Troponin T: how high is high? Relationship and differences between serum cardiac markers according to level of creatine kinase and type of myocardial infarction.

Cardiac troponins have emerged over recent years as the "gold standard" serum biochemical marker for the diagnosis and management for patients with acute myocardial infarction (MI). The relationship between old (creatine kinase; CK) and new (troponin T; TT) markers of myocardial injury were examined in this study of 392 consecutive patients admitted to a district hospital with a diagnosis of an acute MI. Significant correlation of serum TT and peak CK levels were seen (R = 0.58, p<0.0001) in all types of MI. A significant relationship was also seen according to type of MI (Q wave or non-Q wave MI) or peak CK level. The regression equation (TT (microg/l) = 0.0027 (peak CK) + 1.1160 (IU/l)) may be used by clinicians to estimate TT release from a known peak CK result and thus provide some guidance on equivalence between the two tests. Our findings provide physicians with a benchmark reference range between the two cardiac markers, according to level of peak CK.

Open access echocardiography: a prospective audit of referral patterns from primary care.

Following recently published recommendations and guidelines, a prospective audit of 222 consecutive patients referred for open access echocardiography was conducted over a period of three months in a large district general hospital in the UK. Our study demonstrated the waiting time for an open access echocardiogram to be shorter than the waiting time for the outpatient clinic, which allowed identification of clinically significant cardiac disease sooner, leading to early advice on patient management. Specialist referral was avoided by the inclusion of management comments by a cardiologist in the technical echocardiogram report. We showed that open access echocardiography for detection of left ventricular systolic function, should be performed only if the ECG is abnormal, confirming previous reports. ECG interpretation in primary care is unreliable. In view of limited resources, hospitals should vigorously screen referrals for open access echocardiography.

Role of carotid sinus syndrome and neurocardiogenic syncope in recurrent syncope and falls in patients referred to an outpatient clinic in a district general hospital.

Carotid sinus syndrome (CSS) and neurocardiogenic syncope (NCS) are recognised as important causes of recurrent syncope and falls in the elderly. In this study the role of CSS (diagnosed with carotid sinus massage) and NCS (diagnosed with prolonged head-up tilt) in a district general hospital were investigated. Over 27 consecutive months carotid sinus massage was performed in 139 patients. Of these 29 (20.8%) patients (mean (SD) age of 78 (9) years) showed a positive response. Of these 18 (62%) patients showed a positive response only when carotid sinus massage was performed with 70( degrees ) head-up tilt. Thirteen (8.7%) of the 149 patients who had prolonged head-up tilt testing were found to have NCS. The mean (SD) age for patients with NCS was 59 (26) years and the mean (SD) time required to produce a positive response during prolonged head-up tilt was 12 (5) minutes. It is concluded that carotid sinus massage and head-up tilt testing are useful in patients presenting with unexplained syncope and falls in a district general hospital setting. Carotid sinus massage should be repeated upon head-up tilt if a negative response is obtained in the supine position.

Permanent pacemaker insertion in a district general hospital: indications, patient characteristics, and complications.

UNLABELLED: This report reviews the experience of permanent pacemaker insertion in a district general hospital (catchment population of 350 000) and makes a comparison with the national database and other hospitals in the UK. METHODS: The records of all patients receiving a permanent pacemaker in the inclusive period January 1996 to December 1998 were reviewed. Data collected included number of patients paced each year, age, sex, indications, and complications. RESULTS: In the three years reviewed 200 patients received new permanent pacemakers, a rate of 190 per million population per year, which is similar to the national implantation rate of permanent pacemakers but lower than that of most European countries (see discussion). The majority of patients paced were elderly (75% were above the age of 70 years). Atrioventricular block (including complete heart block, 45%, and Mobitz type 2 block, 12.5%) was the commonest indication for permanent pacemaker insertion, followed by sick sinus syndrome (25%) and these findings are comparable to those reported previously. However, carotid sinus syndrome was responsible for 16% of the patients paced and this was higher than that reported in the national database (6.5%). Only 1% of the pacemaker modes used was inappropriate and the complication rate was low at 3%. CONCLUSIONS: This report confirms that permanent pacemaker insertion can be effectively and safely provided locally for the increasingly ageing population. The implantation rate both locally and nationally is still much lower than that of some countries in Europe.

