Telemedicine for genetic and neurologic evaluation in the neonatal intensive care unit.

OBJECTIVE: Evaluate whether telemedicine can be used to perform dysmorphology and neurologic examinations in the neonatal intensive care unit (NICU) by determining the examination accuracy, limitations and optimized procedures. STUDY DESIGN: Prospective evaluation of NICU patients referred for subspecialty consultation for dysmorphic features (n=10) or encephalopathy (n=10). A physician at bedside (bedside clinician) performed an in-person examination that was viewed in real time by a remote physician (remote consultant). Standardized examinations were recorded and compared. Subsequently, a qualitative approach established technique adjustments and optimization procedures necessary to improve visualization. RESULT: Telemedicine examinations identified 81 of 87 (93%) dysmorphology examination abnormalities and 37 of 39 (92%) neurologic examination abnormalities. Optimization of remote consultant visualization required an active bedside clinician assisting in camera and patient adjustments. CONCLUSION: Telemedicine can be used to perform accurately many components of the dysmorphology or neurologic examinations in NICU patients, but physicians must be mindful of specific limitations.

The cardiovascular effects of bupropion and nortriptyline in depressed outpatients.

The cardiovascular effects of bupropion hydrochloride and nortriptyline were compared in a double-blind, randomized, 6-week trial in adult outpatients with major depression. After a 1-week placebo phase, 58 patients were randomized to treatment with bupropion (225-450 mg/day) and 57 to nortriptyline (75-150 mg/day). Nortriptyline-treated patients had statistically significant heart rate increases at each assessment as determined by RR intervals on electrocardiogram (14.5-18 bpm). Bupropion-treated patients had small but statistically significant increases in supine diastolic blood pressure of 5.6 mm Hg on day 7 and 7.5 mm Hg on day 28. A few patients in each treatment group had orthostatic changes, but only nortriptyline-treated patients had symptomatic orthostatic hypotension. A slowing of cardiac conduction and possibly of rate-corrected repolarization occurred in patients treated with nortriptyline that did not occur in patients treated with bupropion. Compared to nortriptyline, bupropion appears to have a wider safety margin with regard to cardiovascular effects. This may be particularly true in the elderly, in patients with preexisting cardiovascular disease, or in overdose.

Terfenadine alters action potentials in isolated canine Purkinje fibers more than acrivastine.

Acrivastine and terfenadine are second-generation antihistamines with similar pharmacologic profiles and comparable clinical efficacies for allergic rhinitis. However, terfenadine therapy has been associated with cardiovascular side effects that include prolonged QT interval, torsades de pointes, and ventricular fibrillation (VF). We examined the adverse effects induced by terfenadine on evoked action potentials (APs) in isolated canine cardiac Purkinje fibers and determined whether acrivastine causes similar disturbances in this preparation. Terfenadine produced a statistically significant decrease in the maximal rate of increase in the AP (dV/dt) at 10(-7) M, which corresponds to the highest plasma concentration observed clinically. The IC50 (mean +/- SEM) value for terfenadine-induced inhibition of dV/dt was 1.3 +/- 0.3 x 10(-6) M. The decrease in dV/dt caused by terfenadine became more pronounced with faster rates of stimulation. Acrivastine at a concentration of 10(-5) M, a value 10 times higher than plasma concentrations observed in clinical studies, caused no significant changes in AP duration (APD) or dV/dt. The IC50 (mean +/- SEM) value for the acrivastine-induced inhibition of dV/dt was estimated to be 8.0 +/- 3.7 x 10(-3) M. Terfenadine blocked the evoked AP at 3 x 10(-6) M, whereas no block was observed with acrivastine at 10(-3) M. The effective serum concentration of acrivastine is approximately 100 times higher than that of terfenadine. Because the IC50 value for inhibition of dV/dt for acrivastine is approximately 6,000 times greater than that for terfenadine, we estimate that acrivastine is approximately 60-fold less likely to cause disturbances in cardiac conduction than terfenadine.

Cost-effectiveness analysis of the use of digoxin immune Fab (ovine) for treatment of digoxin toxicity.

