Comparison of PR, QRS, and QT interval measurements by seven ECG interpretation programs.

BACKGROUND: Electrocardiograph-generated measurements of PR, QRS, and QT intervals are generally thought to be more precise than manual measurements on paper records. However, the performance of different programs has not been well compared. METHODS: Routinely obtained digital electrocardiograms (ECGs), including over 500 pediatric ECGs, were used to create over 2000 10 s analog ECGs that were replayed through seven commercially available electrocardiographs. The measurements for PR interval, QRS duration, and QT interval made by each program were extracted and compared against each other (using the median of the programs after correction for program bias) and the population mean values. RESULTS: Small but significant systematic biases were seen between programs. The smallest and largest variation from the population mean differed by 4.7 ms for PR intervals, 5.8 ms for QRS duration, and 12.4 ms for QT intervals. In pairwise comparison programs showed similar accuracy for most ECGs, with the average absolute errors at the 75th percentile for PR intervals being 4-6 ms from the median, QRS duration 4-8 ms, and QT interval 6-10 ms. However, substantial differences were present in the numbers and extent of large, clinically significant errors (e.g at the 98th percentile), for which programs differed by a factor of two for absolute errors, as well as differences in the mix of overestimations and underestimations. CONCLUSIONS: When reading digital ECGs, users should be aware that small systematic differences exist between programs and that there may be large clinically important errors in difficult cases.

Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures.

OBJECTIVE: To evaluate the cardiac safety of adjunctive lacosamide in a large pool of adults with partial-onset seizures (POS). METHODS: Post-randomization changes from baseline for electrocardiographic (ECG) measurements, diagnostic findings, and relevant adverse events (AEs) were compared for pooled data from three randomized, placebo-controlled trials of adjunctive lacosamide for the treatment of POS. RESULTS: Lacosamide did not prolong the QTc interval or affect heart rate as determined by an analysis of data from patients randomized to lacosamide 200, 400, or 600 mg/day (n = 944) compared with placebo (n = 364). After 12-week maintenance treatment, mean changes from baseline for QRS duration were similar between the placebo and lacosamide 200 and 400 mg/day groups (0.0, -0.2, and 0.4 ms), but slightly increased for lacosamide 600 mg/day (2.3 ms). A small, dose-related mean increase in PR interval was observed (-0.3, 1.4, 4.4, and 6.6 ms for the placebo and lacosamide 200, 400, and 600 mg/day groups, respectively). First-degree atrioventricular (AV) block was reported as a non-serious AE in 0.0%, 0.7%, 0.2%, and 0.5% of patients in the same respective groups. Second- or higher degree AV block was not observed. There was no evidence of a PR-interval-related pharmacodynamic interaction of lacosamide with either carbamazepine or lamotrigine. CONCLUSIONS: Evaluation of the pooled cardiac safety data from patients with POS showed that adjunctive lacosamide at the maximum recommended dose (400 mg/day) was not clearly associated with any cardiac effect other than a small, dose-related increase in PR interval that had no evident symptomatic consequence.

Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil.

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

Psychogenic lowering of urinary cortisol levels linked to increased emotional numbing and a shame-depressive syndrome in combat-related posttraumatic stress disorder.

OBJECTIVE: The purpose of the study was to search for the intrapsychic correlates of individual differences in cortisol levels in male Vietnam combat veterans with posttraumatic stress disorder. METHODS: The study involved measurement of urinary cortisol levels and clinical assessment with a broad profile of psychometric tests during a single 48-hour period in 30 inpatients. RESULTS: The main finding by both correlation and t test analyses was a significant inverse relationship between urinary cortisol levels and a symptom complex composed of two closely interrelated clinical subgroupings, "disengagement" (principally involving emotional numbing) and "shame-laden depression." CONCLUSIONS: The findings support the concept that cortisol levels reflect the ongoing balance between the undifferentiated emotional arousal state of engagement (associated with higher cortisol levels) and opposing antiarousal disengagement defense mechanisms (associated with lower cortisol levels). It appears that the low cortisol levels often seen in patients with posttraumatic stress disorder are psychogenic and reflect a dominating effect of disengagement coping strategies, which represent secondary compensatory adaptations during the chronic course of this disorder to counteract primary arousal symptoms, especially those related to an intractable shame-laden depressive syndrome. The psychoendocrine findings suggest that the relatively inconspicuous clinical feature of shame resulting from both the primary and secondary traumatizations is a particularly powerful, preoccupying, and overwhelming source of emotional engagement. Shame may represent a "sleeper" that is worthy of greater attention in both research and clinical efforts to understand the pathogenesis and psychopathology of this devastating stress-related disorder.

Clinical significance of syncope in the electrophysiologic study versus electrocardiographic monitoring (ESVEM) trial. The ESVEM Investigators.

