Paying research subjects: participants' perspectives.

OBJECTIVE: To explore the opinions of unpaid healthy volunteers on the payment of research subjects. DESIGN: Prospective cohort. SETTING: Southern Alberta, Canada. PARTICIPANTS: Medically eligible persons responding to recruiting advertisements for a randomised vaccine trial were invited to take part in a study of informed consent at the point at which they formally consented or refused trial participation. Of 72 invited, 67 (62 trial consenters, 5 trial refusers) returned questionnaires at baseline and 54 at follow-up. OUTCOME MEASURES: Proportions of persons who agreed or disagreed with three close-ended statements on the payment of research subjects; themes and categories identified by content analysis of responses to an open-ended question. RESULTS: A minority (43.3%) agreed with paying either patient or healthy volunteer participants. Opinions did not change over time. Participants' comments addressed: benefits and drawbacks to research participation; benefits and drawbacks to paying research participants; conditions under which payment of research subjects would be acceptable, and the nature of acceptable recognition. Acceptable conditions were to improve problematic recruitment, to reimburse costs, and to recognise participants, particularly for their time investment. Both non-monetary and monetary recognition of volunteers were thought to be appropriate. CONCLUSIONS: Most unpaid volunteers disagreed with paying research participants. The themes arising from their comments are similar to those that have been raised by ethicists and suggest that recognising the time and effort of participants should receive greater emphasis than presently occurs.

Hyperhomocyst(e)inemia and the prevalence of atherosclerotic vascular disease in patients with end-stage renal disease.

Hyperhomocyst(e)inemia is now recognized as an independent risk factor for atherosclerotic cardiovascular disease in patients with normal renal function. Hyperhomocyst(e)inemia is common in patients with chronic renal failure. This study is designed to look for an association between hyperhomocyst(e)inemia and atherosclerotic vascular disease in patients with end-stage renal disease (ESRD). Two hundred eighteen patients undergoing hemodialysis were enrolled onto the study and had predialysis bloodwork performed for total homocyst(e)ine, red blood cell folate, and vitamin B(12) levels. A history of clinically significant atherosclerotic vascular disease (ischemic heart disease, cerebrovascular disease, or peripheral vascular disease) was elicited by patient questionnaire and verified by careful inpatient and outpatient chart review. Atherosclerotic vascular disease was present in 45.9% of patients. Mean homocyst(e)ine concentration was 26.7 micromol/L (95% confidence interval [CI], 25.0 to 28.4) overall. Mean homocyst(e)ine concentration was 28.6 micromol/L (95% CI, 25.6 to 31.7) and 25.0 micromol/L (95% CI, 23.2 to 26.8) in patients with and without atherosclerotic disease, respectively (P = 0.036). The adjusted odds ratio for atherosclerotic disease was 2.12 (95% CI, 1.03 to 4.39) for those subjects with a homocyst(e)ine level in the highest quartile compared with the lowest 3 quartiles. In the 126 men, the adjusted odds ratio for atherosclerotic disease was 3.4 (95% CI, 1. 24 to 9.42) for those with homocyst(e)ine levels in the highest quartile compared with the lowest 3 quartiles. No association was found between homocyst(e)ine level and atherosclerotic disease in women. In conclusion, there is an association between hyperhomocyst(e)inemia and atherosclerotic vascular disease in patients undergoing dialysis. Prospective studies need to further examine the relationship between homocyst(e)ine level and atherosclerosis in women with ESRD.

Hyperhomocysteinemia, anticardiolipin antibody status, and risk for vascular access thrombosis in hemodialysis patients.

