Beny Charbit

Prolongation of QTc Interval after Postoperative Nausea and Vomiting Treatment by Droperidol or Ondansetron

Background:At dosages above 0.1 mg/kg, droperidol inducesa dose-dependent QTc interval prolongation. Although subject to controversy, low-dose droperidol has recently been suspected to induce cardiac arrhythmias. Hence, 5-hydroxytryptamine type 3 antagonists have become the first-line drug for management of postoperative nausea and vomiting. These drugs are also known to prolong the QTc interval at high dosages. This study describes QTc interval changes associated with postoperative nausea and vomiting treatment by droperidol or ondansetron at low doses. Methods:Eighty-five patients with postoperative nausea and vomiting were included in this prospective, single-blind study. Patients received either 0.75 mg intravenous droperidol (n = 43) or 4 mg intravenous ondansetron (n = 42). Electrocardiographic recordings were obtained before administration of antiemetic drug and then 1, 2, 3, 5, 10, and 15 min after. Electrocardiographic monitoring was maintained for 3 h in eight patients in each group. Results:The QTc interval was prolonged (> 450 ms in men, > 470 ms in women) in 21% of the patients before antiemetic drug administration. This was significantly correlated with lower body temperature and longer duration of anesthesia. Compared with predrug QTc measurement, both antiemetics were associated with a significant QTc interval prolongation (P < 0.0001). The mean maximal QTc interval prolongation was 17 ± 9 ms after droperidol occurring at the second minute and 20 ± 13 ms after ondansetron at the third minute (both P < 0.0001). Compared with predrug measurement, the QTc interval was significantly lower after the 90th minute in both groups. Conclusions:Droperidol and ondansetron induced similar clinically relevant QTc interval prolongations. When used in treatment of postoperative nausea and vomiting, a situation where prolongation of the QTc interval seems to occur, the safety of 5-hydroxytryptamine type 3 antagonists may not be superior to that of low-dose droperidol.

Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study.

Background:Droperidol and ondansetron have previously been found to prolong the QT interval in the treatment of postoperative nausea and vomiting. However, this adverse effect has never been confirmed and compared with both drugs under controlled conditions. The objective was to study the effects of droperidol and ondansetron alone or in combination on QT interval duration in healthy subjects. Methods:Sixteen healthy volunteers, eight males and eight females, were enrolled in this prospective, double-blind, randomized, placebo-controlled study. Subjects received 1 mg droperidol, 4 mg ondansetron, 1 mg droperidol plus 4 mg ondansetron, or a placebo, intravenously in a crossover design. Fridericia-corrected QT interval (QTcF) and plasma concentrations were measured repeatedly during 10 h at each study period. The primary endpoint was the maximal placebo time-matched and baseline-subtracted QTcF prolongation (&Dgr;&Dgr;QTcF). Results:Compared with placebo, both droperidol and ondansetron significantly prolonged the QTcF interval. &Dgr;&Dgr;QTcF prolongation was 25 ± 8 ms after droperidol, significantly greater than the 17 ± 10-ms prolongation with ondansetron (P = 0.014). The combination of droperidol and ondansetron significantly increased the mean maximal &Dgr;&Dgr;QTcF by 28 ± 10 ms. The combination induced greater QTcF prolongation compared with ondansetron alone (P = 0.001), but not with droperidol alone (P = 0.33). There was no significant pharmacokinetic interaction between droperidol and ondansetron. Conclusions:Under controlled conditions, both droperidol and ondansetron either alone or in combination induced significant marked QTc interval prolongation. However, the combination of both drugs did not significantly increase QTc prolongation compared with that induced by droperidol alone.

QT interval measurement: evaluation of automatic QTc measurement and new simple method to calculate and interpret corrected QT interval.

Background:Assessment of repolarization duration is often recommended to avoid administration of QT-prolonging drugs in patients with prolonged QTc interval, a frequent situation in the postoperative period. Bazett QT correction inappropriately increases QTc when heart rate is increased, and the use of the Fridericia formula may avoid a falsely prolonged QTc interval. The authors assessed automatic QT interval measurement to detect prolonged QTc interval (women >450 ms; men >440 ms) in the postoperative setting. Methods:Automatic and manual electrocardiograms were performed in 108 patients after anesthesia. Automatic electrocardiographic measurement used the Bazett formula. Manual measurements were made from each electrocardiogram and used as the reference. Agreement between the two methods was analyzed. Bazett and Fridericia QT corrections were compared in this population. Results:Agreement between automatic and manual measurements was low. The Fridericia correction, but not the Bazett correction, was independent from heart rate and allowed adequate QT correction. Sensitivity of automatic measurements to detect prolonged QTc-Bazett interval was 54%. Automatic QTc-Bazett interval less than 430 ms ruled out a manual prolonged QTc interval. When automatic QTc-Bazett was greater than 430 ms, this value was converted according to Fridericia. Automatic QTc-Fridericia greater than 430 ms identified all patients with prolonged manual QTc with a negative predictive error of 0% (95% confidence interval, 0–7%). QTc-Fridericia can be approximated by respectively adding or subtracting 5% to the uncorrected QT for each increase or decrease by 10 beats/min in heart rate from 60 beats/min. Conclusions:Automatic QTc-Bazett measurement, if abnormal, associated with calculation of QTc-Fridericia reliably identifies patients in whom manual QTc measurement must be performed to confirm postoperative prolonged QTc interval.

