High risk of QT interval prolongation and torsades de pointes associated with intravenous quinidine used for treatment of resistant malaria or babesiosis.

Cardiac toxicity may be associated with drugs used for malaria. Torsades de pointes (TdP) is a well-known adverse effect of quinidine when used for atrial fibrillation. Intravenous quinidine doses for resistant malaria are 2 to 3 times higher than those used for arrhythmias. Among 6 patients receiving quinidine for malaria or babesiosis, 4 developed QT interval prolongation and 2 experienced TdP. Clinicians should be aware that recommended doses of quinidine for malaria carry a high TdP risk.

The influence of progesterone alone and in combination with estradiol on ventricular action potential duration and triangulation in response to potassium channel inhibition.

INTRODUCTION: Females are at increased risk for torsades de pointes (TdP). Some evidence suggests that progesterone may protect against TdP, but few data exist regarding the effects of progesterone on cardiac repolarization. We determined the effects of progesterone alone and in combination with estradiol on ventricular action potential duration (APD) and triangulation in response to potassium channel inhibition. METHODS AND RESULTS: Female New Zealand white rabbits (n = 30) underwent ovariectomy and were implanted with 21-day sustained release pellets (each n = 6): progesterone; estradiol; progesterone; & estradiol combined; dihydrotestosterone (DHT); and placebo. After 20 days, hearts were excised, mounted, perfused with modified Krebs-Henseleit buffer, and paced at 150 bpm. After baseline measurements, hearts were perfused with quinidine 3 µmol/L. The degree of quinidine-associated prolongation of ventricular APD at 90% repolarization (APD(90) ) in the progesterone group was significantly less than that in the estradiol and the combined estradiol and progesterone groups, and not significantly different than in the DHT group. The degree of prolongation of action potential triangulation (APD(90) - APD(30) ) in hearts from progesterone-treated rabbits was significantly less than that in the estradiol group, and not significantly different from that in hearts from DHT-treated rabbits. There were no significant differences in quinidine effects on ventricular APD(90) or action potential triangulation between hearts exposed to estradiol alone or those exposed to both estradiol and progesterone. CONCLUSIONS: Progesterone protects against prolongation of APD(90) and triangulation associated with potassium channel inhibition. However, progesterone does not attenuate the effects of estradiol on prolongation of ventricular APD(90) associated with potassium channel inhibition.

Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction.

STUDY OBJECTIVE: To assess whether the increased risk of ibutilide-induced torsade de pointes in patients with heart failure may be due to increased ibutilide exposure, we sought to determine if the pharmacokinetics of ibutilide are altered in patients with heart failure due to left ventricular systolic dysfunction. DESIGN: Multicenter, prospective pharmacokinetic study. SETTING: Four academic medical centers in the United States. PATIENTS: Sixteen adult patients with atrial fibrillation or atrial flutter requiring conversion to normal sinus rhythm: six patients who had New York Heart Association (NYHA) class II or III heart failure due to left ventricular dysfunction (mean +/- SD left ventricular ejection fraction [LVEF] 30 +/- 9%); 10 patients who did not have left ventricular dysfunction (mean +/- SD LVEF 54 +/- 5% in six of these 10 patients) served as controls. INTERVENTION: All patients received a single dose of ibutilide 1.0 mg administered intravenously over 10 minutes. Blood samples were obtained through an indwelling catheter in the contralateral arm before ibutilide administration, at the end of the infusion, and at 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after the infusion. MEASUREMENTS AND MAIN RESULTS: Serum ibutilide concentrations were determined by using high-performance liquid chromatography and mass spectrometry. No significant differences were noted between the heart failure and normal left ventricular function groups in the following parameters: maximum serum ibutilide concentration (median [interquartile range] 3.8 [2.3-5.7] vs 5.8 [3.1-14.4] microg/L, p=0.31), area under the serum concentration-time curve from time zero extrapolated to infinity (mean +/- SD 11.0 +/- 9.4 vs 13.2 +/- 10.6 microg*hr/L, p=0.88), steady-state volume of distribution (1380 +/- 334 vs 1390 +/- 964 L, p=0.99), systemic clearance (129 +/- 60 vs 125 +/- 81 L/hr, p=0.92), or half-life (12.5 +/- 10.7 vs 12.4 +/- 8.6 hrs, p=0.99). CONCLUSION: The pharmacokinetics of ibutilide do not appear to be altered in patients with NYHA class II or III heart failure due to left ventricular systolic dysfunction. Therefore, the increased risk of ibutilide-induced torsade de pointes in patients with heart failure does not appear to be due to increased ibutilide exposure.

