Hydroxychloroquine-azithromycin, doubase C, and QTc prolongation in congolese patients with COVID-19: Myth or reality?

BACKGROUND: QTc interval prolongation with an increased risk of torsade de pointes (Tsd) has been described in coronavirus disease 2019 (COVID-19) patients treated with hydroxychloroquine (HCQ) and azithromycin (AZI) in Western countries. In the DR Congo, few studies have evaluated the safety of this association or proposed new molecules. AIM: To determine the incidence of QTc prolongation and Tsd in COVID-19 patients treated with HCQ-AZIs vs doubase C (new molecule). METHODS: In present randomized clinical trial, we have included patients with mild or moderate COVID-19 treated with either HCQ-AZI or doubase C. Electrocardiogram (ECG) changes on day 14 of randomization were determined based on pretreatment tracing. Prolonged QTc was defined as ≥ 500 ms on day 14 or an increase of ≥ 80 ms compared to pretreatment tracing. Patients with cardiac disease, those undergoing other treatments likely to prolong QTc, and those with disturbed ECG tracings were excluded from the study. RESULTS: The study included 258 patients (mean age 41 ± 15 years; 52% men; 3.4% diabetics, 11.1% hypertensive). Mild and moderate COVID-19 were found in 93.5% and 6.5% of patients, respectively. At baseline, all patients had normal sinus rhythm, a mean heart rate 78 ± 13/min, mean PR space 170 ± 28 ms, mean QRS 76 ± 13 ms, and mean QTc 405 ± 30 ms. No complaints suggesting cardiac involvement were reported during or after treatment. Only four patients (1.5%) experienced QTc interval prolongation beyond 500 ms. Similarly, only five patients (1.9%) had an increase in the QTc interval of more than 80 ms. QTc prolongation was more significant in younger patients, those with high viral load at baseline, and those receiving HCQ-AZI (P < 0.05). None of the patients developed Tsd. CONCLUSION: QTc prolongation without Tsd was observed at a lower frequency in patients treated with HCQ-AZI vs doubase C. The absence of comorbidities and concurrent use of other products that are likely to cause arrhythmia may explain our results.

Safety of outpatient commencement of sotalol.

Background: Inpatient monitoring is recommended for sotalol initiation. Objective: The purpose of this study was to assess the safety of outpatient sotalol commencement. Methods: This is a multicenter, retrospective, observational study of patients initiated on sotalol in an outpatient setting. Serial electrocardiogram monitoring at day 3, day 7, 1 month, and subsequently as clinically indicated was performed. Corrected QT (QTc) interval and clinical events were evaluated. Results: Between 2008 and 2023, 880 consecutive patients who were commenced on sotalol were evaluated. Indications were atrial fibrillation/flutter in 87.3% (n = 768), ventricular arrhythmias in 9.9% (n = 87), and other arrhythmias in 2.8% (n = 25). The daily dosage at initiation was 131.0 ± 53.2 mg/d. The QTc interval increased from baseline (431 ± 32 ms) to 444 ± 37 ms (day 3) and 440 ± 33 ms (day 7) after sotalol initiation (P < .001). Within the first week, QTc prolongation led to the discontinuation of sotalol in 4 and dose reduction in 1. No ventricular arrhythmia, syncope, or death was observed during the first week. Dose reduction due to asymptomatic bradycardia occurred in 3 and discontinuation due to dyspnea in 3 within the first week. Overall, 1.1% developed QTc prolongation (>500 ms/>25% from baseline); 4 within 3 days, 1 within 1 week, 4 within 60 days, and 1 after >3 years. Discontinuation of sotalol due to other adverse effects occurred in 41 patients within the first month of therapy. Conclusion: Sotalol initiation in an outpatient setting with protocolized follow-up is safe, with no recorded sotalol-related mortality, ventricular arrhythmias, or syncope. There was a low incidence of significant QTc prolongation necessitating discontinuation within the first month of treatment. Importantly, we observed a small incidence of late QT prolongation, highlighting the need for vigilant outpatient surveillance of individuals on sotalol.

Comparison of electrocardiogram and blood pressure recording methods in non-rodent toxicology studies: A retrospective analysis.

