QTc interval prolongation associated with intravenous methadone

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (+/- standard error) per patient in QTc intervals on and off methadone was 41.7 (+/- 7.8)ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (+/- 6.1)ms, p=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20 +/- 2 microM and 4.4 +/- 0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.     

QTc prolongation in apheresis platelet donors

BACKGROUND: Citrate infusion during apheresis procedures can cause lowering of the plasma ionized calcium leading to prolongation of the QT interval and hypotension. At the myocardial level, QTc measurement is a sensitive marker of subphysiologic calcium values caused by citrate toxicity. STUDY DESIGN AND METHODS: Seventy-six regular platelet donors were recruited into this study. QTc intervals were measured continuously for 3 minutes at four different points during the apheresis procedures. The blood pressure was recorded every 5 minutes throughout the procedure. RESULTS: The baseline QTc value for men was 406.5 +/- 13.1 milliseconds(1/2) and for women was 417.6 +/- 13.3 milliseconds(1/2) (p = 0.0016). OTc prolongation occurred in all procedures in all donors. Maximum recorded values were significantly higher in women than in men (450.8 +/- 20.8 vs. 424.8 +/- 14.3 ms(1/2); p = 0.0025). All QTc values returned to baseline by 15 minutes after the procedure. Changes in blood pressure were minimal and no donor experienced severe symptoms. CONCLUSIONS: QTc prolongation always occurs during plateletpheresis. This prolongation is greater in women than in men. This study indicates that it may be advisable to assess donors for family or personal history of syncope and family history of sudden death to exclude those at increased risk of arrhythmias because of asymptomatic carriage of a long-QT gene. In addition baseline QTc measurement is a simple noninvasive procedure that could be applied to further studies with a view to enhancing donor safety in apheresis.     

Lack of an effect of standard and supratherapeutic doses of linezolid on QTc interval prolongation

A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the population T(max), the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted.     

Loperamide metabolite-induced cardiomyopathy and QTc prolongation

Loperamide is an over-the-counter, peripherally acting, μ-opioid receptor agonist used for the treatment of diarrhea. In recent times users have found that at higher doses, loperamide crosses the blood–brain barrier and reaches central μ-receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report a case of a 37-year-old female who attempted suicide with over 200 loperamide tablets. During her overdose, her QTc was significantly prolonged at >600?ms. Our case aims to add to the growing body of literature describing life-threatening ventricular arrhythmias associated with loperamide toxicity and further suggests that a metabolite of loperamide, desmethylloperamide, may play a role in the pathogenesis.     

Emergency department approach to QTc prolongation

QTc prolongation has been associated with increased risk of developing ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). QTc prolongation is influenced by many factors including congenital causes, heart rate, metabolic imbalances, and pharmacotherapy. Several commonly used medications in the emergency department (ED), such as antipsychotics and antiemetics, are known to prolong the QT interval. In addition, ED patients may present with conditions that may predispose them to QTc prolongation, such as drug overdose or hypokalemia, which can further complicate management. ED providers should not only be aware of which medications have these effects, but must also thoroughly investigate any pertinent patient history that may contribute to QTc prolongation. This review discusses commonly encountered medications that are associated with QTc prolongation, the mechanisms by which they prolong the QTc interval, and other factors that may influence ED medication administration and management.     

QT interval prolongation

The QT interval is a function of ventricular repolarization time and is measured from the onset of the QRS complex to the end of the T wave. The length of this interval is inversely related to heart rate. A prolonged QT interval is most often secondary to the use of Type I antidysrhythmic medications (quinidine, procainamide). It is also associated with phenothiazines, organophosphates, hypocalcemia, liquid protein diets and the congenital long QT syndromes. QT prolongation is associated with a variety of ventricular dysrhythmias, most characteristically Torsades des pointes. Treatment consists of correction of the underlying metabolic disorder or discontinuation of the offending medication.     