Prospective evaluation of serum amiodarone concentrations when administered via a nasogastric tube into the stomach conduit after transthoracic esophagectomy.

BACKGROUND: Atrial fibrillation occurs in up to 46% of patients following esophagectomy; amiodarone may be used for prophylaxis or treatment in these patients. There are few data regarding drug absorption following esophagectomy. OBJECTIVE: The aim of this study was to determine serum amiodarone concentrations when the drug is administered into the stomach conduit following esophagectomy. METHODS: Patients who underwent noncardiac thoracic surgery were enrolled in this prospective, controlled study. One group of patients underwent esophagectomy, and a second group of patients comprised a control group who underwent pulmonary resection (PR). A continuous IV amiodarone infusion (0.73 mg/min) was initiated at anesthesia induction and continued for 24 hours (total IV dose 1050 mg), followed by 400 mg via a nasogastric tube (in the esophagectomy group) or orally (in the PR group) every 12 hours for 6 days. Blood samples for determination of serum amiodarone concentrations were obtained at completion of the infusion (postoperative day [POD] 1), and before the third (POD 2) and seventh (POD 4) enteral doses. RESULTS: A total of 27 patients were enrolled (esophagectomy group, 13 patients; PR group, 14 patients). Patients in the 2 groups had statistically similar ages (mean [SD], 60 [10] vs 53 [10] years; P = 0.07) and proportions of men (12/13 [92%] vs 8/14 [57%]; P = 0.08). Patients in the 2 groups were statistically similar with respect to race (white, 13/13 [100%] vs 13/14 [93%]) and preoperative weight (mean [SD], 83.3 [11.5] vs 77.7 [18.6] kg). On POD 1, age-adjusted and sex-adjusted serum amiodarone concentrations were not significantly different in the esophagectomy group versus the PR group (mean [SD] 0.65 [0.22] vs 0.84 [0.20] microg/mL). Mean (SD) serum amiodarone concentrations were significantly lower in the esophagectomy group on POD 2 (0.35 [0.27] vs 0.60 [0.18] microg/mL; P = 0.02) and on POD 4 (0.30 [0.34] vs 0.87 [0.16] microg/mL; P < 0.001). Serum amiodarone concentrations were undetectable in 33% and 50% of patients in the esophagectomy group on PODs 2 and 4, respectively, compared with 0% in the PR group (both, P = 0.03). CONCLUSIONS: Serum amiodarone concentrations were significantly lower (and in some cases undetectable) when the drug was administered via a nasogastric tube into the stomach conduit in patients after esophagectomy compared with those concentrations after oral administration in a PR population. Nasogastric administration of amiodarone should probably be avoided for prophylaxis or treatment of postesophagectomy tachyarrhythmias.

Prevalence of QT interval prolongation in patients admitted to cardiac care units and frequency of subsequent administration of QT interval-prolonging drugs: a prospective, observational study in a large urban academic medical center in the US.

