A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients.

Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.

Multiple sclerosis as a cause of atrial fibrillation and electrocardiographic changes.

We present the case of a young woman with an acute exacerbation of multiple sclerosis associated with paroxysmal atrial fibrillation and electrocardiographic changes characteristic of central nervous system effects on cardiac conduction. The patient presented with ataxia, vertigo, and left facial paresthesia, and was found to have a large demyelinating lesion involving the left middle and inferior cerebellar peduncles with extension rostrally into the brain stem. Profound pulmonary edema, out of proportion with the cardiac abnormalities, also developed. This confirms that demyelinating disease, like other central nervous system abnormalities, can lead to alterations in cardiac conduction, and may induce neurogenic pulmonary edema.

Verification of sleep apnea using a portable sleep apnea screening device.

Sixty-seven patients referred to a sleep laboratory with a tentative diagnosis of obstructive sleep apnea were examined with a device designed for home use as an apnea screening system. Direct comparison was made between data obtained by the portable device and by data acquired simultaneously with standard polysomnographic techniques. The portable recorder measured nasal/oral airflow, chest wall movement, cardiac rhythm, and blood oxygen saturation. There was no significant difference in the number of disordered breathing events (apneas and hypopneas) recorded by the two systems. The portable device was found to have a sensitivity of 95% and a specificity of 96%. Indications and limitations for use of the portable home apnea screening test are reviewed and guidelines for normalcy suggested.