Atrial fibrillation in the elderly: physicians' attitudes to anticoagulation.

The use of warfarin and aspirin for the primary prevention of stroke in elderly patients with atrial fibrillation (AF) is controversial. To establish current practice we circulated a questionnaire to 300 geriatricians (G) and 300 cardiologists (C). The response rates were 47% G and 51% C. Most physicians prescribed warfarin in AF associated with mitral stenosis (G vs C, 86% vs 89%, NS). Cardiologists were more likely to prescribe warfarin in AF associated with dilated cardiomyopathy (G vs C, 52% vs 86%, P < 0.01). A minority would prescribe warfarin in aortic valve disease and AF (G vs C, 37% vs 24%, P < 0.05) and lone AF (G vs C, 10% vs 26%, P < 0.01). Aspirin was favoured in aortic valve disease and lone AF. The cardiologists were less reluctant to use warfarin in the young and more likely to electrically cardiovert the young with chronic AF.

Survey of cardiac arrests and cardiac arrest trolleys in a district general hospital.

In a 12-month period there were 137 cardiac arrests in a district general hospital. Cardiopulmonary resuscitation was instituted within 3 minutes in 82%. Delay in 18% was due to equipment failure. Survival at 6 months was 12%. Of the 18% of inappropriate arrests, 42% had 'do-not-resuscitate' orders in the casenotes. Survival did not depend on age, sex, location, presence of an anaesthetist, experience of house officer, time of day or admission diagnosis. Survival was more likely in the presence of ventricular fibrillation and absence of intubation. Of the 32 arrest trolleys, 66% were geographically acceptable to the area they served and 9% had significant deficiencies (these were situated in patient waiting areas and were infrequently checked).

Cardiac amyloidosis in the presence of Bence-Jones proteinuria and normal serum immunoglobulins.

We describe a case of cardiac amyloidosis, which is an uncommon cause of heart failure. This case is unusual, as the patient presented with symptoms of angina in the presence of normal coronary arteries and subsequently developed heart failure. Amyloidosis was secondary to myeloma with Bence-Jones proteinuria alone, which is rare.

Professional attitudes to cardiopulmonary resuscitation in departments of geriatric and general medicine.

Cardiopulmonary resuscitation for the elderly has long been a contentious issue. We have established by means of a postal survey the attitudes of 300 consultant geriatricians, 300 consultant physicians and 249 registered nurses to cardiopulmonary resuscitation. We also audited 400 case notes to document current practice in departments of general medicine and medicine for the elderly. No formal resuscitation policies were in operation. Geriatricians were more likely than physicians to make a positive resuscitation decision (p < 0.001), and involve nursing staff in the decision-making (p < 0.001). All professional groups felt age was unimportant in deciding on resuscitation, while the patients' prognoses and their wishes were most important. Case note audit revealed that geriatricians were better at documenting resuscitation decisions. Inappropriate resuscitation of patients is unacceptable. Each department or hospital ought to have agreed guidelines for cardiopulmonary resuscitation.

Could the increased antihypertensive efficacy of ketanserin in the elderly be due to altered pharmacokinetics?

