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Background: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection., Methods: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years)., Results: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different., Conclusions: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

Plasma and cerebrospinal fluid (CSF) indinavir concentrations were measured by high-performance liquid chromatography. The median concentration in plasma exceeded that in CSF 10-fold. The modeled CSF curve was flat at 155 nM, and the estimated ratio of the areas under the CSF and plasma concentration-time curves was 6%. We conclude that CSF indinavir concentrations are lower than levels in plasma but exceed the clinical 95% inhibitory concentration range.

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The primary pharmacokinetic parameters (average +/- SD) analyzed were volume of distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82 ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.

Objective: To determine the prevalence and outcome of intravenous gamma-globulin (IVIG) retreatment in patients with Kawasaki disease (KD)., Method: Multicenter, retrospective survey of all children with KD evaluated at nine clinical centers across North America during a 15-month period., Results: Data were available for 378 patients. At 48 h after completion of the initial IVIG infusion, 50 patients (13.2%) remained febrile, 29 (58.0%) of whom were retreated with IVIG, including 4 (13.8%) with coronary artery abnormalities before their first IVIG infusion. Among 25 retreated patients with a normal baseline echocardiogram, 5 (20.0%) developed coronary abnormalities and were termed "treatment failures." Among the 323 patients with a normal baseline echocardiogram, only 9 (2.8%) were treatment failures; treatment failure occurred in 4 of 282 (1.4%) patients who became afebrile post-IVIG and in 5 of 41 (12.2%) patients with persistent or recrudescent fever after their first course of IVIG therapy (P=0.002)., Conclusions: The overall prevalence of new coronary abnormalities in KD patients treated with IVIG and aspirin remains low. Persistent or recrudescent fever after the first course of IVIG was associated with an increased risk of treatment failure (P=0.002). IVIG retreatment in patients who remain febrile after the first course of IVIG is now common (58.0%), although the efficacy of this practice requires assessment with a randomized trial.

Background: Kawasaki disease (KD) is an acute vasculitis of infancy and early childhood for which there is currently no diagnostic test. The clinical presentation of KD may initially resemble other infectious diseases, including bacterial or viral meningitis. For this reason lumbar puncture (LP) is sometimes performed during the evaluation of these patients. To understand the range of cerebrospinal fluid (CSF) changes that may be associated with acute KD, a retrospective review of unselected KD patients from three pediatric centers was performed., Methods: Retrospective chart review was performed on KD patients evaluated during the first 10 days of illness who had an LP performed before the administration of intravenous gamma-globulin., Results: During the 6.5-year study period, 46 KD patients underwent LP as part of their clinical evaluation. Of these patients 18 (39.1%) had CSF pleocytosis, 1 (2.2%) had a CSF glucose <45 mg/dl and 8 (17.4%) had an elevated CSF protein. Of the patients with CSF pleocytosis, the median white blood cell count was 22.5 cells (range, 7 to 320 cells), with a median of 6.0% neutrophils (range, 0 to 79%) and 91.5% mononuclear cells (range, 11 to 100%)., Conclusions: In the present series approximately one-third of KD patients who underwent an LP had CSF pleocytosis with a mononuclear cell predominance. No patient had significant hypoglycorrhachia, and elevation of the CSF protein was uncommon. CSF abnormalities were similar between US and Japanese KD patients. The basis for the CSF pleocytosis in acute KD patients remains unknown.

This study was undertaken to evaluate the intravitreal and plasma concentrations of cidofovir (HPMPC) after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis. Cohort series; undiluted vitreous and blood were collected from 9 patients at the time of pars plana vitrectomy. Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 microg 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling. The intravitreal concentration of cidofovir in humans is consistent with pharmacokinetics data in laboratory animals, and suggests that the long duration of antiviral effect (1-3 months) in clinical trials is due to a prolonged intracellular half-life in retinal tissue.

