal routes of elimination. During this time period it is evident that Fab retains its capability of binding digoxin while it resides in plasma.There is no evidence to support a dissociation between the Fab-digoxin complex over extended periods of time. This was demonstrated in a report where the free fraction of digoxin, in the presence of Fab remained less than the free fraction in the absence of Fab. Recent evidence also supports the role of monitoring free digoxin concentrations in certain patients who received digoxin-specific Fab therapy as they are more predictive of the pharmacological activity of digoxin than either total or bound digoxin concentrations. Indeed, free digoxin concentrations correlate with recurrences of digoxin toxicity, the need for supplemental Fab doses, and the efficacy of digoxin therapy initiated during Fab therapy.

Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias

Basic and clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) decrease fatal arrhythmias and infarct sizes. This study investigated if pericardial delivery of n-3 PUFAs would protect the myocardium from ischemic damages and arrhythmias. Acute myocardial infarctions were induced in 23 pigs with either 45 min balloon inflations or clamp occlusions of the left anterior descending coronary arteries and 180 min reperfusion. Docosahexaenoic acid (C22:6n-3, DHA, 45 mg), one of the main n-3 PUFAs in fish oil, was infused within the pericardial space only during the 40-min stabilizing phase, 45 min ischemia and initial 5 min reperfusion. Hemodynamics and cardiac functions were very similar between the DHA-treated and control groups. However, DHA therapy significantly reduced infarct sizes from 56.8 +/- 4.9% for controls (n = 12) to 28.8 +/- 7.9% (P < 0.01) for DHA-treated animals (n = 11). Compared with controls, DHA-treated animals significantly decreased heart rates and reduced ventricular arrhythmia scores during ischemia. Furthermore, three (25%) control animals experienced eight episodes of ventricular fibrillation (VF), and two died subsequent to unsuccessful defibrillation. In contrast, only 1 (9%) of 11 DHA-treated pigs elicited one episode of VF that was successfully converted via defibrillation to normal rhythm; thus, mortality was reduced from 17% in the controls to 0% in the DHA-treated animals. These data demonstrate that pericardial infusion of n-3 PUFA DHA can significantly reduce both malignant arrhythmias and infarct sizes in a porcine infarct model. Pericardial administration of n-3 PUFAs could represent a novel approach to treating or preventing myocardial infarctions.

Understanding Atrial Symptom Reports: Objective versus Subjective Predictors

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a variety of symptoms such as dizziness, palpitations, shortness of breath, and other signs of heart failure, which in turn impact quality of life (QOL). Implantable cardioverter defibrillators with atrial therapies (ICDs‐ATs) have been shown to reduce AF symptoms and improve QOL in select AF samples.

Do Patients Accept Implantable Atrial Defibrillation Therapy

Introduction: The Medtronic Jewel AF 7250 is an implantable cardioverter defibrillator with atrial and ventricular therapies (ICD‐AT). The ICD‐AT is effective in managing atrial tachyarrhythmias (atrial fibrillation [AF]), but patient acceptance remains an issue. This aim of this study was to measure ICD‐AT acceptance.

Regional hyperkalemia increases ventricular defibrillation energy requirements: role of electrical heterogeneity in defibrillation.

Regional Hyperkalemia and Defibrillation. Introduction: Increased spatial electrical heterogeneity has heen associated with impaired defibrillation efficacy. The current study investigated the relationship between electrical heterogeneity and defibrillation efficacy by manipulating spatial electrical heterogeneity. n n n nMethods and Results: We increased spatial electrical heterogeneity by infusing potassium chloride (2 to 4 mEq/hour) or placebo In the left anterior descending artery in 13 pentobarbital anesthetized swine. Electrophysiologic measurements at five myocardial sites and defibrillation energy requirement (DER) values were determined at baseline and during regional hyperkalemia (n = 7) or placebo (n = 6). Regional potassium infusion was titrated to a 20% reduction in action potential duration in the perfused region. Regional hyperkalemia increased biphasic DER values by 87% (P = 0.02), whereas infusion of placebo did not alter defibrillation efficacy. Regional hyperkalemia decreased myocardial repolarization and refractoriness in the perfused region by 21% (P < 0.001) and 18% (P = 0.01), respectively. However, regional hyperkalemia increased ventricular fibrillation cycle length (VFCL) by 39% (P = 0.008). Consequently, dispersions of repolarization, refractoriness, and VFCL were significantly increased by 169%, 92%, and 200%, respectively. Regional hyperkalemia also increased ventricular conduction time to the perfused region by 54% (P = 0.006), indicating conduction velocity dispersion, while not affecting local pacing threshold or local voltage gradient. n n n nConclusion: Regional hyperkalemia increased DER values. Regional hyperkalemia likely impairs defibrillation by increasing myocardial electrical heterogeneity, which supports the theory that electrical heterogeneity promotes nonuniform propagation of early postshock activations, thereby inhibiting defibrillation.Regional Hyperkalemia and Defibrillation. Introduction: Increased spatial electrical heterogeneity has heen associated with impaired defibrillation efficacy. The current study investigated the relationship between electrical heterogeneity and defibrillation efficacy by manipulating spatial electrical heterogeneity.

