Mortality from venous thromboembolism and myocardial infarction in young adults in England and Wales.
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Adult↗
Biomedical subjects
S H Thomas
Publications and source records attributed to S H Thomas.
Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans.
OBJECTIVE: To measure cardiac and other effects of thioridazine and relate these to the plasma concentration of the parent drug and its principal metabolites. METHODS: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of single doses of thioridazine (10 mg and 50 mg) with placebo. Plasma concentrations of thioridazine and its ring sulfoxide, side-chain sulfoxide, and side-chain sulfone metabolites were measured, together with effects on the ECG, blood pressure, salivary flow, and a batch of psychomotor tests for 72 hours after administration. RESULTS: Thioridazine, 50 mg, reduced standing systolic blood pressure (mean peak changes from baseline [95% CI] -32 mm Hg [-55, 10 mm Hg]; p < 0.01 versus placebo) and diastolic blood pressure (-14 mm Hg [-26, -2 mm Hg]; p < 0.05), increased standing heart rate (7 beats/min [-1, 16 beats/min]; p < 0.05), impaired psychomotor function, and prolonged the JT (20 ms1/2 [7, 34 ms1/2]; p < 0.05), QTa (22 ms1/2 [8, 36 ms1/2]; p < 0.05), and QTc (22 ms1/2 [11, 33 ms1/2]; p < 0.01) intervals, but had no effect on QT dispersion (-12 ms1/2 [-31, 6 ms1/2]). Thioridazine, 1.0 mg, also significantly increased QTc, but the effect was less marked (9 ms1/2 [-1, 19 ms1/2]; p < 0.05). Plasma thioridazine and metabolite concentrations did not correlate significantly with these effects. Maximum effects on QTc occurred after peak concentrations of thioridazine but before peak concentrations of the ring sulfoxide and side-chain sulfone metabolites. CONCLUSIONS: These data suggest that thioridazine has dose-related effects on ventricular repolarization and that the parent drug causes an important proportion of these effects, although its metabolites may also contribute.
Adult↗
Stereoselective cardiotoxic effects of terodiline.
OBJECTIVE: To study the cardiovascular and electrocardiographic (ECG) effects of the R(+)- and S(-)- enantiomers of terodiline. The racemic drug was previously used to treat detrusor instability but was withdrawn after it caused serious ventricular arrhythmias associated with prolongation of the QT interval. METHODS: A double-blind, placebo-controlled, randomized crossover study was performed that involved nine healthy volunteers who were given single oral doses of racemic terodiline hydrochloride (200 mg), R(+)-terodiline hydrochloride (100 mg), S(-)-terodiline tartrate (100 mg), or placebo. Plasma concentrations of each enantiomer and cardiovascular and ECG effects, including QT intervals and QT dispersion, were measured over 14 days after each treatment. RESULTS: Both racemic and R(+)-terodiline significantly increased QT interval, corrected QT interval (QTc), and QRS duration (all p < 0.05), without affecting QT dispersion. S(-)-Terodiline tartrate (100 mg) did not affect QTc. Peak effects occurred 8 hours after dosing when increases in QTc from baseline (95% confidence intervals) were -3 (-20, 13) for placebo, 23 (8, 37) for racemic terodiline, 19 (6, 33) for R(+)-terodiline, and 0 (-10, 9) ms1/2 for S(-)-terodiline. Although differences were observed between the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and elimination half-lives were similar. Elimination of terodiline enantiomers was not significantly delayed in two genotypic poor metabolizers of debrisoquin (CYP2D6). CONCLUSIONS: QT prolongation associated with racemic terodiline is caused exclusively by the R(+)-enantiomer, which therefore appears to be responsible for the ventricular arrhythmias caused by the drug.
Adolescent↗
Cardiac dysrhythmias in severe verapamil overdose: characterization with a canine model.