Tamoxifen-induced QT interval prolongation

We report on a case of tamoxifen-induced QT interval prolongation in a 56-year-old-female patient with hormone-dependent carcinoma of the right breast, stage T2N0M0, grade 3 and HER-2 negative. Partial mastectomy with axillary lymph node excision was performed in July 2007 with adjuvant hormonal and radiation therapy. This case highlights the risk of tamoxifen causing depression of electrical impulse in the sino-atrial node, leading to symptomatic sinus bradycardia with prolonged QT interval. It indicates the necessity of regular monitoring of patients undergoing tamoxifen treatment. ECG should be performed not only before and after, but also during treatment. with an average duration of treatment of 5 years, we would advise an annual ECG for asymptomatic patients. In the presence of symptomatic sinus bradycardia, constant monitoring is necessary. We also highlight potential drug interactions, between tamoxifen and acitretin and the need to be aware of drugs which may induce QT interval prolongation.     

Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose‐response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration‐QTc (C‐QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non‐human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin‐induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C‐QTc slope values were 0.7‐ (dog) and 1.2‐ (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C‐QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Typical cardiovascular studies usually employ timepoint analysis. Published in vivo corrected QT (QTc) assay data has exhibited variability in QTc sensitivity that results in challenges in nonclinical‐clinical assessment of translation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Comparison of nonclinical timepoint and concentration QTc (C‐QTc) analyses and how it relates to clinical moxifloxacin data.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Dog and non‐human primate (NHP) QTc timepoint and C‐QTc analyses detect QTc internal prolongation, have equivalent sensitivity, and improve confidence in these models for proarrhythmic risk mitigation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Risk assessment in nonclinical models translates well to human thorough QT (TQT) data for moxifloxacin. The new data highlights the value of a high‐quality dog or NHP QTc assay to support clinical risk assessment and regulatory decision making.     

QTc interval prolongation is independently associated with severe hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study

OBJECTIVE

Our aim was to assess whether severe hypoglycemic attacks were cross-sectionally associated with abnormalities of the QTc interval in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS

The study included 3,248 type 1 diabetic patients from the EURODIAB IDDM Complications Study. Severe hypoglycemia was defined as an attack serious enough to require the help of another person. A corrected QTc interval (QTc) >0.44 s was considered abnormally prolonged.

RESULTS

Nineteen percent of patients declared one to two attacks, and 13.2% of patients had three or more attacks. Prevalence of QTc prolongation was greater in patients who experienced three or more hypoglycemic attacks. Logistic regression analysis showed that the frequency of severe hypoglycemia was independently associated with QTc prolongation, even after adjustment for diabetes complications, including autonomic neuropathy (odds ratio 1.27, 95% CI 1.02–1.58).

CONCLUSIONS

We have provided evidence that severe hypoglycemic attacks are independently associated with a prolonged QTc interval in type 1 diabetic patients from the EURODIAB IDDM Complications Study.Intensive glucose control increases the risk of severe hypoglycemia, and in the Diabetes Control and Complications Trial severe hypoglycemic episodes requiring assistance affected approximately one third of the intensively treated patients (1). Prolonged corrected QTc interval (QTc) reflects abnormalities of ventricular myocardial repolarization and is an independent marker of increased mortality in patients with type 1 diabetes (2). Physiologic and clinical studies have shown that provoked and spontaneous hypoglycemia induces QT lengthening (3,4). In the EURODIAB cohort, hypoglycemia was independently associated with autonomic neuropathy (5), which is common in patients with type 1 diabetes with prolonged QTc (6); however, the relationship between hypoglycemia and QTc prolongation was not explored. The aim of the current study was to assess whether severe hypoglycemic attacks were cross-sectionally associated with QTc abnormalities in this cohort.     