BACKGROUND: Vascular access failure is an important cause of morbidity in end-stage renal failure patients on hemodialysis. Currently, little is known about risk factors that predispose certain hemodialysis patients to recurrent access thrombosis. Hyperhomocysteinemia (common in patients with renal failure) predisposes people with normal renal function to recurrent and early-onset venous thrombosis, although the effect on vascular access thrombosis is currently unknown. Previous studies have suggested that high titers of IgG anticardiolipin antibody (IgG-ACA) predispose hemodialysis patients to access thrombosis. This cross sectional study was designed to assess for an association between two predictive variables, hyperhomocysteinemia and elevated titers of IgG-ACA, and vascular access thrombosis in patients undergoing chronic hemodialysis. METHODS: Risk factors for vascular access thrombosis were documented, and the number of episodes of access thrombosis was recorded for the previous three years in patients undergoing hemodialysis. Midweek predialysis total homocysteine and IgG-ACA levels were measured in all subjects. RESULTS: Of the 118 patients who were enrolled, 75.4% had a native arteriovenous fistula. Episodes of vascular access thrombosis were recorded for the previous three years; 34 (28.8%, 95% CI 20.9 to 37.9%) patients had 72 episodes of access thrombosis over the period of risk. Mean homocysteine levels were not significantly different between these 34 patients (28.6 micromol/liter, 95% CI 24.5 to 32.7) and the patients who had no episodes of graft thrombosis (29.8 micromol/liter, 95% CI 26.7 to 32.9). Sixty-seven unselected patients had IgG-ACA levels drawn for analysis, and all assays were negative. The only variable that was associated with a higher risk for graft thrombosis was the type of vascular access placed (odds ratio 4.0, 95% CI 1.6 to 9.6 for patients with a synthetic graft compared with those with an arteriovenous fistula). CONCLUSIONS: No association was found between homocysteine levels or anticardiolipin antibody and vascular access thrombosis in our patient population.

1999 Canadian recommendations for the management of hypertension. Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension.

OBJECTIVE: To provide updated, evidence-based recommendations for health care professionals on the management of hypertension in adults. OPTIONS: For patients with hypertension, there are both lifestyle options and pharmacological therapy options that may control blood pressure. For those patients who are using pharmacological therapy, a range of antihypertensive drugs is available. The choice of a specific antihypertensive drug is dependent upon the severity of the hypertension and the presence of other cardiovascular risk factors and concurrent diseases. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: MEDLINE searches were conducted from the period of the last revision of the Canadian Recommendations for the Management of Hypertension (January 1993 to May 1998). Reference lists were scanned, experts were polled and the personal files of the authors were used to identify other studies. All relevant articles were reviewed, classified according to study design and graded according to levels of evidence. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS: Harms and costs: The diagnosis and treatment of hypertension with pharmacological therapy will reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and mortality. RECOMMENDATIONS: This document contains detailed recommendations pertaining to all aspects of the diagnosis and pharmacological therapy of hypertensive patients. With respect to diagnosis, the recommendations endorse the greater use of non-office-based measures of blood pressure control (i.e., using home blood pressure and automatic ambulatory blood pressure monitoring equipment) and greater emphasis on the identification of other cardiovascular risk factors, both in the assessment of prognosis in hypertension and in the choice of therapy. On the treatment side, lower targets for blood pressure control are advocated for some subgroups of hypertensive patients, in particular, those with diabetes and renal disease. Implicit in the recommendations for therapy is the principle that for the vast majority of hypertensive patients treated pharmacologically, practitioners should not follow a stepped-care approach. Instead, therapy should be individualized, based on consideration of concurrent diseases, both cardiovascular and noncardiovascular. VALIDATION: All recommendations were graded according to the strength of the evidence and the consensus of all relevant stakeholders. SPONSORS: The Canadian Hypertension Society and the Canadian Coalition for High Blood Pressure Prevention and Control.

Improved tolerability of felodipine compared with amlodipine in elderly hypertensives: a randomised, double-blind study in 535 patients, focusing on vasodilatory adverse events. The International Study Group.