Three methods of determining digoxin population pharmacokinetic parameters were compared for their abilities to predict 118 measured serum digoxin concentrations (SDCs) in 49 patients. NONMEM software (version IV) was used to generate a residual and a weighted residual for each measured-concentration-predicted-concentration pair. Prediction error analysis was done by a maximum likelihood technique that accounted for several within-patient measures. Data analysis also included graphic observation of weighted residuals (WRES) and calculation of the mean WRES and median absolute prediction error. A further parallel analysis was also carried out on subpopulations with and without concurrent quinidine and congestive heart failure (CHF). Method III was without bias in all subpopulations studied and had the smallest WRES in all populations. Method I was without bias in the overall population, however, it underpredicted SDCs in patients receiving quinidine and in those with CHF. Method II underpredicted SDCs in the overall population, those receiving quinidine, and in patients without CHF. There were no between-method differences in precision as assessed by absolute prediction error.

This study evaluated intravitreous and plasma ganciclovir and foscarnet concentrations after intravenous administration in AIDS patients with cytomegalovirus (CMV) retinitis and retinal detachment. Undiluted vitreous samples were prospectively obtained from 60 eyes (52 patients) at the time of pars plana vitrectomy. Thirty-three plasma samples (from 27 patients in the initial group of 52) were obtained simultaneously during surgery on 33 eyes. High-pressure liquid chromatography showed the mean vitreous ganciclovir concentrations in patients on induction and maintenance therapy were, respectively, 4.74 +/- 1.49 microM (n = 24) and 3.29 +/- 1.84 microM (n = 30; P = .005). Simultaneous plasma ganciclovir concentrations were less than the vitreous concentrations in 78% of the patients. The mean intravitreous foscarnet concentrations in patients receiving induction dosages were 189 +/- 177 microM (n = 5) versus 163 +/- 167 microM (n = 4; P > .20) for those receiving maintenance therapy. The foscarnet vitreous plasma concentration ratio averaged 1.43. Current drugs and doses for CMV retinitis result in borderline or progressively subtherapeutic concentrations.

Purpose: To determine if scleral buckling is of any benefit in surgical repair of cytomegalovirus (CMV)-associated retinal detachment if combined with vitrectomy, silicone oil, and inferior midperipheral endolaser., Materials and Methods: Twenty-two consecutive eyes with CMV-associated retinal detachments were repaired with vitrectomy and endolaser to all breaks and to the inferior midperipheral retina using silicone oil without scleral buckling (group 1, control group) between July 1987 and May 1992. Results were compared with another series of 56 consecutive eyes undergoing vitrectomy, silicone oil injection, endolaser to all breaks, and 360 degrees encircling scleral buckling (group 2, study group) between June 1992 and July 1993., Results: Total retinal reattachment rates were 84% for group 1 and 86% for group 2. Rates of macular reattachment were 91% for group 1 and 91% for group 2. Mean best postoperative refracted visual acuity was 20/66 for group 1 and 20/67 for group 2. Median best postoperative refracted visual acuity was 20/74 for group 1 and 20/80 for group 2. These differences in results between the two groups were not statistically significant. Mean postoperative refractive error was +3.95 for group 1 and +4.92 for group 2. Patients who underwent surgery with the macula attached had a better postoperative visual outcome., Conclusion: Scleral buckling may not be necessary in CMV-related retinal detachment if repaired with vitrectomy, silicone oil, and inferior midperipheral endolaser. Elimination of scleral buckling may reduce intraoperative time, patient morbidity, and the risk of an accidental needle stick. Patients with macula-on retinal detachments also should be considered for surgery before macular detachment.

Purpose: Intravitreal HPMPC ([S]-1-[3-hydroxy-2 phosphonylmethoxypropyl cytosine) has a long antiviral effect in patients with cytomegalovirus retinitis. The authors evaluated the pharmacokinetics of intravitreal injections of HPMPC to understand major route of HPMPC elimination in a pigmented rabbit that had undergone scatter laser photocoagulation over half of the retinal surface., Methods: The authors treated the inferior half of the retina, receiving an average of 605 grade 3 or 4 (gray-white or white) diode laser burns in a scatter fashion in the left eyes of 13 rabbits. After 4 weeks, 13 rabbits received intravitreal injection of HPMPC (100 micrograms in 0.1 mL) in both eyes. Forty-eight hours after injection, unfixed vitreous samples were obtained for high-pressure liquid chromatography analysis. Two rabbits were used for light microscopic examination of diode laser photocoagulated retina with the perfusion fixation., Results: The HPMPC concentration in the vitreous was 5.93 +/- 1.75 micrograms/mL in the laser-treated group and 4.76 +/- 1.2 micrograms/mL in the control group 48 hours after intravitreal HPMPC injection. The difference was statistically different (P = 0.037)., Conclusions: Results showed a higher concentration of intravitreal HPMPC in the eye that had approximately 25% of the retina destroyed by the laser photocoagulation. The higher concentration is likely the result of reduced elimination and a concomitant increase in half-life. This suggests that HPMPC may be eliminated via the retinal route. Eyes with more extensive retinal involvement with human cytomegalovirus may have an even longer duration of action of intravitreal HPMPC. This may lead to modification of dosing regimens.

