QT/QTc Prolongation in Placebo-Treated Subjects: a PhRMA Collaborative Data Analysis

In an ongoing effort to try to understand the variability of QT/QTc data and determine how that variability would affect the design, analysis, and conclusions drawn from data collected in thorough QT/QTc studies, five Pharmaceutical Research and Manufacturers Association (PhRMA) companies recently performed retrospective analyses of placebo and nondrug 12-lead resting electrocardiogram (ECG) data. The data were obtained from five rigorously conducted studies in which the collection and analysis of QT/QTc intervals was a primary objective. Variables that are known to affect variability of QT/QTc intervals, such as adequate resting time before recording the ECGs, food, and consistency of lead placement, had been well controlled in each of the studies. Single ECGs were recorded at each time point, and the QT intervals were measured by ECG laboratories.     

QT/QTc prolongation in placebo-treated subjects: a PhRMA collaborative data analysis

In an ongoing effort to try to understand the variability of QT/QTc data and determine how that variability would affect the design, analysis, and conclusions drawn from data collected in thorough QT/QTc studies, five Pharmaceutical Research and Manufacturers Association (PhRMA) companies recently performed retrospective analyses of placebo and nondrug 12-lead resting electrocardiogram (ECG) data. The data were obtained from five rigorously conducted studies in which the collection and analysis of QT/QTc intervals was a primary objective. Variables that are known to affect variability of QT/QTc intervals, such as adequate resting time before recording the ECGs, food, and consistency of lead placement, had been well controlled in each of the studies. Single ECGs were recorded at each time point, and the QT intervals were measured by ECG laboratories.     

Near-thorough QT study as part of a first-in-man study

Detailed electrocardiographic (ECG) support was provided to a first-in-man, single-ascending-dose study that included 6 cohorts of 8 male volunteers each. In each cohort, 6 and 2 subjects received active compound and placebo, respectively. Long-term 12-lead ECGs were obtained on baseline day -1, dosing day 1, and day 2. Automatic QT-interval measurements were made at 63 time points (28 at baseline and 35 on treatment). Based on QT/RR distribution, 20% of measurements were visually verified. Baseline-corrected time-matched DeltaQTc values were obtained at 35 postdose time points. Placebo subjects of all cohorts were pooled. When 2 cohorts of the lowest, middle, and highest doses were pooled (12 subjects per active treatment group), the spreads of placebo-corrected DeltaDeltaQTc values were within the regulatory requirements (single-sided 95% confidence interval <10 milliseconds) at all time points. Thus, this ECG support of the first-in-man study provided data of regulatory acceptable accuracy at a small fraction of the cost of a full thorough QT study.     

Evaluating ECG and carboxyhemoglobin changes due to smoking narghile

Purpose: This study aimed to investigate whether increased carboxyhemoglobin (COHB) levels and ECG changes, which associated with fatal ventricular dysrhythmias, including increased QT, P-wave and T peak (Tp)-Tend (Te) dispersion, can be detected after smoking narghile, which is a traditional method of smoking tobacco that is smoked from hookah device.

Materials and methods: After local ethics committee approval, this prospective study was conducted using healthy volunteer subjects at a “narghile café,” which is used by people smoking narghile in an open area. Before beginning to smoke narghile, all subjects’ 12-lead electrocardiographs (ECG), measurements of COHB levels, and vital signs were recorded. After smoking narghile for 30?min, the recording of the 12-lead ECGs and the measurements of COHB level and all vital signs were repeated.

Results: The mean age of subjects was 26.8?±?6.2 years (min-max: 18–40), and 28 subjects (84.8%) were male. Before smoking narghile, the median value of subjects’ COHB levels was 1.3% (min-max: 0–6), whereas after smoking, the median value of COHB was 23.7% (min-max: 6–44), a statistically significant increase (p?<?0.001). Analysis of the subjects’ ECG changes after smoking narghile showed that dispersions of QT, QTc, P-wave and Tp-Te were increased, and all changes were statistically significant (p?<?0.001 for all parameters).