Our study retrospectively examines 51 non-rodent general toxicology studies conducted over the past 8 years to ascertain the influence of recording methodologies on baseline cardiovascular (CV) parameters and statistical sensitivity. Specifically, our work aims to evaluate the frequency of cardiovascular parameter recording categorized by therapeutic modality and study type, to assess the variability in these parameters based on measurement techniques, and to determine the sample sizes needed for detecting relevant changes in heart rate (HR), blood pressure (BP), and QTc interval in non-human primate (NHP) studies. Results indicate that electrocardiogram (ECG) measurements in dogs and NHP were recorded in 63% of studies, combined with BP recording in 18% of studies, while BP was never recorded alone. Trend analysis reveals a decline in the utilisation of restraint-based methods for ECG measurements post-2017, to the benefit of telemetry-based recordings, particularly Jacketed External Telemetry (JET). There was a marked difference in baseline values, with restraint-based methods showing significantly higher HR and QTc values compared to JET, likely linked to animal stress. Further analysis suggests an unrealistic and unethical sample size requirement in NHP studies for detecting biologically meaningful CV parameter changes using restraint-based methods, while JET methods necessitate significantly smaller sample sizes. This retrospective study indicates a notable shift from snapshots short-duration, restraint-based methods towards telemetry approaches over the recent years, especially with an increased usage of implanted telemetry. The transition contributes to potential consensus within industry or regulatory frameworks for optimal practices in assessing ECG, HR, and BP in general toxicology studies.

Prevalence, Outcomes, and Predictors of Prolonged Corrected QT Interval in Hydroxychloroquine-Naïve Hospitalized COVID-19 Patients.

The studies regarding prevalence, outcomes, and predictors of prolonged corrected QT (QTc) among COVID-19 patients not on QTc-prolonging medication are not available in the literature. In this retrospective cohort study, the QTc of 295 hospital-admitted COVID-19 patients was analyzed and its association with in-hospital mortality was determined. The QTc was prolonged in 14.6% (43/295) of the study population. Prolonged QTc was seen in patients with older age (P = 0.018), coronary artery disease (P = 0.001), congestive heart failure (P = 0.042), elevated N-terminal-pro-B-type natriuretic peptide (NT-ProBNP) (P < 0.0001), and on remdesivir (P = 0.046). No episode of torsades de pointes arrhythmia or any arrhythmic death was observed among patients with prolonged QTc. The mortality was significantly high in patients with prolonged QTc (P = 0.003). The multivariate logistic regression analysis showed coronary artery disease (odds ratio (OR): 4.153, 95% CI 1.37-14.86; P = 0.013), and NT-ProBNP (ng/L) (OR: 1.000, 95% CI 1.000-1.000; P = 0.007) as predictors of prolonged QTc. The prolonged QTc was associated with the worst in-hospital survival (p by log-rank 0.001). A significant independent association was observed between prolonged QTc and in-hospital mortality in multivariate cox-regression analysis (adjusted hazard ratio: 3.861; (95% CI 1.719-6.523), P < 0.0001). QTc was found to be a marker of underlying comorbidities among COVID-19 patients. Prolonged QTc in hospitalized COVID-19 patients was independently associated with in-hospital mortality.

Case report: Phosphoinositide 3-kinase inhibitor with fulvestrant in a patient with ER+/HER2- metastatic breast carcinoma induced fatal arrhythmias: a preventable event?

Phosphoinositide 3-kinase (PI3K) inhibitors have shown synergistic anticancer effects with endocrine therapy against ER+/PIK3CA-mutated breast cancer. PI3K inhibitors for cancer therapy are becoming more common. There is an increasing need to understand their cardiac adverse events. In this report, we describe the features of near-fatal mixed arrhythmias in a patient who was undergoing a phase Ib clinical study of PI3Kα inhibitor with fulvestrant. Subsequently, the patient survived by cardiopulmonary resuscitation and therefore did not die. This case highlights that PI3K inhibitors can induce QT/QTc prolongation and predispose patients to TdP. The combination of QT/QTc prolongation in combination with prolonged cardiac repolarization, such as an AV block during treatment with PI3Kα inhibitor, may aggravate the occurrence of TdP. It is likely to be a safer strategy to adjust the standard of discontinuing drugs and continuing drugs (QTc interval was <500 and <60 ms at baseline) or choose other types of alternative treatment options. This report provided some ideas for clinicians to identify early and prevent the occurrence of fatal arrhythmias during anticancer treatment.

Meta-analysis application to hERG safety evaluation in clinical trials.