Verapamil overdose, because of its frequency and severity, represents a significant problem for the emergency physician. With recent search recommending specific therapies for verapamil toxicity, aids to rapid diagnosis hold promise for decreasing morbidity and mortality from overdose of all calcium channel blockers. At this time, diagnosis of verapamil toxicity depends primarily on patient history and identification of cardiac dysrhythmias. This study attempts to improve the diagnostic armamentarium available for verapamil poisoning by analysing cardiac conduction problems seen in a canine model of verapamil toxicity, with the goal of identifying clinically useful dysrhythmia patterns. In 43 verapamil-toxic animals, junctional rhythm without organized atrial activity was the most frequently identified rhythm (55.6%). The next most commonly seen rhythms were tertiary atrioventricular (AV) block (16.3%) and idioventricular rhythm (11.6%); other animals manifested low grade AV block. Of interest, prominent U waves were noted in 25.6% of animals. While these results are subject to the limitations inherent in the use of an animal model, the data generated provide potentially useful patterns of dysrhythmia which may be encountered in humans with verapamil toxicity.
Animals↗
Effect of oxybutynin on the QTc interval in elderly patients with urinary incontinence.
1. Terodiline, an anticholinergic drug with calcium antagonist properties, is associated with QT prolongation and ventricular arrhythmias. It is not known if oxybutynin, a drug with a similar pharmacological profile, causes QT prolongation. ECGs were obtained before and at least 4 weeks after commencement of oxybutynin (mean daily dose 7.6, range 2.5-10 mg), in 21 elderly (mean age 75, range 58-88 years) patients treated for urinary incontinence. Heart rate, (mean +/- s.d.) 74 +/- 11 vs 69 +/- 11 beats min-1, -6 (-13,2), before vs during oxybutynin therapy, mean difference (95% confidence intervals); PR interval, 168 +/- 27 vs 156 +/- 27 ms, -11 (-26,3); QTc 454 +/- 27 vs 447 +/- 31 ms1/2, -9 (-23,5), and QTc dispersion, QTc max-QTc min, 68 +/- 24 vs 63 +/- 26 ms1/2, -1 (-15,14) were all unaltered by oxybutynin therapy. The lack of an effect on resting heart rate suggests that oxybutynin has little anticholinergic action at cardiac M2 receptors at usually administered doses. Oxybutynin therapy is not associated with QTc interval prolongation and is unlikely to produce ventricular arrhythmias.
Aged↗
Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects.
The inhalation of nebulized morphine has been advocated to treat dyspnoea and pain in patients with cancer. We have compared plasma morphine concentrations in healthy volunteers after nebulized (50 mg in 4 ml saline), oral (10 mg solution) and intravenous (5 mg) morphine sulphate. Bioavailability was estimated by dividing the morphine concentration AUC/dose by that obtained after intravenous morphine. Peak plasma morphine concentrations were achieved more rapidly after nebulized than oral morphine, occurring within 10 min in all subjects. The systemic bioavailabilities of morphine (mean +/- s.d.) were 5 +/- 3% and 24 +/- 13% for the nebulized and oral routes respectively. Nebulization is a rapid but inefficient method of administering morphine. It may provide more rapid pain relief compared with oral morphine but clinical studies are needed to confirm this.
Administration, Oral↗
Glucagon and phenylephrine combination vs glucagon alone in experimental verapamil overdose.