Bupropion overdose: QTc prolongation and its clinical significance

OBJECTIVE: To investigate the cardiotoxicity of bupropion hydrochloride in deliberate self-poisoning. METHODS: A prospective study was conducted in a national poisons information center (PIC) of cases of adult deliberate self-poisoning with medical record follow-up of the patients. Fifty-nine cases of bupropion deliberate self-poisoning managed in the hospital, in which the New South Wales PIC was contacted for advice, were evaluated from November 2000 through July 2001. Clinical effects and electrocardiographic (ECG) parameters (QRS, QT, QTc) were the main outcome measures. RESULTS: ECGs were available for 17 of the 59 patients for analysis, 9 patients (53%) were women, and median patient age was 28 years (interquartile range 22-37). The mean +/- SD ingested bupropion dose was 3.8 +/- 3.1 g. Tachycardia occurred in 13 patients (76%; 95% CI 50 to 93) and hypertension in 8 patients (47%). There were no reports of hypotension or arrhythmias. There was a significantly increased QTc of 461 +/- 34 msec in the patients with bupropion overdose compared with previously developed controls; 13 of the 17 cases had a QTc >440 msec (76%; 95% CI 50 to 93). The uncorrected QT interval did not differ from that of controls. CONCLUSIONS: A moderately prolonged QTc (>440 msec) is common in bupropion overdose. However, this may not be a result of intrinsic cardiac toxicity, but overcorrection of the QTc due to the tachycardia that occurs. It is important that the QTc is interpreted with caution in overdoses of agents that cause significant tachycardia (>100 beats/min).     

QTc prolongation and torsades de pointes associated with methadone therapy

Oral methadone therapy is an effective and increasingly popular treatment for opioid dependency and chronic pain. Although it is not typically considered pro-dysrhythmic, we present the unique case of a 52-year-old HIV-positive woman without underlying cardiac disease who developed QTc prolongation and pulseless Torsades secondary to high dose methadone therapy.     

Risk factors and predictors of QTc prolongation in critically ill Chinese patients

BackgroundTo recognize and validate the predictor of risk factors for ICU patients with QTc intervals ≥500 ms.MethodsWe retrospectively reviewed 160 ICU patients with their medical electronic records including all demographic data, diagnosis measurements, ECGs and medication from March 1, 2018 to December 1, 2018. All information of patients' baseline, comorbidities, electrolytes and Long QT syndrome (LQTS)-inducing medications of patients with QT interval corrected (QTc) ≥ 500 ms (n = 80) and <500 ms (n = 80) were collected and analyzed using univariate and multivariate analyses to find predictors.ResultsComparing to patients with QTc < 500 ms, patients with QTc ≥ 500 ms had increased SOFA (P = 0.010) and APACHE II scores (P = 0.002), longer lengths of ICU stays (P < 0.001), greater incidence of congestive heart failure (P = 0.005) and more preset risk factors (P < 0.001). The frequency of administration of mosapride (P = 0.015), amiodarone (P = 0.027) and number of combined LQTS-inducing medications (P = 0.012) were greater in patients with QTc ≥ 500 ms than in those with QTc < 500 ms. But after multivariate analysis, we found that risk factors related to a QTc ≥ 500 ms were only congestive heart failure (OR: 5.28), number of combined LQTS-inducing medications (OR: 1.60) and APACHE II score (OR: 1.08).ConclusionsFor critically ill patients, congestive heart failure, number of combined LQTS-inducing medications and APACHE II score are proved as risk factors associated with QTc > 500 ms.     

Effect kinetics of N-acetylprocainamide-induced QT interval prolongation

We attempted to correlate clinical response with the effects of N-acetylprocainamide (NAPA) on the QT interval in five patients with stable chronic ventricular arrhythmias. A 15 mg/kg dose of NAPA was administered and a pharmacokinetic-pharmacodynamic model was used to relate plasma NAPA concentrations to changes in corrected QT interval (QTc). NAPA volume of distribution, elimination clearance, and elimination half-life averaged 1.37 +/- 0.19 L/kg, 174 +/- 63 ml/min, and 8.2 +/- 1.4 hours, respectively (mean +/- SD), and NAPA renal clearance averaged 1.9 +/- 0.6 times creatinine clearance. QTc prolongation was characterized by a linear-effect model in the first four patients and averaged 2.4 msec for every microgram per milliliter NAPA in a hypothetic biophase. QTc prolongation in patient 5 was exaggerated and was analyzed with an Emax model. Nonetheless, NAPA did not control this patient's arrhythmia. Conversely, patient 1 subsequently developed torsade de pointes even though QTc prolongation in this patient was comparable to that in patients 2 through 4, who responded satisfactorily to NAPA. We conclude that QT interval changes during initial NAPA administration do not reliably predict subsequent clinical response.