BACKGROUND: Cardiac arrest due to torsades de pointes (TdP) is a rare but catastrophic event in hospitals. Patients admitted to cardiac units are at higher risk of drug-induced QT interval prolongation and TdP, due to a preponderance of risk factors. Few data exist regarding the prevalence of QT interval prolongation in patients admitted to cardiac units or the frequency of administering QT interval-prolonging drugs to patients presenting with QT interval prolongation. OBJECTIVE: The aim of this study was to determine the prevalence of Bazett's-corrected QT (QT(c)) interval prolongation upon admission to cardiac units and the proportion of patients presenting with QT(c) interval prolongation who are subsequently administered QT interval-prolonging drugs during hospitalization. METHODS: This was a prospective, observational study conducted over a 1-year period (October 2008-October 2009) in 1159 consecutive patients admitted to two cardiac units in a large urban academic medical centre located in Indianapolis, IN, USA. Patients were enrolled into the study at the time of admission to the hospital and were followed daily during hospitalization. Exclusion criteria were age <18 years, ECG rhythm of complete ventricular pacing, and patient designation as 'outpatient' in a bed and/or duration of stay <24 hours. Data collected included demographic information, past medical history, daily progress notes, medication administration records, laboratory data, ECGs, telemetry monitoring strips and diagnostic reports. All patients underwent continuous cardiac telemetry monitoring and/or had a baseline 12-lead ECG obtained within 4 hours of admission. QT intervals were determined manually from lead II of 12-lead ECGs or from continuous lead II telemetry monitoring strips. QT(c) interval prolongation was defined as ≥470 ms for males and ≥480 ms for females. In both males and females, QT(c) interval >500 ms was considered abnormally high. A medication was classified as QT interval-prolonging if there were published data indicating that the drug causes QT interval prolongation and/or TdP. Study endpoints were (i) prevalence of QT(c) interval prolongation upon admission to the Cardiac Medical Critical Care Unit (CMCCU) or an Advanced Heart Care Unit (AHCU); (ii) proportion of patients admitted to the CMCCU/AHCU with QT(c) interval prolongation who subsequently were administered QT interval-prolonging drugs during hospitalization; (iii) the proportion of these higher-risk patients in whom TdP risk factor monitoring was performed; (iv) proportion of patients with QT(c) interval prolongation who subsequently received QT-prolonging drugs and who experienced further QT(c) interval prolongation. RESULTS: Of 1159 patients enrolled, 259 patients met exclusion criteria, resulting in a final sample size of 900 patients. PATIENT CHARACTERISTICS: mean (± SD) age, 65 ± 15 years; female, 47%; Caucasian, 70%. Admitting diagnoses: heart failure (22%), myocardial infarction (16%), atrial fibrillation (9%), sudden cardiac arrest (3%). QT(c) interval prolongation was present in 27.9% of patients on admission; 18.2% had QT(c) interval >500 ms. Of 251 patients admitted with QT(c) interval prolongation, 87 (34.7%) were subsequently administered QT interval-prolonging drugs. Of 166 patients admitted with QT(c) interval >500 ms, 70 (42.2%) were subsequently administered QT interval-prolonging drugs; additional QT(c) interval prolongation ≥60 ms occurred in 57.1% of these patients. CONCLUSIONS: QT(c) interval prolongation is common among patients admitted to cardiac units. QT interval-prolonging drugs are commonly prescribed to patients presenting with QT(c) interval prolongation.

Enhanced sensitivity to drug-induced QT interval lengthening in patients with heart failure due to left ventricular systolic dysfunction.

Patients with heart failure (HF) are at increased risk for drug-induced torsades de pointes (TdP) due to unknown mechanisms. Our objective was to determine if sensitivity to drug-induced QT interval lengthening is enhanced in patients with HF. In this multicenter, prospective study, 15 patients with atrial fibrillation or flutter requiring conversion to sinus rhythm were enrolled: 6 patients with New York Heart Association class II to III HF (mean ejection fraction [EF], 30% ± 9%), and 9 controls (mean EF, 53% ± 6%). Patients received ibutilide 1 mg intravenously. Blood samples and 12-lead electrocardiograms were obtained prior to and during 48 hours postinfusion. Serum ibutilide concentrations at 50% maximum effect on Fridericia-corrected QT (QT(F)) intervals (EC(50)) were determined, and areas under the effect (QT(F) interval vs time) curves (AUECs) were calculated. Ibutilide concentration-QT(F) relationships were best described by a sigmoidal E(max) model with a hypothetical effect compartment. Median [interquartile range] AUEC from 0 to 4 hours was larger in the HF group than in controls (1.86 [1.86-1.93] vs 1.82 [1.81-1.84] s·h; P = .04). Median EC(50) was lower in the HF group (0.48 [0.46-0.49] vs 1.85 [1.10-3.23] µg/L; P = .008). Sensitivity to drug-induced QT interval lengthening is enhanced in patients with systolic HF, which may contribute to the increased risk of drug-induced TdP.

Prophylaxis of atrial fibrillation after noncardiac thoracic surgery.

Atrial fibrillation (AF) occurs commonly after noncardiac thoracic surgery, including lobectomy, pneumonectomy and esophagectomy. While not as extensively investigated as AF following cardiac surgery, some strategies for prophylaxis of AF after noncardiac thoracic surgery have been studied. Evidence from prospective, randomized controlled studies supports the use of beta-blockers, diltiazem, amiodarone or magnesium for prevention of AF after pulmonary resection. Limited evidence supports the efficacy of intravenous amiodarone for prevention of AF after esophagectomy. Further study is necessary to determine the safest and most effective methods of prophylaxis of AF after noncardiac thoracic surgery, and to identify patients most likely to benefit from AF prophylaxis.