Effects of Testosterone on Ventricular Repolarization in Hypogonadic Men

QT-interval duration is shorter in men than in women. Estrogens do not significantly influence the duration of repolarization. The effect of testosterone has not been studied directly in humans. The aim of this study was to assess the effects of testosterone on corrected QT duration in hypogonadic men. Eleven hypogonadic men were enrolled in this prospective interventional study. Digital electrocardiograms were recorded for each participant at 3 levels of testosterone, high, medium, and low, after a single intramuscular administration of testosterone. Heart rate-independent assessment of QT-interval duration was used. QT(1,000) (QT at 60 beats/min) was determined for each subject. Total blood testosterone and the ratio of testosterone to sex hormone-binding globulin were assessed at each visit. The median values of QT(1,000) were 352 ms (interquartile range 340 to 363), 357 ms (interquartile range 349 to 367), and 363 ms (interquartile range 357 to 384) at high, medium, and low testosterone concentrations, respectively (p <0.013 for the 3 comparisons). A maximal mean difference of 13.6 +/- 2.8 ms (p = 0.0007) was observed between high and low levels of testosterone. A negative linear relation was found between QT(1,000) and testosterone concentration (p = 0.0001) or the ratio of testosterone to sex hormone-binding globulin (p = 0.004). In conclusion, the difference in QT-interval duration between men and women might be explained by differences in testosterone levels, and testosterone shortens ventricular repolarization.

Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine

Halofantrine, an antimalarial drug that prolongs the QT interval, is metabolized into N‐debutyl‐halofantrine by cytochrome P450 (CYP) 3A4. Grapefruit juice increases the bioavailability of several orally administered CYP3A4 substrates by inhibiting CYP3A4 at the enterocyte level and could therefore increase the risk of halofantrine‐induced QT interval prolongation. We studied the effect of grapefruit juice on halofantrine bioavailability and on QT interval prolongation associated with its oral administration.

QT interval prolongation after oxytocin bolus during surgical induced abortion.

Although oxytocin, a uterotonic agent, may cause short‐term vasodilation that results in severe hypotension, it is still routinely given as an intravenous bolus injection during surgical suction curettage. Two reported cases of ventricular tachycardia after oxytocin bolus in patients with long QT interval syndrome led us to assess the effect of oxytocin on QT interval.

Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study

AIMS QTc interval prolongation and torsades de pointes have been reported in HIV-infected patients. Protease inhibitors (PIs) are suspected to contribute to this adverse reaction. However, many factors can prolong QTc interval. We examined factors influencing QTc duration in HIV-infected patients. METHODS Unselected HIV-infected patients (n = 978) were enrolled in this prospective, single-centre cross-sectional study. Variables related to infection and treatments were collected. A digital electrocardiographic record was recorded in each patient and QT interval duration was measured and corrected using both Bazetts (QTcB) and Fridericias (QTcF) formula. Results were analysed with a multivariable linear model. RESULTS After excluding arrhythmias and complete bundle branch blocks, QT interval was measured in 956 patients. The mean (SD) QTcB was 418 ms (23) and QTcF was 405 ms (20). QTc was found prolonged (>450 ms in women and >440 ms in men) in 129 [13.5%; 95% confidence interval (CI) 11.5, 15.8] and 38 (4%; 95% CI 2.9, 5.4) patients using Bazett and Fridericia corrections, respectively. On multivariable analysis, incomplete bundle branch block, ventricular hypertrophy, signs of ischaemic cardiopathy, female gender, White ethnic origin and age were significantly associated with QTc prolongation. The only HIV variable independently associated with QTc prolongation was the duration of infection (P = 0.023). After adjustment, anti-HIV treatment, in particular PI (P = 0.99), was not associated with QTc prolongation. CONCLUSIONS Although PIs block in vitro hERG current, they are not independently associated with QTc interval prolongation. Prolonged QTc interval in HIV-infected patients is primarily associated with factors commonly known to prolong QT and with the duration of HIV infection.