Each year many people have digitalis toxicity severe enough to require extensive hospital treatment. Digoxin immune Fab[ovine]-Fab fragments (Digibind) have been shown to reverse digitalis toxicity and substantially reduce the risk of death. Data were used from uncontrolled studies of patients treated with Fab fragments as well as clinical, medical care and pharmacokinetic data from symptomatically treated patients to derive estimates of the difference in clinical outcomes and medical care costs when treating with this new drug. Estimates are derived separately for treatment of patients with toxicity that is immediately life-threatening and patients whose manifestations are not immediately life-threatening. Treatment with Fab fragments reduces the probability of dying more for the seriously toxic than for the less seriously toxic patient. Such treatment is generally associated with an increase in total medical care costs for the seriously toxic patients because more of them survive the toxic episode and require additional medical care before discharge from the hospital. For these patients, the estimated cost per life-year saved is between $1,900 and $5,400. When Fab fragments are used to treat less seriously toxic patients, total medical care costs decrease because of an estimated decreased number of days in the coronary care unit and decreased use of pacemakers and other aggressive treatments.

Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.

An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.

Results of multicenter studies of digoxin-specific antibody fragments in managing digitalis intoxication in the pediatric population.

Digitalis toxicity continues to be a problem for pediatric patients undergoing therapy with cardiac glycosides for heart failure or arrhythmias, as well as in accidental ingestions. In this article the previous use of digoxin-specific antibody Fab fragments to treat digitalis overdose or intoxication in children is reviewed. The case reports cited in the medical literature and the 57 pediatric cases gathered as a result of the multicenter clinical trial and postmarketing surveillance study reported here indicate that digoxin-specific antibody Fab fragments are effective in ameliorating signs of digitalis poisoning in children. Not only can Fab fragments rapidly eradicate potentially life-threatening arrhythmias and conduction defects, but they are also effective in treating hyperkalemia and other noncardiac manifestations of digitalis toxicity. In the small samples of patients studied to date, complications have been minimal and no allergic reactions to digoxin-specific Fab fragments have been observed. Recommendations for the management of digitalis intoxication in children are outlined.

Experience with digoxin immune Fab (ovine) in patients with renal impairment.

Digibind is a purified antigen binding fragment (Fab) of immunoglobulin G antibodies raised to bind digoxin. Studies in animals suggest renal excretion accounts for a substantial portion of Fab's elimination. Thus it is expected that elimination of antidigoxin Fab fragments would be prolonged in patients with renal impairment; it remains unclear whether digoxin might be released with possible recurrence of toxicity. To shed light on this potential for recrudescent digitalis toxicity following release of bound digoxin, the author scrutinized the records of patients with impaired renal function who were treated with Digibind. Data are available from three sources: the original multicenter investigation of Digibind in 150 patients with life-threatening digoxin or digitoxin toxicity, a postmarketing surveillance study of 745 patients treated with Digibind, and all other reports in the literature or to Burroughs Wellcome Co of physician experience with any antidigoxin Fab. Sixty percent of patients in the multicenter trial and 80% of patients in the postmarketing surveillance trial had some degree of renal impairment. Patients with poor renal function had no evidence of decreased effectiveness or safety either in terms of percent of patients responding, onset of effect or evidence of recrudescence. From all sources the authors identified 28 patients treated with Fab who were functionally anephric. Twenty-seven of these patients had no evidence of recrudescent toxicity. One patient was reported to have complete resolution of digoxin-induced third-degree atrioventricular (AV) block, but AV block recurred 10 days after Fab treatment and persisted for 10 days thereafter. Although this case offers the only clinical evidence suggesting recrudescence can occur, there were no likely alternative explanations for the clinical findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study.