The non-oxidative metabolic reactions of methylation, acetylation, sulfation, glucuronidation, conjugation with amino acids (primarily with glycine), glutathione conjugation and esterase hydrolysis function to detoxify and enhance the elimination of drugs and pro-drugs, many of them as phase II reactions subsequent to oxidation. While the influence of maturation has been recognized in the development of hepatic oxidative capacity and specific pathways studied, considerably less attention has focused on the maturational effect in non-oxidative metabolism despite its role in drug deactivation, detoxification, and elimination. Consequently phase II metabolic capacities during adolescence remain primarily speculative. Conflicting data about one of these pathways, glucuronidation, suggest unexplored puberty- or gender-related phenomena influencing function in this system.

Purpose: The management of cytomegalovirus (CMV)-related rhegmatogenous retinal detachments in patients with acquired immune deficiency syndrome (AIDS) has been the subject of recent attention and controversy because of the high degree of variability in visual outcome, as well as significant differences in the reported incidence of profound postoperative optic atrophy. This study was designed to evaluate the various parameters affecting postoperative visual outcome, and to quantitate the degree of postoperative optic disc pallor., Methods: The results of 65 consecutive surgeries for CMV-related retinal detachments in 51 patients with AIDS were prospectively studied. Postoperative vision, survival, optic disc pallor, and retinitis extent were analyzed. Serial photographs of optic discs underwent masked evaluation., Results: Mean postoperative survival was 30 weeks (range, 2-146 weeks). Mean best postoperative visual acuity was 20/66 (range, 20/20-2/200) and mean final postoperative visual acuity was 20/100 (range, 20/25-no light perception). Analysis of visual outcome for eyes with no macular or papillo-macular retinitis showed a best postoperative visual acuity of 20/60 (range, 20/25-2/200) and mean final postoperative visual acuity of 20/80 (range, 20/25-no light perception). Postoperative vision was not affected by the presence of a preoperative macular detachment, with both groups (macula on or off detachments), achieving a best postoperative visual acuity of 20/60 in the absence of macular retinitis. Mild postoperative optic disc pallor was observed in 30% of surgical eyes at the final postoperative visit, and moderate pallor was noted in 13%. The mean degree of optic disc pallor was not different from the degree of optic disc pallor seen in fellow, nonsurgical eyes with CMV retinitis (surgical versus fellow nonsurgical eyes, 29% +/- 23% versus 26% +/- 30%; P = 0.64)., Conclusion: In this largest reported series of reattachment surgery for CMV-related retinal detachments, patients are experiencing increased postoperative survival, good vision, and relative optic nerve health.

To determine whether therapeutic intravitreal concentrations of ganciclovir are achieved after intravenous administration, vitreous samples were obtained intraoperatively from 23 eyes of 22 AIDS patients with retinal detachments associated with cytomegalovirus (CMV) retinitis. The mean intravitreal ganciclovir concentration of all samples was 0.93 +/- 0.39 microgram/mL (3.6 +/- 1.5 microM). This level is near the published trough serum concentrations obtained with every-12-h intravenous dosing and well below the peak. It is significantly below the concentration of ganciclovir required to achieve 50% of viral plaque formation for many human CMV strains. Only a small decrease in vitreous drug levels was observed as a function of time after last dose. Intravenous administration of ganciclovir results in near-steady-state subtherapeutic intravitreal ganciclovir concentrations for many CMV isolates. This may explain the difficulty of long-term complete suppression of CMV retinitis.