The primary aim of this double-blind, parallel group trial was to compare incidence of newly occurring vasodilatory adverse events in elderly patients treated with recommended once-daily doses of felodipine extended release (ER) or amlodipine. A total of 535 patients over 65 years old with a sitting diastolic blood pressure of 90-115 mmHg and/or systolic blood pressure 160-220 mmHg, were recruited at 46 centres worldwide. Patients were randomised to felodipine ER 2.5 mg or amlodipine 5 mg. If blood pressure was > 160/90 mmHg after three or six weeks, felodipine ER was increased to 5 and 10 mg and amlodipine to 10 mg. After nine weeks, average doses of felodipine ER and amlodipine were 5.5 mg and 7.3 mg, respectively. Newly occurring vasodilatory adverse events were reported by 32% of felodipine ER patients and 43% of amlodipine patients (p = 0.007). Both treatments effectively reduced blood pressure 24 hours post-dose. Using a low starting dose and individual titration, felodipine ER achieves good control of blood pressure with few vasodilatory side-effects.

The health interview: automated assessment in a multidisciplinary outpatient hypertension treatment program.

We studied patients' acceptance of a computer-administered health assessment and educational program at an outpatient hypertension clinic. The program was designed to be user-friendly and minimized the need for keyboard skills. Thirty patients > or = 50 years of age participated. The computer assessment took an average of 39 minutes to complete. Completion time was related to age but not to other demographic factors such as sex, education, or previous computer use. The program was well accepted by patients. Its personalized risk-factor summary and life style advice were particularly well received. We conclude that automated history-taking and educational programs can be used in this health care setting.

Live and learn: patient education delays the need to initiate renal replacement therapy in end-stage renal disease.

During a longitudinal study of the quality of life of end-stage renal disease, 204 patients with deteriorating renal function were identified before dialysis or transplantation was required to preserve their lives. These patients were randomly assigned to either an enhanced or a standard education condition. The enhanced education condition consisted of a specially prepared slide-lecture show concerning kidney diseases and their treatment that was delivered by a trained research assistant. The standard education condition consisted of whatever educational procedures were routinely available at the participating hospital. All but six patients have now started treatment by maintenance dialysis. Individuals in the enhanced education condition survived an average of 4.6 months longer than did those in the standard education group without requiring the initiation of renal replacement therapy. This effect could not be attributed to physical differences between the groups, to cohort effects, to delays in contacting the patients, or to when or where they were identified. Possible mechanisms for this effect are discussed.

Clinical pharmacokinetics of propafenone.

Propafenone is a class 1C antiarrhythmic agent which is administered as a racemate of S(+)- and R(-)-enantiomers. It is well absorbed and is predominantly bound to alpha 1-acid glycoprotein in the plasma. The enantiomers display stereoselective disposition characteristics, the R-enantiomer being cleared more quickly. The hepatic metabolism of propafenone is polymorphic and genetically determined: about 10% of Caucasians have a reduced capacity to hydroxylate the drug. This polymorphic metabolism accounts for the marked interindividual variability in the relationships between dose and concentration, and between concentration and pharmacodynamic effects. During long term administration, the metabolism is saturable in patients with the 'extensive metaboliser' phenotype, leading to accumulation of the parent compound. Propafenone blocks fast inward sodium channels in a frequency-dependent manner, and also has moderate beta-blocking effects. Both the enantiomers and the 5-OH metabolite have a potency to block sodium channels comparable with that of the parent compound. The S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Propafenone typically slows conduction markedly but only modestly prolongs refractoriness. These cardiac effects are determined by the extent of its myocardial accumulation. The drug should be used with caution in patients with serious structural heart disease, as it may cause or aggravate life-threatening arrhythmias. Significant interactions occur when propafenone is coadministered with other drugs. It increases the plasma concentrations of digoxin, warfarin, metoprolol and propranolol as well as enhancing their respective pharmacodynamic effects. Doses of these drugs should therefore be decreased if they are coadministered with propafenone.

Interaction of 1,25-dihydroxyvitamin D and plasma renin activity in high renin essential hypertension.