One objective of meta-analysis, which synthesizes evidence across multiple studies, is to assess the consistency and investigate the heterogeneity across studies. In this project, we performed a meta-analysis on moxifloxacin (positive control in QT assessment studies) data to characterize the exposure-response relationship and determine the safety margin associated with 10-msec QTc effects for moxifloxacin based on 26 thorough QT studies submitted to the FDA. Multiple meta-analysis methods were used (including two novel methods) to evaluate the exposure-response relationship and estimate the critical concentration and the corresponding confidence interval of moxifloxacin associated with a 10-msec QTc effect based on the concentration-QTc models. These meta-analysis methods (aggregate data vs. individual participant data; fixed effect vs. random effect) were compared in terms of their precision and robustness. With the selected meta-analysis method, we demonstrated the homogeneity and heterogeneity of the moxifloxacin concentration-QTc relationship in studies. We also estimated the critical concentration of moxifloxacin that can be used to calculate the hERG safety margin of this drug.

Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone.

INTRODUCTION: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process. METHODS: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec). RESULTS: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected. DISCUSSION: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single­lead ECGs collected from freely moving dogs and monkeys.

Supporting an integrated QTc risk assessment using the hERG margin distributions for three positive control agents derived from multiple laboratories and on multiple occasions.

BACKGROUND: Determination of a drug's potency in blocking the hERG channel is an established safety pharmacology study. Best practice guidelines have been published for reliable assessment of hERG potency. In addition, a set of plasma concentration and plasma protein binding fraction data were provided as denominators for margin calculations. The aims of the current analysis were five-fold: provide data allowing creation of consistent denominators for the hERG margin distributions of the key reference agents, explore the variation in hERG margins within and across laboratories, provide a hERG margin to 10 ms QTc prolongation based on several newer studies, provide information to use these analyses for reference purposes, and provide recommended hERG margin 'cut-off' values. METHODS: The analyses used 12 hERG IC50 'best practice' data sets (for the 3 reference agents). A group of 5 data sets came from a single laboratory. The other 7 data sets were collected by 6 different laboratories. RESULTS: The denominator exposure distributions were consistent with the ICH E14/S7B Training Materials. The inter-occasion and inter-laboratory variability in hERG IC50 values were comparable. Inter-drug differences were most important in determining the pooled margin variability. The combined data provided a robust hERG margin reference based on best practice guidelines and consistent exposure denominators. The sensitivity of hERG margin thresholds were consistent with the sensitivity described over the course of the last two decades. CONCLUSION: The current data provide further insight into the sensitivity of the 30-fold hERG margin 'cut-off' used for two decades. Using similar hERG assessments and these analyses, a future researcher can use a hERG margin threshold to support a negative QTc integrated risk assessment.

A simple accurate method for concentration-QTc analysis in preclinical animal models.

INTRODUCTION: In preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling. METHODS: Cardiovascular telemetry studies were conducted in non-human primates (NHP; n = 48) and canines (n = 8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage0-X) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled. RESULTS: In NHP, a 10.9 ± 0.06 ms (mean ± 95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10 ms QTc change in humans, based on a 0-24 h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6 ± 0.1 ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04 ± 0.1 ms change was seen for mock. CONCLUSIONS: While simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24 h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations.

Characterization of ascending dose canine telemetry model supports its use in E14/S7B QT integrated risk assessments.

INTRODUCTION: Nonclinical evaluation of the cardiovascular effects of novel chemical or biological entities (NCE, NBEs) is crucial for supporting first-in-human clinical trials. One important aspect of these evaluations is the assessment of potential QT/QTc prolongation risk, as drug-induced QT prolongation can have catastrophic effects. The recent publication of E14/S7B Q&As allows for the situational incorporation of nonclinical QTc data as part of an integrated risk assessment for a Thorough QT (TQT) waiver application provided certain best practice criteria are met. Recent publications provided detailed characterization of nonclinical QTc telemetry data collected from the commonly used Latin square study design. METHODS: To understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design. RESULTS: The data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment. DISCUSSION: These findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications.

QTc interval changes among patients on psychotropic medications: A prospective observational study.

Background: Psychotropic medications are commonly prescribed for the treatment of psychiatric disorders. Various studies have reported QT interval (QTc) prolongation with the use of psychotropics. However, some studies have found no significant risk of QTc changes with these medications. Aim: To assess the effect of psychotropics on QTc in drug-naive psychiatric patients. Materials and Methods: Our study was a prospective observational study, conducted at a tertiary care hospital. Patients aged 18-45 years, drug-naïve, with no medical comorbidity or substance use history, were recruited for the study. ECG to assess QTc was recorded at baseline, second and fourth week after the starting of psychotropic medications. Results: N=8 (4%) patients had QTc prolongation at baseline and were excluded. No clinically significant QTc prolongation was noticed, after 2 weeks and 4 weeks of treatment with any of the psychotropic medications. However, among patients on escitalopram, a significant effect on QTc was noted (P = 0.001) as compared to those on sertraline, risperidone, and olanzapine (P > 0.05). Conclusion: The short-term risk of QTc prolongation with the use of newer psychotropics at optimal doses appears low among young patients with normal baseline QTc and no significant medical or substance use comorbidity.