A randomized, controlled study of amiodarone for prevention of atrial fibrillation after transthoracic esophagectomy.

OBJECTIVE: Atrial fibrillation is common after esophagectomy. The objective of this study was to determine the efficacy and safety of amiodarone for prevention of atrial fibrillation after transthoracic esophagectomy. METHODS: Eighty patients undergoing transthoracic esophagectomy were randomly, prospectively assigned to receive amiodarone (n = 40) or no prophylaxis (control group, n = 40). Amiodarone-treated patients received the drug by continuous infusion, initiated at the time of induction of anesthesia, at a rate of 0.73 mg/min (43.75 mg/h), and continued for 96 hours (total dose 4200 mg). The primary end point was atrial fibrillation requiring treatment. Secondary end points included any atrial fibrillation lasting longer than 30 seconds and postoperative hospital and intensive care unit stays. RESULTS: There were no significant differences between the amiodarone and control groups in demographic characteristics, comorbid conditions, or preoperative or postoperative use of beta-blockers or calcium-channel blockers. The incidence of atrial fibrillation requiring treatment was lower in the amiodarone group than in the control group (15% vs 40%, P = .02, relative risk reduction 62.5%). There were no significant differences between the amiodarone and control groups in median hospital stay (11 days vs 12 days, P = .31) or median intensive care unit stay (68 hours vs 77 hours, p = .097). There were no significant difference between the groups in the incidences of adverse effects. CONCLUSIONS: Amiodarone prophylaxis significantly reduced the incidence of atrial fibrillation after transthoracic esophagectomy.

A randomized trial evaluating amiodarone for prevention of atrial fibrillation after pulmonary resection.

BACKGROUND: Atrial fibrillation (AF) occurs commonly after anatomic pulmonary resection. In this study, the efficacy of amiodarone for prevention of post-pulmonary resection AF was investigated. METHODS: One hundred thirty patients undergoing lobectomy, bilobectomy, or pneumonectomy were randomly assigned prospectively to receive amiodarone (n = 65) or no prophylaxis (control group, n = 65). The amiodarone group received 1,050 mg by continuous intravenous infusion over 24 hours, initiated at the time of anesthesia induction, followed by 400 mg orally twice daily until hospital discharge or for a maximum of 6 days. The primary endpoint was AF requiring treatment during hospitalization. Secondary endpoints included postoperative length of hospital and intensive care unit stays. RESULTS: There were no significant differences between the amiodarone and control groups in demographics, comorbid conditions, extent of pulmonary resection, or preoperative or postoperative use of beta-blockers or calcium-channel blockers. The incidence of AF was lower in the amiodarone group than in the control group (13.8% versus 32.3%, p = 0.02; relative risk reduction = 57%). There was no difference between the amiodarone and control groups in median length of hospital stay (7 versus 8 days, p = 0.79), but median length of intensive care unit stay was shorter in the amiodarone group (46 versus 84 hours, p = 0.03). There was no significant difference between the amiodarone and control groups in the incidence of pulmonary complications or other adverse effects. CONCLUSIONS: Amiodarone prophylaxis significantly reduces the incidence of AF after anatomic pulmonary resection, and is associated with a significant reduction in length of intensive care unit stay.

Postoperative outpatient chest tube management: initial experience with a new portable system.

PURPOSE: Prolonged air or fluid chest tube drainage may delay chest tube removal in thoracic surgery patients otherwise ready for discharge. We reviewed 20 months of experience at our institution with postoperative, outpatient chest tube management using a new portable chest tube device. DESCRIPTION: From May 2003 to December 2004, 457 major thoracic procedures were performed at our institution. Besides excessive chest tube output or air leak, 50 patients met the criteria for discharge. There were 36 patients who were discharged with a new portable chest tube system (Express Mini 500; Atrium Medical Corp, Hudson, NH). Patients received written instructions and demonstrated competence on system use. Patients returned for chest tube removal after satisfactory resolution of air leak or fluid drainage. EVALUATION: Postoperative outpatient chest tube management accounted for 404 days. There were no major complications. Four patients experienced minor complications. Thirty-two patients (89%) experienced uneventful and successful outpatient chest tube management. CONCLUSIONS: These data suggest that successful postoperative outpatient chest tube management can be accomplished in select patients. This program resulted in substantial hospital cost reduction and enhanced patient satisfaction by allowing earlier discharge.