One hundred fifty patients with potentially life-threatening digitalis toxicity were treated with digoxin-specific antibody fragments (Fab) purified from immunoglobulin G produced in sheep. The dose of Fab fragments was equal to the amount of digoxin or digitoxin in the patient's body as estimated from medical histories or determinations of serum digoxin or digitoxin concentrations. The youngest patient received Fab fragments within several hours of birth, and the oldest patient was 94 years old. Seventy-five patients (50%) were receiving long-term digitalis therapy, 15 (10%) had taken a large overdose of digitalis accidentally, and 59 (39%) had ingested an overdose of digitalis with suicidal intent. The clinical response to Fab was unspecified in two cases, leaving 148 patients who could be evaluated. One hundred nineteen patients (80%) had resolution of all signs and symptoms of digitalis toxicity, 14 (10%) improved, and 15 (10%) showed no response. After termination of the Fab infusion, the median time to initial response was 19 minutes, and 75% of the patients had some evidence of a response by 60 minutes. There were only 14 patients with adverse events considered to possibly or probably have been caused by Fab; the most common events were rapid development of hypokalemia and exacerbation of congestive heart failure. No allergic reactions were identified in response to Fab treatment. Of patients who experienced cardiac arrest as a manifestation of digitalis toxicity, 54% survived hospitalization.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of flecainide on occlusion and reperfusion arrhythmias in dogs.

To assess flecainide's ability to suppress ventricular fibrillation during reperfusion, we compared flecainide acetate (2 mg/kg i.v.) with saline placebo in 50 pentobarbital-anesthetized dogs undergoing proximal anterior descending coronary artery occlusion for 20 min followed by sudden release. Treatment selection was blinded and randomized. Flecainide (1 mg/kg) was given for 5 min before ligation and 1 mg/kg over the 20 min occlusion period. Heart rate, blood pressure, myocardium at risk, and QRS duration before drug infusion were similar between treatment groups. Flecainide prolonged the QRS duration 12% with no effect on heart rate or blood pressure. Dogs successfully cardioverted from ventricular fibrillation during occlusion were subjected to reperfusion. One of the 25 dogs treated with placebo fibrillated during occlusion, whereas 13 of the 25 dogs treated with flecainide fibrillated during occlusion and 10 of these 13 could not be resuscitated. Thirteen of the 25 dogs in the placebo group fibrillated during reperfusion, whereas 3 of the remaining 15 dogs in the flecainide treatment group fibrillated during reperfusion. The proarrhythmic effects of flecainide during occlusion confound interpretation of its antiarrhythmic activity during reperfusion. Thus, although flecainide may have prevented ventricular fibrillation during reperfusion, it clearly caused ventricular fibrillation during occlusion in this preparation of acute myocardial ischemia.

Effects of different paced heart rates on canine coronary occlusion and reperfusion arrhythmias.

Little information exists regarding the effect of heart rate on arrhythmias induced by coronary reperfusion. We therefore evaluated the effects of different heart rates on arrhythmias following canine coronary artery occlusion and reperfusion. Dogs were paced at either 350 msec cycle length (171 bpm; n = 30) or 480 msec cycle length (125 bpm; n = 30). They were then subjected to a 20-minute occlusion of the proximal left anterior descending coronary artery, followed by sudden reperfusion. Ligated vessel perfusion bed size (myocardial "at risk") was measured with monastral blue and red dyes. The incidence of both occlusion and reperfusion arrhythmias correlated with the myocardium at risk. Dogs paced at 171 bpm had more ventricular ectopic depolarizations (37/1000 beats vs 8/1000 beats, p less than 0.01) and a higher incidence of ventricular tachycardia during occlusion than those paced at 125 bpm (67% vs 33%, p less than 0.05). Dogs paced at the faster rate also had a higher incidence of ventricular tachycardia (83% vs 60%, p = 0.08) and ventricular fibrillation (70% vs 40%, p less than 0.05) after reperfusion. Thus, heart rate can have a substantial effect on occlusion and reperfusion arrhythmias and should be considered when making therapeutic interventions and risk assessments in this setting.

Meobentine sulfate: antiarrhythmic and electrophysiologic effects assessed by programmed electrical stimulation and ambulatory monitoring in patients with complex ventricular tachyarrhythmia. Report of a multicenter evaluation.