Determining QTc in acute care settings: What we (don't) know.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Early Screening for Long QT Syndrome and Cardiac Anomalies in Infants: A Comprehensive Study.

(1) Background: Sudden Infant Death Syndrome (SIDS) represents sudden and unexplained deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for a prolonged QTc interval, a marker for Long QT Syndrome (LQTS), should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiograms (ECGs) could identify congenital heart defects (CHDs) early, especially those not detected at birth. Infants with prolonged QTc intervals typically undergo genetic analysis for Long QT Syndrome. (2) Methods: The study involved infants aged 20-40 days, born with no apparent clinical signs of heart disease, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHDs identified immediately after birth, as well as infants who had previously had an ECG or echocardiogram for other medical reasons, were excluded from the study. We used statistical software (SPSS version 22.0) to analyze the data. (3) Results: Of the 42,200 infants involved, 2245 were enrolled, with 39.9% being males. Following this initial screening, 164 children (37.8% males) with prolonged QTc intervals underwent further evaluation. Out of these 164 children, 27 children were confirmed to have LQTS. However, only 18 children were finally investigated for genetic mutations, and mutations were identified in 11 tests. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Treatment options included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%. (4) Conclusions: This screening approach has demonstrated effectiveness in the early identification of LQTS and other cardiac rhythm anomalies, with additional identification of mutations and/or prolonged QTc intervals in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening.

Case report of QT interval prolongation induced by anamorelin in an obese patient with non-small cell lung cancer.

BACKGROUND: Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer. CASE PRESENTATION: A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child-Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided. CONCLUSIONS: When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring.

Two Cases of Symptomatic Familial Hypocalciuric Hypercalcemia: Treatment Response to Calcimimetic Therapy.

Familial hypocalciuric hypercalcemia (FHH) is marked by mild to moderate hypercalcemia, normal-elevated serum PTH levels, and relative hypocalciuria. Cinacalcet, a calcimimetic therapy, has been reported to reduce symptom burden and serum calcium levels in FHH. We report 2 adult males with chronic hypercalcemia, with initial concerns for primary hyperparathyroidism. Urine calcium screening and genetic testing confirmed FHH in both patients. Shortened QTc normalized while on cinacalcet in the first patient and reductions in serum calcium and PTH levels without symptomatic hypercalcemia were noted in the second patient. Calcimimetic therapy can potentially be offered to FHH patients, particularly those with hypercalcemia symptoms, serum calcium levels >1 mg/dL (0.25 mmol/L) above normal or at risk of cardiac arrhythmias. Cinacalcet treatment was overall well tolerated and significantly reduced serum calcium and PTH levels in 2 adult FHH patients over time. Calcimimetic therapy has shown promise in managing persistent hypercalcemia and potential adverse events in FHH patients. Potential barriers include indefinite treatment, cost, and possible adverse effects.

Clofazimine serum concentration and safety/efficacy in nontuberculous mycobacterial pulmonary disease treatment.

BACKGROUND: Clofazimine (CFZ) has shown promising effects against Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) and Mycobacterium abscessus species pulmonary disease (MABS-PD). However, the optimal CFZ dose remains unknown. We aimed to explore the relationship between steady-state CFZ concentration and its safety and efficacy in MAC-PD and MABS-PD. METHODS: This prospective observational study focused on patients with MAC-PD and MABS-PD treated with CFZ (UMIN 000041053). To understand the safety and efficacy profile of CFZ and elucidate its optimal concentration, we analyzed CFZ-induced pigmentation grade, QTc interval, and culture conversion outcomes in relation to serum CFZ concentration using Student's t-test, a concentration-QTc model, and multivariable logistic regression analysis, respectively. In total, 64 patients (34 with MAC-PD; 30 with MABS-PD) were included. RESULTS: The steady-state concentration of CFZ was higher in the moderate-to-severe pigmentation group than in the none-to-light pigmentation group (P < 0.001). At a CFZ concentration of 1 mg/L, the QTc interval was prolonged by 17.3 ms (95 % confidence interval [CI], 3.9-25.4) from baseline. Culture conversion was achieved in 33 (51.6 %) patients. The only significant predictor of culture conversion was surgery (adjusted odds ratio, 5.4; 95 % CI, 1.3-38.0). CFZ concentration and MIC of CFZ less than 0.25 mg/L were not associated with culture conversion in this study. CONCLUSION: CFZ-induced pigmentation and QT interval prolongation are associated with serum CFZ concentrations. CFZ dosage may be optimized by monitoring serum CFZ concentration.