Renin secretion by the kidney is inhibited by an increase in free intracellular calcium concentration. This increase in free intracellular calcium content may be augmented by serum 1,25-dihydroxyvitamin D. In 10 subjects with high renin hypertension, an increase in dietary sodium intake resulted in an increase in urinary calcium excretion (2.5 to 3.4 mmol/L, P = .011) and an increase in serum 1,25-dihydroxyvitamin D (51.2 to 61.0 pmol/L, P = .045). An inverse correlation existed between the change in vitamin D and the change in plasma renin activity (r = -0.765, P = .01). An inverse correlation also existed between the change in plasma renin activity and the change in mean arterial blood pressure (r = -0.757, P = .011). It is postulated that the increase in dietary sodium led to an increase in serum 1,25-dihydroxyvitamin D concentration, which may have contributed to an increase in intracellular calcium concentration, a decrease in renal secretion of renin, and a fall in plasma renin activity. The resultant fall in PRA in part effected the change in blood pressure to the increased sodium intake. Therefore, 1,25-dihydroxyvitamin D may be a mediator in the response of high renin hypertension to increased sodium intake.

Intraperitoneal administration of acyclovir in patients receiving continuous ambulatory peritoneal dialysis.

In subjects with normal renal function, acyclovir is rapidly removed from the body via the kidneys. In subjects with end-stage renal disease, the half-life is significantly prolonged. The half-life in subjects receiving hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) is similarly prolonged (10.0 +/- 2.2 and 13.2 +/- 4.7 hours, respectively). After intravenous dosage, peritoneal clearance was 3.4 +/- 0.2 mL/min. Intraperitoneal dosing in subjects receiving CAPD resulted in a bioavailability of 61 +/- 10% and drug levels sufficient to inhibit herpes simplex virus (HSV) and varicella zoster virus (VZV). Intraperitoneal administration is an alternative route of administration in patients with poor vascular access.

Psychosocial predictors of survival in end-stage renal disease.

Several psychosocial variables were investigated as predictors of 4-year survival in a sample of 97 end-stage renal disease (ESRD) patients undergoing treatment by hemodialysis, continuous ambulatory peritoneal dialysis, or renal transplantation. Hypothesized psychosocial predictors included depression, mood disturbance, life happiness, affect, pessimism, self-esteem, knowledge of renal disease and its treatment, perceived control over important life domains, perceived intrusiveness of ESRD into important life domains, illness-related concerns, difficulties in daily activities, number of regular leisure activities, somatic symptoms of distress, social networks, recent negative life events, and defensive response styles. Methodological controls were incorporated to test the prognostic significance of these variables and included a) exclusion of deaths attributable to "unnatural" causes; b) multivariate statistical controls for physical and demographic determinants of survival; c) widely used standardized psychosocial instruments; and d) temporally aggregated psychosocial measurements to enhance reliability. Hierarchical multiple regression analyses identified four variables as significant and independent predictors of increased survival times in ESRD: a) comparatively fewer serious nonrenal comorbid illnesses; b) younger age; c) regular involvement in an increased number of leisure activities; and d) overall life happiness described as "an even mixture of unhappiness and happiness" (as compared with "very happy"). However, no evidence was obtained to support the hypothesis that increased depressive symptoms and/or moods contribute to compromised survival in ESRD.

Illness intrusiveness and quality of life in end-stage renal disease: comparison and stability across treatment modalities.

Investigated the degree to which chronic, life-threatening illness and its treatment interfere with continued involvements in valued activities and interests--that is, illness intrusiveness--and its impact on quality of life in end-stage renal disease. Data were collected on two occasions separated by a lag of 6 weeks. Mixed analyses of variance indicated that life domains were affected differentially across treatments. Perceived illness intrusiveness correlated significantly with treatment time requirements, uremic symptoms, intercurrent nonrenal illnesses, fatigue, and difficulties in daily activities. Significant quality-of-life differences were observed across treatment modalities for satisfaction/happiness and pessimism/illness-related concerns but not for depression/distress. Perceived illness intrusiveness correlated significantly with each of these quality-of-life measures. Results were stable over time. These findings substantiate the construct of illness intrusiveness as a mediator of the psychosocial impact of chronic, life-threatening illness.