Five cardiology centers conducted open-label prospective trials of meobentine sulfate, an intravenously and orally available analog of bethanidine, to assess its potential for treatment of recurrent, drug refractory ventricular tachycardia (VT) or fibrillation (VF), and complex ventricular arrhythmias. The study population comprised 26 patients (mean age, 61 years); 18 were men. Coronary artery disease was present in 15, cardiomyopathy in six, and valvular heart disease in three. Patients presented with both VT and VF (seven), sustained VT alone (12), or frequent ventricular ectopy (PVCs) and nonsustained VT (seven). Of the 26 patients, 5 were enrolled in antiarrhythmic studies (chronic PVC suppression) and 21 were enrolled in programmed electrical stimulation (PES) studies. Two of five in the chronic PVC study showed greater than 75% arrhythmia suppression. Among 21 patients in PES studies, there were eight intravenous (16 mg/kg) and 19 oral trials (400 to 1000 mg every 6 hours, 3 days/dose interval). Five of 22 patients showed efficacy at repeat PES study (neither VT nor VF), one showed partial efficacy, and four were not restudied because of clinical arrhythmia (three) and/or adverse effects (two). Overall, three patients (12%) were continued on the drug for an extended period of time. Adverse experience included hypotension in 50% and gastrointestinal effects (nausea, vomiting, or diarrhea) in 56% (oral trials only). Adverse reactions led to drug discontinuation in six and dosage reduction in eight patients. Thus, meobentine may prevent induction of VT or VF or reduce frequency of complex PVCs in selected patients refractory to other antiarrhythmic agents, but the response rate is relatively low. Symptomatic hypotension or gastrointestinal adverse effects are common and may limit utility of meobentine as a chronic oral antiarrhythmic agent.

Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments.

Sixty-three patients with life-threatening digitalis intoxication were treated with purified fragments of digoxin-specific antibodies (Fab) obtained from sheep. Twenty-eight patients developed toxicity as the result of digitalis ingestion in a suicide attempt, 5 ingested a large amount of digoxin accidentally and 30 developed toxicity in the course of treatment for underlying heart disease. The dosage of digoxin-specific Fab was calculated to be equimolar to the amount of cardiac glycoside in the patient's body. Digitalis toxicity was completely reversed in most cases, with onset of effect usually within 30 minutes of administration of Fab fragments. Unbound and, therefore, active digoxin serum concentrations decreased to undetectable levels within minutes after administration of the fragments. In all patients who had elevated serum potassium concentrations caused by massive digitalis toxicity, treatment with the Fab fragments reversed the hyperkalemia. There were no obvious adverse reactions to treatment. Potentially life-threatening digitalis intoxication can be rapidly and safely reversed by treatment with purified digoxin-specific Fab fragments.

Simultaneous determination of lidocaine and its metabolites in plasma and myocardium.

No validated method exists for measuring lidocaine and its metabolites in myocardial tissue. We modified a previously described high-performance liquid chromatographic assay and applied it to plasma and to homogenized myocardial samples obtained from dogs that had received lidocaine by a double-infusion technique. Recovery of lidocaine, monoethylglycylxylidide and glycylxylidide after homogenization and extraction is reported. Assay variability, sensitivity and linearity over a wide range of sample sizes are also described. The results obtained with high-performance liquid chromatographic analysis are compared to quantitation of 14C-labeled lidocaine plus metabolites measured by an oxidation-scintillation technique. Myocardium to plasma partition coefficients for lidocaine, monoethylglycylxylidide and glycylxylidide were 2.16, 4.27, and 2.91, respectively.

Ventricular fibrillation following canine coronary artery reperfusion: different outcomes with pentobarbital and alpha-chloralose.

We compared the incidence of ventricular fibrillation after release of a 20 min-proximal left anterior descending coronary artery ligation in dogs anesthetized with either pentobarbital (N = 26) or morphine sulfate plus alpha-chloralose (N = 26). Results were analyzed using the logistic risk regression model. In each group, outcome correlated with the amount of myocardium perfused by the ligated vessel (myocardium "at risk") as measured by postmortem coronary injection of monastral dyes. At any given myocardium at risk, animals anesthetized with alpha-chloralose were less likely to fibrillate after release than those anesthetized with pentobarbital (p less than 0.01). This difference in outcome can be described by the myocardium at risk at which half the animals are expected to fibrillate (MAR50). MAR50 was 20.9 g for the pentobarbital group and 30.7 g for the alpha-chloralose group. Myocardium at risk should be taken into account in intervention studies using this coronary reperfusion arrhythmia model. We chose the logistic risk regression model to correct for this variable because it allowed a good fit of the data and offered a concise standard format for expressing the results. Outcome in reperfusion studies may be influenced by the choice of anesthetic agent.