Conclusion: Although, especially among young people, it is commonly thought that smoking narghile has less harmful or toxic effects than other tobacco products. The results of this study and past studies clearly demonstrated that smoking narghile can cause several ECG changes - including increased QT, P-wave and Tp-Te dispersion - which can be associated with ventricular dysrhythmias.     

Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects

In this phase I trial, the effect of aclidinium, a novel, inhaled long-acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 μg, aclidinium 800 μg, matching placebo, or open-label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate-corrected QT interval (QTcI). Secondary measures included Bazett-corrected QT interval (QTcB), Fridericia-corrected (QTcF) intervals, 12-lead electrocardiogram (ECG) readings, and 24-hour 12-lead Holter ECG parameters. Adverse events, vital signs, and laboratory and pharmacokinetic parameters were also assessed. Maximum mean QTcI change from time-matched baseline on day 3 was -1.0 milliseconds at 2 hours for aclidinium 200 μg, -1.8 milliseconds at 5 minutes for 800 μg, +11.0 milliseconds at 4 hours for moxifloxacin, and -1.2 milliseconds at 23.5 hours for placebo. Aclidinium had no significant effects on secondary ECG measures. Aclidinium plasma concentrations were generally below the lower limit of quantitation (0.05 ng/mL) after 200 μg and were detected only up to 1 hour after the 800-μg dose in the majority of cases. It is concluded that aclidinium bromide, at doses up to 800 μg, has a favorable cardiovascular safety profile with no effect on QT interval.     

QT and JT dispersion in the drug-induced long QT syndrome in anaesthetized rabbits is accurately detected by a three-lead surface ECG measurement

INTRODUCTION: QT dispersion (QTd) can be measured from three leads of the ECG in patients with myocardial ischemia. However, whether QT and JT dispersion (QTd, JTd) can be calculated from a three-lead of the ECG in drug-induced long QT syndrome (LQTS) in animals remains elusive. Therefore, we determined to what extent a three-lead measurement of the surface ECG accurately detects dispersion of QT and JT in comparison with multi-lead assessments in anaesthetized rabbits, challenged with methoxamine and additionally infused intravenously with solvent or dofetilide. METHODS: Using several ECG leads in anaesthetized rabbits challenged intravenously with an alpha(1)-adrenoceptor agonist methoxamine, we assessed the QT and JT interval, as well as QT and JT dispersion, at baseline and in response to solvent or dofetilide (0.02 or 0.04 mg/kg/min iv for 60 min), an I(Kr) blocker. For that purpose, we recorded and analyzed the surface ECG and assessed QT and JT dispersion by four methods: (1) 12-lead ECG; (2) six precordial leads (V1-V6); (3) three leads most likely to contribute to the dispersion (aVF, V1, and V4); (4) three quasi-orthogonal leads (aVF, I, and V2). QT and JT dispersion were significantly lower in 6- and 3-lead measurements than in 12-lead measurement, both at baseline and during infusion of solvent or dofetilide. At 5 and 10 min of infusion, dofetilide at 0.02 or 0.04 mg/kg/min iv markedly increased QT and JT dispersion by 100% to 500% in all four ECG lead combinations. This dose regimen of dofetilide markedly prolonged QT and JT intervals in lead II, and was associated with high incidences of polymorphous ventricular tachycardia (PVT: 30% at 0.02 mg/kg/min; 100% at 0.04 mg/kg/min) and of ventricular fibrillation (VF: 17% with 0.02 mg/kg/min; 58% with 0.04 mg/kg/min). CONCLUSIONS: Our present study shows that the measurement of QT and JT dispersion in three surface ECG leads only (aVF, I, V2 or aVF, V1 V4), instead of 12 ECG leads, is an appropriate approach to assess drug-induced heterogeneity or dispersion of ventricular repolarization in anaesthetized rabbits, both at baseline and during arrhythmogenic sensitization with methoxamine and challenged with dofetilide.     