The effect of antipsychotic medications on QTc and delirium in paediatric cardiac patients with ICU delirium.

OBJECTIVE: Children with prolonged hospital admissions for CHD often develop delirium. Antipsychotic medications (APMs) have been used to treat delirium but are known to prolong the QTc duration. There is concern for prolongation of the QTc interval in cardiac patients who may be more vulnerable to electrocardiogram (ECG) changes and may have postoperative QTc prolongation already. The goal of this study was to determine the effect of APM on QTc duration in postoperative paediatric cardiac patients and determine the effect of quetiapine and risperidone in treating delirium and QTc prolongation. DESIGN: Retrospective study, July 1, 2017-May 31, 2022. SETTING: Tertiary children's hospital. PATIENTS: Included were patients admitted to the paediatric cardiac ICU at Children's Healthcare of Atlanta. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ECGs, delirium scores, and drug information were collected. Delirium was defined as Cornell Assessment of Pediatric Delirium (CAPD) score >9. Mixed effect models were performed to evaluate the effect of surgery on QTc change and the effect of antipsychotics on QTc and CAPD changes. There were 139 children, 55% male and 67% surgical admissions. Median age was 5.9 months. Mean QTc increased after cardiac surgery by 18 ms (p = 0.014, 95% CI 3.65-32.4). There was no significant change in QTc after antipsychotic administration (p = 0.064). The mean CAPD score decreased (12.5-7.2; p < 0.001). Quetiapine had the most improvement in delirium, and risperidone had the least improvement (77.8%, n = 14; 37.8%, n = 34, respectively; p = 0.002). CONCLUSIONS: The QTc interval did not have a statistically significant change after the administration of antipsychotics, while there was improvement in the CAPD score. APMs may be administered safely without significant prolongation of the QTc and are an effective treatment for delirium.

Effects of weight loss on QTc in people with obesity: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Overweight and obesity have been found to exhibit a statistically significant increase in corrected QT interval (QTc), a major contributing factor to sudden death. However, the influence of widely used weight loss strategies including diet, exercise, anti-obesity drugs, and bariatric surgery on QTc remains inconsistent. Therefore, the present systematic review and meta-analysis aim to quantitatively analyse and evaluate the effect of weight loss on QTc in obese patients after diet control with exercise intervention and anti-obesity drugs, as well as bariatric surgery. METHODS: Twenty randomised controlled trials (RCT) and observational studies were included in the meta-analysis on the effects of weight loss on QTc. The fixed-effects model was employed in the RCTs, and the random-effects model was employed due to the presence of statistical heterogeneity among observational studies. Subgroup analysis was conducted to understand the differences in distinct weight loss methods and follow-up time. RESULTS: Overall, the QTc of people with obesity after weight loss was shorter than that before (mean difference (MD) = 21.97 ms, 95% confidence interval (CI) = 12.42, 31.52, p < .0001). Subgroup analysis restricted to seven included studies whose intervention was diet control with exercise showed a decrease of QTc with statistical significance (MD = 9.35 ms, 95%CI = 2.56, 37.54, p = .007). In the remaining 11 studies, bariatric surgery was the weight loss method. The results also showed a shortening of QTc after surgery, and the difference was statistically significant (MD = 29.04 ms, 95%CI = -16.46, 41.62, p < .00001). A statistically significant difference in QTc shortening at 6 months compared to pre-operation values was further observed (MD = -31.01 ms, 95%CI = -2.89, -59.12, p = .03). The shortening of QTc at 12 months of follow-up was also significantly different from that before surgery (MD = 36.47 ms, 95%CI = 14.17, 58.78, p < .00001). Moreover, the differences became more pronounced as the follow-up time extended. CONCLUSIONS: We demonstrate that weight loss links to a shortened QTc, without considering the means of weight loss. Bariatric surgery has been found to result in a greater reduction in QTc.