BACKGROUND: Syncope may portend risk of death, but which patients with syncope are at high risk remains unclear. OBJECTIVE: The ESVEM trial, a multicenter randomized prospective trial, provided the opportunity to compare mortality rates of patients enrolled with syncope to those enrolled with spontaneous ventricular arrhythmias. METHODS: Patients enrolled in the ESVEM trial presenting with syncope alone (25 patients) or in combination with ventricular tachycardia (24 patients) were compared with patients with spontaneous ventricular tachycardia alone (332 patients) or ventricular fibrillation (105 patients). All patients had ventricular tachyarrhythmias induced at electrophysiology testing of >/=10 premature ventricular complexes per hour on Holter monitor. RESULTS: Of all patients randomly assigned, arrhythmic death and total mortality rates were the same for those with syncope alone, with ventricular tachycardia and syncope, with ventricular tachycardia alone, or with ventricular fibrillation. At 1 year, arrhythmic and total mortality rate for all patients was 21% and 24%, respectively; for patients with syncope alone, 30% and 29%, respectively (P = NS). At 4 years, arrhythmic death and total mortality rate for all patients was 33% and 42%, respectively; for patients with syncope alone, 37% and 42%, respectively (P = NS). CONCLUSION: Syncope, associated with induced ventricular tachyarrhythmias at electrophysiologic testing, indicates high risk for death, similar to that of patients with documented spontaneous ventricular tachyarrhythmias.

Abbreviated aerosol therapy for improved efficiency.

BACKGROUND: The Circulaire nebulizer system (WestMed, Tucson, AZ) has been shown to minimize the potential for side effects from adrenergic bronchodilator aerosols by minimizing extrapulmonary deposition. This study evaluates the utility, safety, and efficacy of a shortened treatment protocol utilizing a timed treatment with concentrated drug in this device. METHODS: Prospective, randomized, controlled comparison was conducted of a 2-minute treatment of concentrated (5 mg/mL) albuterol in the Circulaire nebulizer versus a conventional unit dose treatment as assessed by pulmonary function testing. RESULTS: Both treatments were equally efficacious and safe. The abbreviated treatment consumed about 8 to 10 minutes less and was preferred by patients. CONCLUSIONS: Abbreviated treatments provide equal bronchodilation with improved efficiency and potential cost savings.

Predictors of arrhythmic death and cardiac arrest in the ESVEM trial. Electrophysiologic Study Versus Electromagnetic Monitoring.

BACKGROUND: The purpose of this study was to determine if the presenting ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation/cardiac arrest) predicted the type of arrhythmia recurrence in patients treated with antiarrhythmic drugs. METHODS AND RESULTS: In the previously reported Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial, there were 486 patients who were randomized to antiarrhythmic drug testing guided by electrophysiological study or by ambulatory ECG monitoring. Use of a defibrillator (implantable cardioverter-defibrillator, ICD) without stored electrograms among 81 patients precluded determination of the type of arrhythmia recurrence; thus these patients were censored at the time of ICD implantation. Of the 486 patients, 381 presented with ventricular tachycardia and 105 with cardiac arrest. Over a 6-year follow-up period, 285 of the 486 patients had an arrhythmia recurrence; of these, 97 had an arrhythmic death or cardiac arrest as a first recurrence. In the current analysis, all 129 arrhythmic deaths/cardiac arrests that occurred any time during follow-up were evaluated as end points. CONCLUSIONS: Although univariate analysis suggested that there was an association between the presenting arrhythmia and outcome, multivariate analysis failed to substantiate the predictive value of the presenting arrhythmia. Left ventricular ejection fraction was the single most important predictor of arrhythmic death or cardiac arrest. This information may be an important factor in deciding whether to advise ICD therapy.

Inflammatory myocardial diseases and cardiomyopathies.

Inflammatory myocardial disease has been associated with a variety of infectious and noninfectious etiologies. It is associated with the development of dilated cardiomyopathy in some patients. Given its imprecise diagnosis, varied clinical presentation and undefined natural history, it is quite difficult to make broad generalizations regarding its evaluation and treatment. It is hoped continued application of new molecular biological and other techniques will shed further light on the pathophysiologic mechanisms of myocarditis in humans, thus pointing to therapeutic interventions.

Long-term cost-effectiveness of alternative management strategies for patients with life-threatening ventricular arrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) Investigators.

BACKGROUND: Serial antiarrhythmic drug testing guided by Holter monitoring and electrophysiologic study had similar clinical outcomes in the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) trial, while patients treated with sotalol had improved outcomes. The purpose of this study was to compare long-term cost-effectiveness of these management alternatives. METHODS: Patients in the ESVEM trial were linked to computerized files of either the Health Care Finance Administration or the Department of Veterans Affairs. Total hospital costs and survival time over five year follow-up were measured using actuarial methods, and cost-effectiveness was calculated. RESULTS: Patients randomized to therapy guided by electrophysiologic study had more hospital admissions, higher costs, and a cost-effectiveness ratio of $162,500 per life year added compared with therapy guided by Holter monitoring. Patients randomized to sotalol had fewer hospitalizations, lower costs, and better survival than patients randomized to other drugs, and sotalol was a dominant strategy in the cost-effectiveness analysis. Patients for whom an effective drug was found had fewer hospital admissions, lower costs, and longer survival. These findings were robust in sensitivity analyses and in bootstrap replications. CONCLUSIONS: Serial drug testing guided by electrophysiologic study had an unfavorable cost-effectiveness ratio relative to Holter monitoring, while sotalol was cost-effective relative to other antiarrhythmic drugs.