Ketanserin is a serotonin S2-receptor antagonist that is an effective antihypertensive agent with a greater blood pressure reduction in older patients. We have reviewed the data from two studies of ketanserin pharmacokinetics in elderly patients, one in general practice (GP) and one in hospital patients. We compared these data with the results from two of our previous studies in young volunteers. The purpose was to determine whether the enhanced efficacy of ketanserin in elderly hypertensive patients could be due to altered pharmacokinetics. After a single dose of ketanserin, elderly hypertensives showed about a 60% increase in bioavailability compared with young volunteers. This increase is likely to be explained by a reduced metabolism of ketanserin on first pass through the liver. The elimination half-life of ketanserin was found to be longer in elderly hospital outpatients, but not in our elderly subjects in general practice. This prolongation of the elimination half-life of ketanserin appears to be unrelated to age, since the hospital outpatient elderly and elderly subjects in general practice were of similar ages. The elimination half-life of ketanserinol was longer in the hospital elderly subjects. This probably reflects a slight diminution of renal function in the elderly hospital outpatients, resulting in reduced clearance of ketanserinol. The peak and trough ketanserin concentrations were similar in young and elderly subjects during chronic treatment, and it is therefore unlikely that the increased efficacy of ketanserin in elderly patients is due to altered pharmacokinetics.

Stereoselective metabolism of metoprolol in Caucasians and Nigerians--relationship to debrisoquine oxidation phenotype.

The relationship between debrisoquine oxidation phenotype and the stereoselective metabolism of metoprolol was investigated in populations of British Caucasians (n = 139) and Nigerian subjects (n = 117). The 0-8 h urinary S/R-metoprolol (S/R-M) ratio was related to the ability to metabolise metoprolol and debrisoquine in both ethnic groups. The median S/R-M ratio was significantly higher in Caucasians (1.27) than in Nigerians (1.10). In the Caucasian population poor metabolisers of debrisoquine had significantly lower S/R-M ratio (median = 0.84) than extensive metabolisers (median = 1.28). Bimodality in the frequency distribution of the S/R-M ratio was not apparent in either ethnic group.

The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris.

1. The pharmacokinetics and pharmacodynamics of oral verapamil and propranolol were studied in patients with stable angina pectoris during chronic mono- and dual therapy. 2. The peak plasma concentrations (Cmax) and areas under the plasma concentration-time curves (AUC) of verapamil were similar during combined treatment with propranolol (mean +/- s.d.: Cmax = 491 +/- 397 ng ml-1; AUC = 2075 +/- 1524 ng ml-1 h) or atenolol (mean +/- s.d.: Cmax = 372 +/- 320 ng ml-1; AUC = 1985 +/- 1660 ng ml-1 h). 3. No differences in Cmax and AUC were observed during verapamil monotherapy (mean +/- s.d.: Cmax = 287 +/- 105 ng ml-1; AUC = 1375 +/- 455 ng ml-1 h) vs combined treatment with propranolol (mean +/- s.d.: Cmax = 312 +/- 55 ng ml-1; AUC = 1566 +/- 486 ng ml-1 h). 4. Treatment with verapamil increased the Cmax (mean +/- s.d.: 227 +/- 117 vs 116 +/- 62 ng ml-1, P less than 0.05) and AUC (1389 +/- 617 vs 837 +/- 316 ng ml-1 h, P = 0.0625) of propranolol in all subjects. 5. Transient atrioventricular dissociation occurred in two patients 2 h after dosing with verapamil and propranolol or atenolol. 6. Close observation of patients is essential when beta-adrenoceptor antagonists and verapamil are used together.

Lack of relationship between debrisoquine oxidation phenotype and the pharmacokinetics and first dose effect of prazosin.

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of a single oral dose of prazosin has been studied in eight hypertensive patients (four extensive and four poor metabolisers). No significant differences between the two phenotypes were observed in either the area under the plasma prazosin concentration-time curve, the terminal half-life or the first-dose effect of prazosin.

Successful management of Cushing's disease during pregnancy by transsphenoidal adenectomy.