Effects of 4-aminopyridine on cardiac repolarization,PR interval,and heart rate in patients with spinal cord injury

STUDY OBJECTIVE: To determine the effects of 4-aminopyridine (4-AP) on heart rate and PR, QT, and QTc intervals in patients with longstanding spinal cord injury (SCI). DESIGN: Randomized, active-treatment-controlled, dose level-blinded study, with allocation concealed. SETTING: University-affiliated, tertiary care medical center. PATIENTS: Sixty otherwise healthy male and female outpatients with traumatic SCI of more than 1 year's duration. Intervention. Oral administration and dose titration to tolerance of an immediate-release formulation of 4-AP. MEASUREMENTS AND MAIN RESULTS: The PR interval, heart rate, QT interval, and QTc interval obtained from standard 12-lead electrocardiograms (ECGs) at baseline (before administration of 4-AP) and after 1 month of treatment were compared. The QTc intervals were derived by using Bazett's formula (equation) incorporated into standard computerized analyses of 12-lead ECG printouts. The paired t test was performed to test for the significance of differences between means and variances. No statistically significant differences were noted in heart rate or between ECG time intervals measured at baseline and after 1 month of treatment with 4-AP among all patients with SCI or between subgroups stratified by injury level (tetraplegia, paraplegia) or sex. CONCLUSION: During the 1-month period that 4-AP was administered, the heart rate and PR, QT, and QTc intervals all remained unchanged and stayed well within normal range in comparison to literature-derived control values. 4-Aminopyridine does not appear to influence the length of cardiac time intervals or heart rate and, hence, is unlikely to cause potentially life-threatening ventricular dysrrhythmias when administered long-term and taken orally in dosages of up to 30 mg/day. Specifically, cardiac repolarization (QTc interval) is unaffected in patients with SCI who continuously receive 4-AP for up to 1 month.     

Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized,single-blind,crossover study

Aim:

To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers.

Methods:

This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin.

Results:

The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects.

Conclusion:

Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.     

Contrasting time- and rate-based approaches for the assessment of drug-induced QT changes

The authors aim to highlight the pitfalls of different validated methods used for the assessment of drugs' effect on QT duration. Digital 12-lead Holter electrocardiograms were recorded at baseline and after a single dose of sotalol in 39 healthy subjects (age = 27.4 +/- 8.0 years). Using both time- and rate-based approaches, the authors obtained averaged QRS-T complexes every minute ("time bins") and at different RR intervals ("rate bins"). Time bins were corrected for heart rate using a subject-specific approach. The individual alpha coefficients increased from placebo (0.309 +/- 0.052) to sotalol (0.454 +/- 0.136), P < .0001. When the placebo individual alpha coefficients were applied to correct the QT interval on sotalol, the changes were >5 ms smaller than those obtained using the ON drug alpha coefficients. The "rate"-averaging process leads to a complete loss of the time course of drug effect. In conclusion, the individual correction formula calculated from the placebo condition cannot always be used for QT correction on the drug.     

Quality assessment of digital annotated ECG data from clinical trials by the FDA ECG Warehouse

The FDA mandates that digital electrocardiograms (ECGs) from 'thorough' QTc trials be submitted into the ECG Warehouse in Health Level 7 extended markup language format with annotated onset and offset points of waveforms. The FDA did not disclose the exact Warehouse metrics and minimal acceptable quality standards. The author describes the Warehouse scoring algorithms and metrics used by FDA, points out ways to improve FDA review and suggests Warehouse benefits for pharmaceutical sponsors. The Warehouse ranks individual ECGs according to their score for each quality metric and produces histogram distributions with Warehouse-specific thresholds that identify ECGs of questionable quality. Automatic Warehouse algorithms assess the quality of QT annotation and duration of manual QT measurement by the central ECG laboratory.     

Quality assessment of digital annotated ECG data from clinical trials by the FDA ECG warehouse

The FDA mandates that digital electrocardiograms (ECGs) from ‘thorough’ QTc trials be submitted into the ECG Warehouse in Health Level 7 extended markup language format with annotated onset and offset points of waveforms. The FDA did not disclose the exact Warehouse metrics and minimal acceptable quality standards. The author describes the Warehouse scoring algorithms and metrics used by FDA, points out ways to improve FDA review and suggests Warehouse benefits for pharmaceutical sponsors. The Warehouse ranks individual ECGs according to their score for each quality metric and produces histogram distributions with Warehouse-specific thresholds that identify ECGs of questionable quality. Automatic Warehouse algorithms assess the quality of QT annotation and duration of manual QT measurement by the central ECG laboratory.     