Purpose: To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis., Methods: Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune deficiency syndrome (AIDS). In 11 of these patients, clinically resistant retinitis developed, defined as new activity or progression, despite at least 8 consecutive weeks of induction doses of either foscarnet or ganciclovir. Fundus photography, pharmacokinetics, CMV cultures and sensitivities, and survival analyses were studied. The therapeutic interventions attempted after clinically resistant retinitis was identified included continuing a high dose (induction level) of the same antiviral drug, changing the antiviral drug, and combining antiviral therapy with foscarnet and ganciclovir., Results: Clinically resistant retinitis occurred in 11 (11%) of 100 patients with CMV retinitis and appeared to be a manifestation of acquired CMV antiviral drug resistance. Drug metabolism and pharmacokinetics in these patients were normal. The use of combination therapy with foscarnet and ganciclovir was effective in halting the progression of retinitis in three (75%) of four patients (6 of 7 eyes able to be evaluated) receiving combination therapy., Conclusion: Clinically resistant retinitis is a manifestation of infection by CMV that has acquired drug resistance. In these patients, combination antiviral drug treatment should be considered. It is likely that clinically resistant retinitis will become more frequent as patients with CMV retinitis and AIDS survive longer.

Inducible ventricular tachycardia frequently persists despite solitary class I antiarrhythmic drug therapy. To determine the effect of metoprolol as adjuvant therapy, 19 patients with clinical ventricular tachycardia with baseline inducible sustained monomorphic ventricular tachycardia and persistently inducible ventricular tachycardia despite class I drugs were evaluated. Eight of 19 patients (42%) became noninducible when metoprolol was added to class I drug therapy. Sixteen of 19 patients (84%) were harder to induce or noninducible on a regimen of adjuvant metoprolol therapy. In evaluating the clinical characteristics of the 19 patients, no significant differences were found between patients who were persistently inducible and those rendered noninducible. In evaluating the electrophysiologic characteristics, the group eventually rendered noninducible had a significantly shorter baseline induced cycle length (259 +/- 27 vs 305 +/- 53 msec). Combination class I drug and metoprolol therapy significantly lengthened the ventricular effective refractory period in both groups compared with baseline. The long-term follow-up was excellent in all patients remaining on metoprolol in the noninducible group. Therefore adjuvant metoprolol therapy creates a significant improvement in a number of patients with persistently inducible ventricular tachycardia despite class I drug therapy.

Objective: To determine the effect of diltiazem on survival immediately after cardiac arrest and cardiopulmonary resuscitation (CPR) in dogs., Design: Prospective, double-blind, randomized trial., Setting: Laboratory at a large, university-affiliated medical center., Subjects: Twenty-eight mongrel dogs, weighing 12 to 16 kg., Interventions: After the administration of anesthesia, catheters were placed in the pulmonary artery, aortic arch, left ventricle, right ventricle, and great cardiac vein (12 dogs) for sample collection, pressure determinations, and induction of ventricular fibrillation. Dogs were randomized to receive either diltiazem, calcium chloride, or placebo (saline) either before or early during CPR. Dogs underwent 3 mins of unassisted fibrillatory arrest followed by 10 mins of standard CPR using a pneumatic device. After 13 mins of ventricular fibrillation, defibrillation was attempted repeatedly for less than or equal to 10 mins. Successful resuscitation was defined as an organized rhythm with an unassisted systolic BP of greater than 60 mm Hg for greater than or equal to 2 mins., Measurements and Main Results: The resuscitation rate was significantly greater in diltiazem-treated animals (100%) than in those dogs receiving calcium (57%) or placebo (29%). Diltiazem-treated animals were resuscitated faster and required fewer defibrillation attempts than did dogs in the other groups. During CPR, coronary artery perfusion pressure and blood gases (arterial, venous, and myocardial) were similar among treatment groups., Conclusions: Diltiazem improves the resuscitation from experimentally induced ventricular fibrillation when administered before or early during CPR. This response may have important clinical implications in the treatment of patients undergoing cardiac arrest and CPR.