OBJECTIVE: To evaluate glucagon and phenylephrine in combination as a treatment for the hemodynamic effects of verapamil overdose. METHODS: Pentobarbital-anesthetized and instrumented dogs were overdosed using a previously developed verapamil overdose model (15 mg/kg IV over 30 minutes). The animals were maintained and observed for 90 minutes or until death. Cardiac output (CO), heart rate (HR), and mean arterial pressure (MAP) were monitored. Following the 30-minute verapamil infusion (toxicity), the control animals received no treatment; the glucagon animals received a 5-mg glucagon bolus and a drip of 5 mg/90 minutes; and the glucagon/phenylephrine animals received the same glucagon therapy plus a phenylephrine drip titrated to 180 micrograms/min over 15 minutes. The groups were compared using analysis of variance: the experimental variables were group and time; the response variables were changes from toxicity for the hemodynamic parameters. Post-hoc comparisons were done with alpha set at 0.05. RESULTS: A significant change in CO was seen in the glucagon group (delta = 2.6 L/min) and the glucagon/phenylephrine group (delta = 1.9 L/min) compared with the control group (delta = 0.8 L/min). The change in CO was significantly larger for the glucagon animals compared with the glucagon/phenylephrine animals. The change in MAP for the glucagon/phenylephrine group (delta = 24 mm Hg) was significant compared with the control group (delta = 14 mm Hg). The MAP change for the glucagon group (delta = 19 mm Hg) was not significantly different from that of either the control or the glucagon/phenylephrine group. The change in glucagon HR (delta = 6 beats/min) was significant compared with the control group (delta = -4 beats/min) and the glucagon/phenylephrine group (delta = -4 beats/min). CONCLUSION: The glucagon/phenylephrine therapy improved MAP compared with the control, but reduced CO and HR compared with glucagon alone. Glucagon/phenylephrine therapy is not as effective as glucagon alone in reversing the hemodynamic effects of experimental verapamil overdose.
Adrenergic alpha-Agonists↗
Rate of patient workups by non-emergency medicine residents in an academic emergency department.
OBJECTIVE: To quantify the number of patients seen per hour by non-emergency medicine (non-EM) residents in a university hospital ED. METHODS: This retrospective observational study was performed in a university hospital ED and level I trauma center. The facility had no EM residency, but was staffed with 24-hour EM faculty coverage. A computerized tracking system was searched for the number of patients seen by each of 93 non-EM residents for 12 nonconsecutive months. The ED schedule for each month was used to calculate the number of hours worked by each resident. From these figures, the number of patients seen per hour by each resident was calculated. RESULTS: The postgraduate years of training of the residents were as follows: 78 (84%) were PGY1, ten (11%) were PGY2, and five (5%) were PGY3. All the residents combined saw a mean 0.95 +/- 0.20 patients/hour, with a range from 0.58 to 1.75 patients/hour. There was no significant difference between the numbers of patients seen when compared by specialty using the Tukey-Kramer test (alpha = 0.05). CONCLUSION: The rate at which non-EM residents work up patients is consistent with previously reported rates for EM residents.
Education, Medical, Graduate↗
Amrinone as an antidote in experimental verapamil overdose.
OBJECTIVE: To evaluate the effect of amrinone as a treatment for the hemodynamic effects of verapamil overdose in a canine model. METHODS: This nonblind interventional study was performed in an established canine model of verapamil toxicity, without concurrent control animals. Pentobarbital-anesthetized and instrumented dogs (n = 8) were maintained and observed for 60 minutes or until death. The animals were overdosed with verapamil, 15 mg/ kg IV, over 30 minutes. Hemodynamic parameters, including cardiac index (CI), heart rate (HR), and mean arterial pressure (MAP), were monitored. Completion of the verapamil infusion represented the defined point of toxicity; at that point, all the animals received an amrinone bolus of 2 mg/kg IV over 2 minutes followed by an amrinone drip at 10 micrograms/kg/min. The hemodynamic values at the defined point of toxicity were compared with those obtained postinitiation of the amrinone infusion. RESULTS: Two animals died before the 60-minute observation period elapsed. Baseline CI was 5.6 L/min/m2. Following verapamil-induced toxicity, mean CI was 2.2 L/min/m2. After administration of amrinone, a significant (p < 0.05) increase in CI was observed at 30 minutes (CI = 3.6 L/min/m2), 45 minutes (CI = 4.2 L/ min/m2), and 60 minutes (CI = 4.2 L/min/m2). There was no statistically significant difference noted for MAP or HR compared with "point of toxicity" values. CONCLUSION: Amrinone appears to reverse the depressed cardiac index associated with verapamil overdose in a canine model while having no significant effect on the hypotension or bradycardia.
Amrinone↗
Presentation of poisoned patients to accident and emergency departments in the north of England.