Clinically relevant QTc prolongation due to overridden drug–drug interaction alerts: a retrospective cohort study

AIMS

To investigate whether, in patients in whom drug–drug interaction (DDI) alerts on QTc prolongation were overridden, the physician had requested an electrocardiogram (ECG), and if these ECGs showed clinically relevant QTc prolongation.

METHODS

For all patients with overridden DDI alerts on QTc prolongation during 6 months, data on risk factors for QT prolongation, drug class and ECGs were collected from the medical record. Patients with ventricular pacemakers, patients treated on an outpatient basis, and patients using the low-risk combination of cotrimoxazole and tacrolimus were excluded. The magnitude of the effect on the QTc interval was calculated if ECGs before and after overriding were available. Changes of the QTc interval in these cases were compared with those of a control group using one QTc-prolonging drug.

RESULTS

In 33% of all patients with overridden QTc alerts an ECG was recorded within 1 month. ECGs were more often recorded in patients with more risk factors for QTc prolongation and with more QTc overrides. ECGs before and after the QTc override were available in 29% of patients. Thirty-one percent of patients in this group showed clinically relevant QTc prolongation with increased risk of torsades de pointes or ventricular arrhythmias. The average change in QTc interval was +31 ms for cases and −4 ms for controls.

CONCLUSIONS

Overriding the high-level DDI alerts on QTc prolongation rarely resulted in the preferred approach to subsequently record an ECG. If ECGs were recorded before and after QTc overrides, clinically relevant QTc prolongation was found in one-third of cases. ECG recording after overriding QTc alerts should be encouraged to prevent adverse events.     

Improving the detection of subtle I(Kr)-inhibition: assessing electrocardiographic abnormalities of repolarization induced by moxifloxacin.

BACKGROUND: QT prolongation is an incomplete measure of drug-induced changes in repolarization. In this study, we investigated a novel, automatic ECG technique for describing ventricular repolarization morphology and we compared these results to corrected QT (QTc) prolongation for identifying ECGs of healthy individuals on moxifloxacin. METHODS: We analysed data from the US FDA ECG Warehouse involving 160 standard ECGs from 40 healthy subjects enrolled in a randomized, parallel, placebo-controlled, 'thorough QT' study. Computerized ECG analysis included a series of scalar and vectorial parameters describing duration of repolarization segments and T-wave/loop morphology including its symmetry, amplitude and shape. Binary logistic models for the identification of moxifloxacin-induced abnormalities of the repolarization were developed. RESULTS: Moxifloxacin induced significant changes in several ECG parameters including QT and QT apex and early repolarization duration (ERD)(30)(%), T-wave amplitude and slopes of the ascending and descending arm of the T-wave. The logistic model based only on T-wave morphology parameters outperformed the model based on QTc interval for identifying the presence of moxifloxacin. Combining information about repolarization interval duration with T-wave morphology significantly improved the detection of presence of moxifloxacin (p < 0.01). The increased sensitivity of our novel ECG method contributes to a >40% reduction in the sample size required to detect significant QTc prolongation induced by moxifloxacin. CONCLUSIONS: Repolarization morphology is significantly altered by moxifloxacin. The computerized ECG technique provides a novel method for quantifying morphological changes of repolarization segment. Our new parameters reflecting the morphology of the T-wave outperformed QTc measurements when identifying moxifloxacin-induced blockade of the outward rapid components of the delayed rectifier repolarizing potassium current (I(Kr)). These data indicate that the analysis of T-wave morphology could play a role in the assessment of drug toxicity.     