Study Objective: To determine the effect of cardiac arrest with CPR on diltiazem concentrations in dogs., Design: Prospective, double-blind, randomized trial., Setting: Laboratory at a large university-affiliated medical center., Type of Participants: Twenty mongrel dogs., Interventions: Following administration of anesthesia, catheters were placed in the pulmonary artery, aortic arch, left ventricle, and right ventricle. Dogs were randomized to receive diltiazem (0.5 mg/kg) either 60 minutes before or during cardiac arrest with CPR. After 13 minutes of cardiac arrest, defibrillation was attempted., Measurements and Main Results: Frequent blood samples for diltiazem concentrations were obtained before, during, and after cardiac arrest. The mean diltiazem concentration rose 70% during CPR in the group that received diltiazem before cardiac arrest. The group that received diltiazem during CPR had concentrations five times greater than expected during sinus rhythm., Conclusion: Increased diltiazem concentrations are observed during CPR and are probably related to altered distribution encountered during CPR.

Unlabelled: The pharmacokinetics of the controlled-release preparation of disopyramide phosphate (Norpace CR, Searle Laboratories, Chicago, IL) were studied in ten patients with cardiac arrhythmias. Multiple-serum disopyramide concentrations were obtained after a 300-mg oral dose. Each patient then received chronic oral therapy with the controlled-release preparation (400 to 1000 mg/day) on an every-12-hour schedule. At steady state, disopyramide trough concentrations were obtained. Serum disopyramide concentrations were determined by high performance liquid chromatography. The regimen was well tolerated by all patients. The mean (+/- SD) time to maximum concentration, maximum concentration, and concentrations 11 and 24 hours after the initial dose were 5.5 +/- 1.3 hours and 2.8 +/- 0.8, 2.0 +/- 0.9, and 1.2 +/- 0.5 micrograms/mL, respectively. A low Cmax to trough concentration ratio of 1.35 +/- 0.26 was observed after the initial dose. Linear regression analysis of the serum disopyramide concentrations 11 hours after initial dose (trough) versus trough concentrations at steady state (dose adjusted) showed a strong correlation (r = 0.87, intercept = 0.03, and slope = 1.9). Regression analysis also showed a strong relationship between the area under the curve (AUC) from time 0 to 11 hours after the initial dose and the trough at steady state (r = 0.86)., Conclusions: The controlled-release preparation of disopyramide, when administered every 12 hours in patients with cardiac arrhythmias, should produce low peaks to trough fluctuations. Because disopyramide concentrations after the initial dose correlate well with trough concentrations at steady state, these concentrations may provide a simple and convenient method for prospective monitoring of disopyramide therapy in patients receiving the controlled-release preparation.

The single-dose (two 100 mg doses) pharmacokinetics of rimantadine hydrochloride were compared in eight patients with end-stage renal disease who were on hemodialysis and seven age-matched healthy subjects. Plasma and urine rimantadine concentrations were determined by a GC/MS method. The plasma half-life (43.6 vs 27.5 hours) and AUC (9.9 +/- 2.1 vs 6.0 +/- 1.6 micrograms.hr/ml) were significantly (p less than 0.05) increased in the patient population. No significant differences were noted in the maximum rimantadine concentration, time of maximum concentration, or apparent volume of distribution. Urinary excretion of unchanged rimantadine accounted for 16% of the dose in the healthy subjects. Hemodialysis did not appreciably remove rimantadine. These findings suggest that rimantadine dosage may need to be reduced in patients with end-stage renal disease but supplemental doses on dialysis days are not required.

Successful therapy of atrial fibrillation (AF) has been reportedly influenced by a variety of factors including patient age, type of underlying heart disease, duration of arrhythmia, left ventricular function and left atrial (LA) size. To determine which of these factors are associated with maintenance of sinus rhythm after conversion, 43 patients with symptomatic chronic AF in the setting of a dilated left atrium (greater than or equal to 45 mm, range 45 to 78) were followed for at least 6 months after the return of sinus rhythm. Class IA drugs, IC drugs or amiodarone were used for therapy. Life table analysis showed sinus rhythm to be maintained in 81% for 6 months, 79% for 12 months and 60% for 24 months. Factors positively associated with success were conversion with drug therapy alone, duration of chronic AF less than or equal to 1 year, absence of mitral valve disease and LA dimension less than or equal to 60 mm (all p less than 0.05). Patient age, left ventricular function and presence of coronary disease were not associated with outcome. Thus, patients with moderate LA dilatation (45 to 60 mm) and a short duration of chronic AF can often be maintained in sinus rhythm, especially if they convert with pharmacologic intervention alone.