1. A 12 week prospective survey of all patients of any age with confirmed or suspected poisoning presenting to six accident and emergency departments in the North East of England was performed to establish the local incidence and patterns of presentation of poisoning. 2. 945 episodes of poisoning involving 852 patients were recorded representing approximately 1.2% of all A&E presentations and suggesting an annual attendance rate of 2.7 per 1000 persons per year. 3. Attendance rates varied threefold between hospitals and were similar in males and females overall; between the ages of five and 14 attendances were more common in females (1.9 vs 0.6/10(3)/y) while between 0 and 4 y (3.1 vs 2.4) and 25 and 34 y (3.9 vs 2.9/10(3)/y) they were more common in males. 4. The median interval between poisoning and presentation was 2 h (mean 4.1 h) and only 19% of cases presented within 1 h. Presentation was most common between Friday evening and Tuesday morning and in the late afternoon and evening. 5. 6% of the patients presented more than once with poisoning during the study period and 37% had a past history of deliberate self-harm. The most common poisons involved were paracetamol (43%), opioids (15%) and benzodiazepines (15%). 6. The study illustrates the frequency of presentations of poisoning to A&E departments. The high rate of poisoning in young men and the increasing use of paracetamol are particular causes for concern.
Acetaminophen↗
Factors affecting hospital admission and length of stay of poisoned patients in the north east of England.
1. Poisoning is a common reason for presentation to hospital and hospital admission but there is no agreed policy for managing these patients. This study examined the management of patients presenting with poisoning and the factors affecting the probability of hospital admission and prolonged stay. 2. Data on all cases of poisoning presenting to six Accident and Emergency departments in the North East of England over 12 weeks in 1994 was collected prospectively from A&E notes. Length of stay and outcome were recorded from hospital computer records. 3. Overall, 73% of patients were admitted to a medical ward. Probability of admission was not independently affected by age or gender but was increased in those with intentional poisoning (Odds Ratio (OR) 3.3 [95% CI 1.8, 6.1]), a history of self harm (OR 1.7, [1.0, 2.9]) or potentially hazardous poisoning (OR 3.7 [2.1, 6.6]). There were significant variations between hospitals (50-80%) which could not be attributed to case mix. 4. Prolonged stay (> 2 nights) was more common in patients over 65 years (OR 6.8 [2.9, 16.1]), those with intentional poisoning (OR 2.7 [1.1, 6.6]) and those with potentially hazardous poisoning (OR 2.6 [1.4, 4.9]). Mean hospital stay was 1.5 days and varied significantly between hospitals from 0.8 to 2.1 days and this was independent of case mix. 5. There are appreciable variations in the management of poisoning between hospitals which are not explained by patient characteristics. Savings would occur if rates of admission and duration of stay were reduced by those hospitals where admission is more frequent or hospital stay is longer. However, the impact of this on long term morbidity is unknown.
Adolescent↗
Drug-induced QT interval prolongation.
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Arrhythmias, Cardiac↗
Utilization of a pressure-sensing monitor to improve in-flight chest compressions.
Previous research at the Division of Air Medical Services at East Carolina University School of Medicine has demonstrated impairment of chest compression efficacy in the setting of an airborne BO-105 helicopter. This study was undertaken to determine whether in-flight compression efficacy could be improved with utilization of a pressure-sensing monitor providing real-time feedback during cardiopulmonary resuscitation (CPR). Ten flight nurses each performed two minutes of in-flight chest compressions on a mannequin that electronically assessed compression depth and hand placement. The session was then repeated using the pressure-sensing device. The mean proportion of correct compressions (95.7 +/- 3.2%) achieved with utilization of the pressure-sensing monitor was significantly higher (P < .01) than the corresponding proportion for the control group (33.4 +/- 12.1%). This study demonstrated that the difficulties of performing effective in-flight chest compressions are largely overcome with utilization of a pressure-sensing device providing real-time feedback on compression efficacy.
Aerospace Medicine↗
Exacerbation of verapamil-induced hyperglycemia with glucagon.