Fluticasone propionate/salmeterol combination in children with asthma: Key cardiac and overall safety results

This study studied the safety of fluticasone propionate/salmeterol combination (FSC) 100/50 HFA (2 inhalations of 50/25 mcg) twice daily, compared with fluticasone propionate (FP) 100 HFA (two inhalations of 50 mcg) twice daily, over a 12-week treatment period in subjects aged 4–11 years with persistent asthma. Of the 350 subjects randomized to receive double-blind treatment, 173 received FSC 100/50 HFA and 177 received FP 100 HFA. The two treatment groups were comparable in adverse events profiles, vital signs, asthma exacerbations, oropharyngeal examinations, clinical laboratory tests and urinary cortisol levels. The use of spacer did not meaningfully modify cortisol levels. The pre-specified analysis of 12-lead electrocardiograms (ECGs) identified abnormalities during screening as well as post-randomization in both study treatments, even though randomized subjects were without pre-existing cardiovascular disorders. An ad hoc analysis of the ECG data found no clinically relevant ECG abnormalities either prior to randomization or after randomization to study treatments. Thus, the ECG findings were false-positives related to details of the pre-specified analysis. This study highlights the importance of methodology when interpreting ECG data in a pediatric clinical trial. Overall, both FSC 100/50 HFA and FP 100 HFA were well-tolerated in children aged 4–11 years with persistent asthma.     

How many cardiac cycles must be measured to permit accurate RR, QT, and QTc estimates in conscious dogs?

INTRODUCTION: Electrocardiography is an essential tool to assess the liability of test articles to produce torsade de pointes. The number of cardiac cycles that must be measured from a dog to accurately characterize the relationship between RR and QT intervals, and thus assess this liability, is unknown. METHODS: In this study, electrocardiograms (ECGs) were obtained from 12 conscious dogs with sinus rhythm. In each dog, RR and QT intervals were measured for 12 cardiac cycles. Measurements for each were then averaged over all 12 cycles, and those results compared to the average of both the initial 6 and 3 cycles, as well as to the middle cycle alone, for 12, 6, and 4 of the dogs. QTc was calculated by dividing each QT by the cube root of the preceding RR interval. RESULTS: We found no significant differences in the results of measurements of RR, QT, or QTc obtained from 12, 6, 3, or 1 cycle, whether from 12, 6, or 4 dogs. Intraobserver variability of ECG measurements was tested by having a single observer measure 10 copies of 12 different ECGs. The greatest coefficient of variation (S.D./mean) for the measurement of any ECG parameter was less than 2.5%. DISCUSSION: We conclude that measurements of RR and QT intervals made by a trained observer from 1 cardiac cycle accurately reflect those that are averaged from 3, 6, or 12 cycles whether the number of dogs per group is 12, 6, or 4.     

不同钾浓度透析液对维持性血液透析患者QT离散度的影响

目的探讨不同钾浓度透析液对维持性血液透析患者QT离散度的影响。方法选择维持性血液透析患者57例作为透析组,另外选择30名健康体检正常者作为对照组,透析组患者应用钾浓度为2．0mmol／L、3．0mmol／L的透析液各进行血液透析。采用12导联同步心电图记录两组的QT间期并计算QT离散度（QTd）和校正的QT间期（QTcd）。结果透析组QTd、QTcd分别为（52．7±8．2）ms、（63．2±9．O）1118,明显高于对照组的（32．2±6．0）ms、（35．4±7．1）ms（t=2．638、2．750,均P〈0．05）。钾浓度2．0mmol／L组的QTd、QTcd、心律失常发生率分别为（63．5±7．6）ms、（72．3±8．0）ms、22．8％（13／57）,均明显高于3．0mmolfL组的（52．8±7．7）ms、（60．5±6．4）ms、7．0％（4／57）（t=2．245、2．351,X。=5．599,均P〈0．05）。结论QTd主要反映心室复极的不均一性和电不稳定性,采用钾浓度为3．0mmolfL的透析液进行透析可以缩短QT间期并降低心律失常的发生率。     

Evaluation of electrocardiograms recorded in cynomolgus monkeys with short- and long-term intracardiac lead implantations