To assess the efficacy and predictability of solitary beta-adrenergic blocker (BB) therapy for ventricular tachyarrhythmia (VT), 30 patients (16 men and 14 women) with a mean age of 55 years, who initially had sustained ventricular tachycardia (70%) or ventricular fibrillation (30%), were studied. Results of baseline arrhythmia tests showed VT on ECG monitoring in 57% of the patients, during exercise in 50%, induced by programmed stimulation in 69%, increasing to 86% during isoproterenol. BB therapy prevented inducible VT during programmed stimulation in 37% of the patients, prevented VT on ECG monitoring in 54%, and prevented VT during exercise in 83%. Long-term BB therapy was given to 24 of 30 patients, whereas six other patients with hemodynamically unstable VT during BB therapy received other long-term treatment. During a mean follow-up of 824 days, 6 of 24 patients had recurrent VT. BB therapy was discontinued in two patients because of side effects. Long-term success was predicted by left ventricular ejection fraction greater than 45%, absence of coronary disease, and age less than 60 years (all p less than 0.02). Neither suppression of arrhythmia during exercise testing, nor results of programmed stimulation or ECG monitoring were predictive of outcome. Thus beta-adrenergic blockers can be effective as solitary antiarrhythmic therapy in selected patients with VT.

Simultaneous arterial (aortic), mixed venous (pulmonary artery), and myocardial venous (great cardiac vein) blood gas and lactate concentrations were obtained in 12 dogs before and during cardiac arrest and CPR. We observed marked mixed venous and myocardial venous acidosis and increased PaCO2 but normal pHa and reduced PaCO2. Furthermore, the pH was significantly lower and the PCO2 significantly higher at the myocardial venous site compared to the mixed venous site, and marked myocardial lactate production occurred during CPR. Calculated bicarbonate and CO2 content (CCO2) did not increase during CPR from any site compared to control values and actually decreased significantly in arterial and myocardial venous samples. Changes in hydrogen ion concentration in both mixed venous and myocardial venous blood correlated with changes in lactate concentration but not total CCO2. Our results during CPR demonstrate a) a significant discrepancy between arterial and mixed venous blood gases but also a large and significant discrepancy between mixed venous and myocardial venous blood gases, b) significant anaerobic systemic and myocardial metabolism, and c) that mixed venous and myocardial venous acidosis is possibly a result of lactic acidosis.

The electrophysiologic effects and antiarrhythmic efficacy of flecainide were evaluated by electrophysiologic study (EPS) in 20 patients with ventricular tachycardia (VT) refractory to an average 2.9 drugs. In 19 patients EPSs were performed with patients not receiving antiarrhythmic medications and receiving oral flecainide therapy at steady state (mean dose, 235 +/- 67 mg/day). Flecainide significantly increased the QRS complex duration (27%, P less than .001), PR interval (17%, P less than .001), and right ventricular effective refractory periods 8.5% and 21.1% (P less than .01) for the first and second extrastimuli, respectively. During baseline EPS, 17 patients were induced into VT and two were noninducible. Flecainide prevented EPS-induced VT in five patients and the induced VT became slow and hemodynamically stable in three. Two patients who failed flecainide monotherapy were induced into slow hemodynamically stable VT with flecainide in combination with amiodarone. The two noninducible patients, during baseline EPS, had suppression of spontaneous VT with flecainide. Overall, 13 of 20 patients received flecainide either alone or in combination with amiodarone for chronic therapy. Side effects encountered during the study consisted of blurred vision, dizziness, weakness, lethargy, nausea, worsened heart failure and bradyarrhythmias. After a mean 9-month follow-up (3 to 16 months) nine patients remain on flecainide therapy. There were three recurrences of slow, hemodynamically stable VT and no episodes of sudden death. Low-dose flecainide, either alone or in combination with other agents, is effective therapy for certain patients with refractory VT but heart failure remains a significant concern in patients with depressed left ventricular function.