To evaluate the effects of verapamil intoxication and glucagon treatment on blood glucose levels in an intact canine model, 15 mg/kg verapamil was administered intravenously over a 30-minute period to mongrel dogs under pentobarbital anesthesia. Animals in the experimental group subsequently were administered 2.5 mg glucagon followed by an infusion of 2.5 mg per hour; control group animals were administered an equal volume of saline. Blood glucose was assessed before verapamil administration (baseline), and at 10 minutes (time 10) and 60 minutes (time 60) after completion of the verapamil infusion. Glucose values were compared between control and experimental groups using Dunnett's method (P = .05). At baseline, no animals were hyperglycemic and there was no difference in glucose levels. Animals in both groups became hyperglycemic after verapamil infusion. At time 10, the experimental group had significantly higher glucose levels (265 +/- 17.1 mg/dL) than the control group (209 +/- 18.3 mg/dL). By time 60, there was no significant difference between glucose values in the control (262 +/- 31.4) and experimental (246 +/- 24.8) groups. It was concluded that verapamil intoxication consistently resulted in hyperglycemia in this model. Glucagon therapy was associated with an early but nonsustained exacerbation of verapamil-induced hyperglycemia.
Animals↗
Decay in quality of closed-chest compressions over time.
STUDY OBJECTIVE: To characterize fatigue-induced deterioration in the adequacy of closed-chest compressions performed over a period of 5 minutes and to determine whether CPR providers can recognize the effects of fatigue on compression adequacy. DESIGN: Prospective evaluation of study subjects performing closed-chest compressions on an electronic mannequin that assesses compression placement and depth. SETTING: Major resuscitation room in rural university hospital emergency department. PARTICIPANTS: Eleven experienced nursing assistants who regularly provide CPR in the ED. RESULTS: Each study participant performed 5 minutes of closed-chest compressions. Compression adequacy (for placement and depth) was assessed with the mannequin and reported on an attached monitor out of view of the study subjects. Subjects were asked to verbally indicate the point during their 5-minute compression period at which they felt too fatigued to provide effective compressions (arbitrarily defined as a minimum of 90% of all compressions being judged correct by the mannequin). We used one-way repeated-measures ANOVA and regression analysis to determine whether compression adequacy diminished over time. ANOVA was also used to determine whether the total compressions performed per minute diminished over time. The percentage of correct chest compressions decreased significantly after 1 minute of compressions (P = .0001). We found 92.9% of compressions performed during minute 1 to be correct. The percentages for minutes 2 through 5 were as follows: 67.1%, 39.2%, 31.2%, and 18.0%. Regression analysis revealed a decrement in compression adequacy of 18.6% per minute after the first minute of compressions. The number of total compressions attempted per minute did not decrease (P = .98). Study subjects did not accurately identify the point during their 5-minute sessions at which their fatigue caused compressions to become impaired. Whereas mean compression adequacy declined below 90% after only 1 minute, the time of indicated fatigue was 253 +/- 40 seconds (mean +/- SD). CONCLUSION: Although compression rate was maintained over time, chest compression quality declined significantly over the study period. Because CPR providers could not recognize their inability to provide proper compressions, cardiac arrest team leaders should carefully monitor compression adequacy during CPR to assure maximally effective care for patients receiving CPR.
Analysis of Variance↗
Effects of inhaled nebulized morphine on ventilation and breathlessness during exercise in healthy man.