A method for quantitating antifibrillatory effects of drugs after coronary reperfusion in dogs: improved outcome with bretylium.

We developed a quantitative approach to assess the antifibrillatory effects of short-term interventions in a canine preparation of ventricular fibrillation caused by coronary reperfusion, and applied it to evaluate the antifibrillatory effects of bretylium tosylate. Twenty-five dogs were given 10 mg/kg infusions of bretylium over 10 min, subjected to a 20 min proximal left anterior descending coronary artery ligation followed by sudden release, and compared with 25 animals given saline placebo. Drug infusion was begun 90 min before reperfusion to avoid evaluation of outcome during the phase of drug-induced catecholamine release and to allow adequate time for bretylium uptake in the myocardium. The relationship between the likelihood of ventricular fibrillation during reperfusion and the amount of myocardium perfused by the occluded vessel (myocardium at risk) was analyzed with the logistic risk-regression model. This model was developed to control for the effects of amount of myocardium at risk on outcome. For both the bretylium and the placebo groups the incidence of ventricular fibrillation correlated significantly with amount of myocardium at risk. However, animals treated with bretylium had an improved outcome for a given amount of myocardium at risk. In other words, the curve relating outcome to myocardium at risk was shifted significantly to the right. The amount of myocardium at risk required for half the placebo-treated animals to fibrillate was 20.3 g and that required for half the bretylium-treated animals to fibrillate was 27.9 g, or 37% more than that for the placebo group. This logistic risk-regression analysis format permits quantification of treatment effects while accounting for variability in amount of myocardium at risk.

Sinus node dysfunction.

The syndrome of sinus node dysfunction has become increasingly recognized as a cause of symptoms and morbidity, particularly in the elderly population. This syndrome does not represent a homogeneous disease entity. Increased investigation has shown that many pathologic conditions and pathophysiologic mechanism may lead to one of the several clinical and electrocardiographic manifestations of the sick sinus syndrome. Attempts to improve diagnostic accuracy, identify underlying mechanisms and to predict the outcome of therapy have led to the development of various diagnostic tests. However, at present these have proven of limited clinical value and the mainstay of diagnosis remains ECG monitoring. Treatment is directed at the control of symptoms with pacemaker therapy for bradyarrhythmias and combined pacemaker and antiarrhythmic drug therapy for the bradycardiatachycardia syndrome.

Use of bupropion in patients who exhibit orthostatic hypotension on tricyclic antidepressants.

Patients who developed clinically significant and documented orthostatic hypotension during treatment with tricyclic antidepressants were withdrawn from the tricyclic for at least 5 days. During a baseline period of 3-7 days a placebo identical to bupropion was then administered. A baseline electrocardiogram, psychiatric scale ratings, vital signs, clinical laboratory and physical exam were performed on those patients on placebo who were free of orthostatic hypotension for 3 consecutive days. Patients were then transferred to an ascending dosage regimen of bupropion. Only patients who were treated with bupropion for at least 7 days and who received a daily dose of at least 450 mg were considered to have completed the study. The results in 12 inpatients in 2 centers showed that bupropion produced no clinically significant alterations in pulse rate, systolic blood pressure or orthostasis as compared to placebo in patients who had clinically significant orthostatic hypotension caused by tricyclic treatment.

Comparison of the effects of bupropion and amitriptyline on cardiac conduction in depressed patients.

Tricyclic antidepressants may prolong cardiac conduction as a result of their direct cellular membrane depressant effects. These effects can be evaluated by careful quantitative assessment of the electrocardiogram (ECG). This study compared the ECG effects of bupropion and amitriptyline at therapeutically comparable doses. No significant changes were seen with bupropion in any of the ECG parameters measured (PR interval, QRS duration, QTc interval, and QRS height). Amitriptyline, however, caused a significant prolongation in PR interval (p less than .01) and QRS duration (p less than .05), as well as a decrease in QRS height (p less than .001). These results suggest that bupropion is less likely to cause cardiac conduction abnormalities in patients prone to such problems, or in those patients who overdose.