Introduction: minimally invasive placement of intracardiac (IC) ECG leads in monkeys has greatly improved signal quality and the ability to interpret these ECGs. However, information on characteristics of the ECGs recorded using the IC lead is not available in the literature. There are concerns about the potential impact of IC lead placement on the ECG waveform and cardiac function as a result of potential irritation or trauma resulting from the placement and/or long term residence of the IC lead. The purposes of this study were to characterize IC ECG morphology, to obtain information on the recovery processes after IC ECG lead implantation, and to evaluate the IC ECG model application to safety pharmacology studies. Methods: the telemetry transmitter, arterial blood pressure catheter and IC ECG lead were implanted in 40 cynomolgus monkeys, two of which were also implanted with subcutaneous (SC) ECG leads. The data of IC ECG, heart rate (HR) and mean arterial blood pressure (MABP) were collected telemetrically for a period of 1–12 months after implantation, and measured using computer softwares. Results: the IC ECG waveforms varied greatly from those of SC ECG. There was no clearly identifiable S–T segment, and T waves were biphasic in the majority of IC ECGs. The morphology of IC ECG was diversified among animals, progressively changed in the first 2 weeks post-surgery and stabilized approximately 3 weeks post-surgery. MABP and HR were elevated after implant surgery, but recovered to the levels comparable to those of SC in approximately 1 and 4 weeks, respectively. The IC ECG values obtained during week 8 to 10 (HR = 134 ± 25 bpm, PR interval = 87 ± 13 ms, QRS interval = 40 ± 7 ms, and QT interval = 246 ± 30 ms, QTcF = 318 ± 28 ms) were comparable to those from SC ECG. Discussion: the IC ECG provides a clear ECG signal with values comparable to, and waveforms different from, SC recordings. The complicated surgical procedure with long substantial recovery time, high incidence of IC lead malfunction, and high costs for IC leads may limit application of the IC ECG model in safety pharmacology studies.     

High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings

Aims

To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings.

Methods

This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist''s discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QT_cF (Fridericia''s HR correction) was calculated and >500 ms was defined as abnormal.

Results

Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QT_cF >500 ms but only in one taking methadone was the timing of QT_cF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias.

Conclusion

QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.     

Evaluation of electrocardiographic and hemodynamic effects of caffeine with acute dosing in healthy volunteers

STUDY OBJECTIVE: To evaluate the effects of moderate, single-dose caffeine consumption on electrocardiographic variables: PR, QRS, QT, QTc, and RR intervals, and QT and QTc interval dispersion. Effects of caffeine on blood pressure and heart rate also were evaluated. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: University school of pharmacy. PATIENTS: Ten healthy volunteers aged 17 years or older. INTERVENTION: Participants abstained from caffeinated products for at least 2 days before the study began and were randomly designated to receive placebo or caffeine 400 mg on various days. For each of the study phases, a baseline 12-lead electrocardiogram (ECG) was performed and a subsequent 12-lead ECG performed 3 hours after ingesting the study drug. Blood pressure readings were taken with each ECG. MEASUREMENTS AND MAIN RESULTS: No significant changes in any intragroup or intergroup electrocardiographic variables occurred. Caffeine increased blood pressure (systolic blood pressure [SBP]/diastolic blood pressure [DBP]) from 118+/-5/75+/-6 mm Hg to 128+/-8/77+/-7 mm Hg versus baseline (p=0.0022 and p=0.0368 for SBP and DBP, respectively). After drug dosing, SBP in the caffeine group was significantly higher than in the placebo group (128+/-8 mm Hg versus 119+/-7 mm Hg, p=0.0174). CONCLUSION: Moderate caffeine consumption by healthy young adults does not acutely affect PR, QRS, QT, QTc, and RR intervals, or QT and QTc interval dispersion. Caffeine-naive subjects experienced persistent elevations in SBP and DBP 3 hours after caffeine ingestion, indicating that longer caffeine abstinence than that which is recommended is necessary for blood pressure determination in the clinical setting.     

心电图QRS综合波改变对早期诊断急性下壁心肌梗死的意义

目的通过胸痛患者连续心电图监测,以便早期确诊急性下壁心肌梗死。方法在30例患者中,根据胸痛开始5h内连续描记常规12个导联心电图,测定各导联R波、S波振幅及ST段变化,与心肌梗死前正常心电图作比较。结果所记录的心电图改变中,Ⅱ、Ⅲ、aVF导联QRS波群的S波消失,出现高尖R波,下壁心肌梗死aVL导联S波的改变也有重要诊断意义。结论急性下壁心肌梗死早期心电图最显著的改变,表现在Ⅲ、aVF、aVL导联QRS综合波终末电压的增高。