1. Nebulized inhaled morphine has been reported to increase exercise endurance in patients with chronic lung disease and to relieve dyspnoea in patients with malignant disease. Potential mechanisms include a central effect occurring after systemic drug absorption or a local action mediated by receptors in the lung. 2. The ventilatory effects of nebulized morphine (10 and 25 mg) were therefore compared with those of intravenous morphine (1.0 and 2.5 mg) and placebo in a double-blind study involving 12 young healthy males. Submaximal cycle ergometry with respiratory gas analysis was performed 15 min after drug administration and breathlessness assessed using a linear visual analogue scale. 3. Neither dose of inhaled morphine had statistically significant effects on spirometry, heart rate, ventilation, respiratory gases or breathlessness at any level of exercise. The slopes and intercepts of the lines relating ventilation to breathlessness were also unaffected. 4. Intravenous morphine 2.5 mg reduced breathlessness slightly at the highest equivalent workload [mean (least significant range) 33 mm (26-40 mm)] compared with placebo [41 mm (34-48 mm), P < 0.05] but had no other significant effects. 5. These results do not support the hypothesis that intrapulmonary opiate receptors modulate the sensation of breathlessness in healthy man. The possibility that inhaled morphine may affect breathlessness caused by other factors, such as disease, has not been excluded.
Administration, Inhalation↗
Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.
OBJECTIVE: Terodiline, an antimuscarinic and calcium antagonist drug, was used to treat detrusor instability but was withdrawn in 1991 after provoking serious ventricular arrhythmias associated with increases in the corrected QT interval (QTc). This research was performed to relate drug induced electrocardiographic changes in asymptomatic recipients to plasma concentrations of the R(+) and S(-) terodiline enantiomers. SETTING: Urological and geriatric clinics and wards. SUBJECTS: Asymptomatic patients taking terodiline in stable dose. METHODS: Electrocardiograms (50 mm/s) were collected from patients while they were taking terodiline and compared with ECGs obtained before or after terodiline. QT interval, heart rate corrected QT interval (QTc), and QT dispersion (QTd) were measured. Drug induced electrocardiographic changes were related to plasma concentrations of R(+) and S(-) terodiline. RESULTS: During terodiline treatment mean QTc and QTd were prolonged (491(43) and 84 (35) ms 1/2) compared with measurements made off therapy (443 (33) and 42 (17) ms 1/2, paired t tests, P < 0.002 and P < 0.01 respectively) in the 12 patients in sinus rhythm. The mean (95% confidence interval) drug induced increases were 48 (23 to 74) ms 1/2 for QTc and 42 (13 to 70) ms 1/2 for QTd. These increases correlated with total plasma terodiline (QTc: r = 0.77, P < 0.006, QTd: r = 0.68, P < 0.025) and with plasma concentrations of both terodiline enantiomers. CONCLUSIONS: Terodiline increases QTc and QTd in a concentration dependent manner. It is not clear whether this is a stereoselective effect and, if so, which enantiomer is responsible. The results suggest that drug induced torsade de pointes is a type A (concentration dependent) adverse drug reaction.
Aged↗
Appetite suppressants and primary pulmonary hypertension in the United Kingdom.
OBJECTIVE: Amphetamine-like appetite suppressants, particularly fenfluramines, have been implicated in the aetiology of primary pulmonary hypertension. At one specialist centre in France 20% of patients with primary pulmonary hypertension had been exposed to fenfluramine. The prevalence of primary pulmonary hypertension associated with fenfluramines and other appetite suppressants in the United Kingdom is unknown. This study was performed to measure prior exposure to appetite suppressants in patients with primary pulmonary hypertension. SETTING: Heart lung transplantation centres in England. PATIENTS: United Kingdom residents with proven primary pulmonary hypertension referred for consideration of heart lung transplantation. METHODS: Case surveillance study, obtaining data from the hospital and general practitioner's notes and directly from the patients or their relatives. RESULTS: 55 patients were identified. Drug histories were available from hospital records in all patients, from the general practitioner's notes in 51, and from the patients or relatives in 44. Of these, 3 female patients had been exposed to appetite suppressants (2 fenfluramine, 1 diethylpropion): 2 have since died. In each case exposure was brief and apparently predated the development of symptoms by several years. CONCLUSIONS: Exposure of patients with severe primary pulmonary hypertension to fenfluramine and other appetite suppressants is uncommon in the United Kingdom unlike in France, where most of the cases associating primary pulmonary hypertension with fenfluramine use have originated. This may reflect more conservative prescribing of these agents in the United Kingdom.
Adult↗