Pregnancy in patients with Cushing's syndrome is rare. It is associated with a high fetal loss, increased frequency of preterm labour and excessive maternal morbidity. We describe a patient who became pregnant while investigations for hypertension were being done. Cushing's disease was diagnosed and the patient had transsphenoidal pituitary surgery at 22 weeks gestation. To our knowledge this is the first time this operation has been done during pregnancy for this condition. Cushing's disease was controlled, but because of worsening hypertension, she had a caesarean section at 30 weeks gestation. Subsequently her blood pressure fell and her hydrocortisone replacement therapy is being withdrawn. Her daughter is now thriving after initial problems with pneumothoraces.

Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol.

The contribution of debrisoquine polymorphism to the metabolism and action of beta-adrenoceptor antagonists (beta-blockers) varies widely between drugs. Oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The poor metabolizer phenotype is associated with an increased area under the plasma drug concentration vs. time curve, a prolongation of elimination half-life and a more intense and sustained beta-blockade. The stereoselective metabolism of metoprolol also displays phenotypic differences, which should be taken into account when interpreting plasma concentration vs. response relationships. Studies in vivo and in vitro have identified some of the metabolic pathways which are subject to this defect, namely the alpha-hydroxylation and the O-demethylation of metoprolol and the 1'-hydroxylation of bufuralol. In contrast, the pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidized, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is deficient in the poor metabolizer phenotype. The disposition of atenolol, which is almost completely eliminated unchanged by renal and faecal excretion, is independent of oxidation phenotype. If standard doses of some beta-blockers are used in poor metabolizers, these patients may be susceptible to concentration-related adverse reactions and they may also require lower and less frequent dosing for control of angina pectoris.

Metoprolol metabolism and debrisoquine oxidation polymorphism--population and family studies.

The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. The log10 metoprolol to alpha-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P less than 0.001). The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. The major urinary metabolite of metoprolol metabolism was H117-04, the end-product of O-dealkylation. The distribution of the log10 metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P less than 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. These results indicate that both the alpha-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.

Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin.

We studied the pharmacokinetics and beta-blocking effects of a single, oral 20 mg dose of timolol in six poor metabolizers (PMs) and six extensive metabolizers (EMs) of debrisoquin. The plasma timolol concentration was significantly higher in PMs than in EMs. There was a fourfold difference in mean AUC (1590 +/- 1133 vs. 394 +/- 239 ng X hr/ml; P less than 0.01) and a twofold difference in mean t1/2 (7.5 +/- 3 vs. 3.7 +/- 1.7 hours; P less than 0.01), reflecting differences in oral clearance (13.1 +/- 7.8 vs. 48.5 +/- 23.2 L/hr; P less than 0.01). The degree of beta-blockade was greater in PMs than in EMs at 12 hours (30.9% vs. 18.2%; P less than 0.05) and at 24 hours (28.3% vs. 13.1%; P less than 0.05). In the group as a whole the metabolic ratio correlated positively with both kinetic data and beta-blockade, but some overlap was observed. Hence timolol metabolism appears to be subject to debrisoquin-type polymorphism, which results in interphenotypic variation in plasma concentration and beta-blocking effect.

Comparison of two slow-release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients.

We have compared the beta-adrenoceptor blocking and antihypertensive effects of chronic once daily treatment with conventional metoprolol 200 mg, two 'long-acting' formulations of metoprolol 200 mg and atenolol 100 mg in a cross-over study in 12 hypertensive patients concurrently receiving diuretic therapy. The peak effects of all compounds were similar, with significant reductions in exercise heart rate and blood pressure. Twenty-four hours after dosing only atenolol treatment was consistently associated with a reduction in both exercise heart rate (P less than 0.001) and blood pressure (P less than 0.02) when compared with placebo. Once daily treatment of hypertension with metoprolol, even in 'long-acting' formulations, cannot be recommended because of waning antihypertensive effect which would be missed at routine clinic attendance. Metoprolol should be prescribed twice daily in hypertension. So-called long-acting formulations do not always confer benefits over conventional dose forms.