Mechanisms of antiarrhythmic drug-induced changes in defibrillation threshold: Role of potassium and sodium channel conductance☆

OBJECTIVESnWe sought to determine which ion current predominantly affects defibrillation outcomes by using specific pharmacologic probes (lidocaine [a sodium channel blocking agent] and cesium [an outward potassium channel blocking agent]) in 26 swine.nnnBACKGROUNDnThe effect of a drug on sodium or potassium channel conductance, or both, may affect defibrillation threshold values. However, it is unknown which ion channel predominates.nnnMETHODSnEach pig was randomly assigned to one of four treatment groups with two treatment phases: group 1 = placebo (D5W) in treatment phase I followed by placebo plus cesium in treatment phase II (n = 6); group 2 = lidocaine followed by lidocaine plus placebo (n = 7); group 3 = lidocaine followed by lidocaine plus cesium (n = 7); group 4 = placebo followed by placebo plus placebo (n = 6). Defibrillation threshold values and electrocardiographic measurements were obtained at baseline and at treatment phases I and II.nnnRESULTSnLidocaine increased defibrillation threshold values from baseline by 71% in group 2 (p = 0.02) and by 92% in group 3 (p < 0.01). There were no changes in defibrillation threshold values from baseline to D5W in groups 1 and 4. When D5W was added to lidocaine in group 2 and D5W in group 4, there were no significant changes in defibrillation threshold values. However, when cesium was added to lidocaine in group 3, the elevated defibrillation threshold values (mean +/- SD) returned to baseline values (from 15.7 +/- 3.46 to 7.55 +/- 3.19 J, p < 0.01). Cesium added to D5W in group 1 also significantly reduced defibrillation threshold values from 7.10 +/- 1.27 to 4.14 +/- 1.75 J (p < 0.01). The effect of cesium on defibrillation threshold values was similar between groups 1 and 3, regardless of lidocaine, such that these values were reduced by 40 +/- 14% and 51 +/- 18%, respectively (p = 0.28).nnnCONCLUSIONSnCesium, through potassium blockade, reverses lidocaine-induced elevation in defibrillation threshold values. The magnitude of defibrillation threshold reduction when cesium was added to lidocaine was similar to the defibrillation threshold reduction when cesium was added to placebo. Thus, inhibiting outward potassium conductance and prolonging repolarization decreases defibrillation threshold values independent of sodium channel blockade.

Improving the acceptability of the atrial defibrillator: patient-activated cardioversion versus automatic night cardioversion with and without sedation (ADSAS 2).

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.

Induction of Electrical Heterogeneity Impairs Ventricular Defibrillation An Effect Specific to Regional Conduction Velocity Slowing

BACKGROUNDnThis study determined whether dispersion of conduction velocity, refractoriness, or excitability increases biphasic shock defibrillation energy requirements (DERs).nnnMETHODS AND RESULTSnTwenty-four swine were instrumented with a mid-LAD perfusion catheter for regional infusion of lidocaine 0.75 mg. kg(-1). h(-1) (n=7), low-dose d-sotalol (0.16 mg. kg(-1). h(-1)) (n=4), high-dose d-sotalol (0.5 mg. kg(-1). h(-1)) (n=6), or saline (n=7). Effective refractory periods (ERPs) were determined at 5 myocardial sites, and regional conduction velocity was determined in LAD-perfused and -nonperfused regions. Regional lidocaine infusion increased DER values by 84% (P=0.008) and slowed conduction velocity by 23% to 35% (P<0.01) but did not affect ERP. Conversely, regional low- and high-dose d-sotalol infusion did not alter DER values or conduction velocity but increased regional ERP by 14% to 17% (P<0.001). Regional lidocaine increased conduction velocity dispersion by 100% to 200% (P=0.01) but did not change ERP dispersion, whereas d-sotalol increased ERP dispersion by 140% (P<0.001) without affecting conduction velocity dispersion. Lidocaine infusion induced ventricular fibrillation (VF) in 6 of 7 animals, whereas regional d-sotalol was not proarrhythmic. Regional infusion of lidocaine and d-sotalol prolonged VF cycle length by 23% to 41% (P<0.05) in the perfused region and increased VF cycle length dispersion by 85% to 240% (P<0.05). Both agents increased pacing threshold (excitability) in the perfused region by 93% to 116% (P<0.05).nnnCONCLUSIONSnRegional conduction velocity slowing increased DER values, which was probably a result of spatial dispersion of conduction velocity. Increasing refractory period dispersion without changing conduction velocity did not alter DFT values. Thus, dispersion of conduction velocity may be a more likely regulator of defibrillation efficacy than dispersion of refractoriness.

Aging effects on the organic base transporter and stereoselective renal clearance

The organic base transporter is responsible for stereoselective renal excretion. Changes in activity of this system secondary to aging may affect the disposition of an organic base in a stereoselective manner.

Lidocaine Increases the Proarrhythmic Effects of Monophasic but not Biphasic Shocks

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.