Impact of age and gender interaction on circulating endothelial progenitor cells in healthy subjects

OBJECTIVE To assess the level of circulating endothelial progenitor cells (CEPC) in cycling women compared with men and menopausal women. DESIGN Controlled clinical study. SETTING Healthy, nonsmoking volunteers. PATIENT(S) Twelve women, aged 18-40 years, with regular menstrual cycles, 12 menopausal women, and two groups of 12 age-matched men were recruited. Women did not receive any hormone therapy. INTERVENTION(S) Collection of 20 mL of peripheral blood. MAIN OUTCOME MEASURE(S) The number of CEPC, defined as (Lin-/7AAD-/CD34+/CD133+/KDR+) cells per 10(6) mononuclear cells (MNC), was measured by flow cytometry. RESULT(S) The number of CEPC was significantly higher in cycling women than in age-matched men and menopausal women (26.5 per 10(6) MNC vs. 10.5 per 10(6) MNC vs. 10 per 10(6) MNC, respectively). The number of CEPC was similar in menopausal women, age-matched, and young men. CONCLUSION(S) The number of CEPC is influenced by an age-gender interaction. This phenomenon may explain in part the better vascular repair and relative cardiovascular protection in younger women as compared with age-matched men.

Droperidol and ondansetron in vitro electrophysiological drug interaction study

Droperidol and ondansetron are potent anti‐emetic agents which are often administered together. Although both drugs prolong QT interval in man by inhibition of Human Ether‐a‐go‐go Related Gene‐coded potassium channels, only droperidol was tested using more integrated experimental models. Therefore, we studied the effects of both compounds and their combination on action potentials (AP) of rabbit Purkinje fibers using conventional intracellular glass microelectrode. Purkinje fibers, driven at 1 Hz, were exposed to increasing concentrations (from 0.001 to 10 μm) of droperidol (n = 7) or ondansetron (n = 8) at 30 min intervals at 36.5°C. Other fibers were exposed to a constant droperidol concentration (0.1 μm) alone (n = 7) or together with the same increasing concentrations of ondansetron (n = 6). Droperidol increased AP duration measured at 90% repolarization (APD90) in a concentration‐dependent manner from 4.4 ± 0.8% (mean ± SEM) after 1 nm to a maximum of 158 ± 72% after 1 μm. Ondansetron significantly increased APD90 by 5.3 ± 2.1% at 100 nm up to 76 ± 14% after10 μm. Early after‐depolarization occurred in 6/7 fibers exposed to droperidol and 1/8 fibers exposed to ondansetron. When given together, pure additive effects were observed. The concentrations that increased APD90 by 50% were 0.25 ± 0.25 μm droperidol, 3.8 ± 2.4 μm ondansetron and 1.5 ± 0.8 μm ondansetron when given together with droperidol. Both ondansetron and droperidol prolong AP duration in Purkinje fibers, droperidol being 10 times more potent than ondansetron. Combination of ondansetron and droperidol exhibits an additive effect on AP duration. However, within clinically relevant concentrations, ondansetron does not further increase the AP prolongation caused by droperidol alone.

Effect of Intralipid® on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers: A Clinical and Pharmacokinetic Study.

Background:Rapid intravenous administration of lipid emulsion has become the standard treatment of severe local anesthetic systemic toxicity. This experiment in volunteers aimed at determining the effect of Intralipid® administration on the time to neurologic symptoms. Methods:Ropivacaine or levobupivacaine was infused intravenously in 16 volunteers (8 mg/min up to 120 mg) with 120 ml Intralipid® 20% (Fresenius, Paris France) or placebo infused at T + 2 min). Each subject received all four treatments in a crossover manner. The infusion was stopped after the intended dose had been administered or on occurrence of incipient neurologic signs of toxicity. The primary outcome was time-to-event. In addition, blood ropivacaine and levobupivacaine concentrations were measured. Results:The dose infused was not different whether volunteers received placebo (81.7 ± 22.3 vs. 80.8 ± 31.7 mg, ropivacaine vs. levobupivacaine) or Intralipid® (75.7 ± 29.1 vs. 69.4 ± 26.2 mg, ropivacaine vs. levobupivacaine), P = 0.755, Intralipid® versus placebo groups. Plasma concentrations were best modeled with an additional volume of distribution associated with Intralipid®. Simulations suggested that decreased peak concentrations would be seen if Intralipid® was given during a period of increasing concentrations after extravascular administration. Conclusions:At modestly toxic doses of ropivacaine or levobupivacaine, we were unable to find any effect of the infusion of Intralipid® on the time to early signs of neurologic toxicity in volunteers. Peak concentration was decreased by 26 to 30% in the subjects receiving Intralipid®. Simulations showed that Intralipid® might prevent the rapid increase of local anesthetic concentration after extravascular administration.