Phosphate as a factor in sodium sensitivity in normal and high renin hypertension.

Disturbed phosphate (PO4) metabolism has been documented in spontaneously hypertensive rats but poorly studied in humans. Twenty-seven drug-free hypertensive subjects were studied on both a 10- and 100-mmol sodium diet. The response of mean arterial pressure to sodium repletion was directly correlated to the response of plasma renin activity (r = 0.540, p = 0.004) and inversely related to the percent response of serum PO4 concentrations. In the sodium-replete state serum PO4 concentration correlated inversely with plasma vitamin D concentration (r = 0.419, p = 0.026), consistent with PO4 acting as a determinate of vitamin D production. The response of serum calcium and plasma vitamin D concentrations to sodium repletion were correlated (r = 0.392, p = 0.043), consistent with serum calcium levels being a dependent variable, but the responses of serum PO4 and vitamin D concentrations were not. This study suggests that PO4 metabolism may be a determinate of blood pressure response to sodium repletion.

Limited effectiveness of charcoal hemoperfusion in malathion poisoning.

Malathion is an organophosphate pesticide that can cause respiratory failure and death in humans. In vitro studies suggested that hemoperfusion may be valuable in treating malathion poisoning. We found that although the charcoal column may effect reasonable clearance in the first 2 hours of use, prolonged hemoperfusion may require changing the column in severe, acute poisonings.

Blood pressure and serum calcium responses to altered sodium intake in high renin hypertension.

Subjects with high renin hypertension tend to be sodium-resistant showing paradoxical blood pressure responses to alterations in sodium intake. Of twenty-five subjects with high renin essential hypertension (ten females, 15 males, mean age 30 years), 14 were noted to have a decrease in mean arterial blood pressure (MAP) when sodium intake was increased from 10 to 100 mmol/d. The percentage response of plasma renin activity was greater in these patients than in those with an increase in MAP (-55.4 +/- 5.4 v -33.6 +/- 6.9, P = .018). Overall, the response of MAP was directly correlated to the percentage response of plasma renin activity (r = .549, P = .005), and inversely related to the change in serum calcium concentration (corrected for changes in serum albumin) (r = -.547, P = .005). No intercorrelation between the changes in plasma renin activity and serum calcium concentration was detected. The blood pressure response to increased sodium intake in high renin hypertension would appear to be divergent and related not only to the suppression of plasma renin activity, but also to changes in circulating calcium.

Hemodialysis removal of propafenone.

Propafenone kinetics were studied after intravenous and oral dosing in a patient with end-stage renal disease. Hemodialysis was performed within 10 hours of dosing in order to assess its effects. After intravenous administration of 70 mg propafenone, total-body clearance was 10.5 ml/min/kg before and 10.4 ml/min/kg during hemodialysis. After a single oral dose of 300 mg, clearance was 19.4 ml/min/kg before and 18.9 ml/min/kg during hemodialysis. Bioavailability was 48%.

Norepinephrine and calcium responses to altered sodium intake in modulating and non-modulating high-renin hypertension.

Sodium sensitivity in subjects with high-renin hypertension has been associated with non-modulation of cardiovascular and biochemical responses to alteration in sodium intake. Using the percentage suppression of plasma renin activity in response to an increase in dietary sodium intake, high-renin hypertensive subjects were categorized in two groups. In association with the increase in sodium intake, modulators showed greater than 58% suppression of plasma renin activity, and significant reductions in mean arterial pressure, plasma aldosterone, norepinephrine and serum calcium concentration. Non-modulators had no significant change in plasma renin activity, mean arterial blood pressure, plasma aldosterone, norepinephrine or serum calcium concentration. The blood pressure response to an increase in dietary sodium intake may be a composite of responses of the renin-angiotensin-aldosterone axis, the adrenergic nervous system and calcium regulatory system.