Henk J. J. Van Lier

Blood pressure reduction after oral glucose loading and its relation to age, blood pressure and insulin

Recently it was shown that blood pressure (BP) in the elderly may decrease after a meal. The pathophysiologic mechanism of this phenomenon is unknown. It has been suggested that a failure of insulin-mediated sympathetic nervous system activation plays a role. To evaluate the role of endogenous insulin, the effects of oral glucose and oral fructose loading on BP, heart rate and norepinephrine levels were studied in 10 young normotensive volunteers (YN), 10 young hypertensive patients (YH), 10 elderly normotensive volunteers (EN) and 10 elderly hypertensive patients (EH). Fructose, 75 g/300 ml of water, elicited--in contrast to the same amount of glucose--only a small increase in insulin and glucose levels. After glucose loading, mean arterial BP decreased by 17 mm Hg in the EH group (p less than 0.001), 6 mm Hg in the EN group (p less than 0.01) and 7 mm Hg in the YH group (p less than 0.001), and did not change in the YN group. After oral fructose loading, BP did not change in any group. In all groups except the YN group, the increases in norepinephrine level and heart rate after both tests were not significantly different. These findings suggest that the BP reduction after glucose loading is related to glucose-mediated factors. A failure of insulin-mediated sympathetic nervous system activation does not appear to play a major role.

Comparison of intrabrachial and finger blood pressure in healthy elderly volunteers

This study was performed to compare continuous Finapres (FIN) and intrabrachial (IAP) blood pressure in healthy elderly volunteers. Fifteen elderly subjects (age 71 to 83) without cardiovascular disease and an intraarterial mean (range) systolic and diastolic blood pressure of 162 (122 to 195) and 73 (62 to 88) mm Hg, respectively, participated in the study. A 10-min head-up tilt, 10 min active standing, a 15-sec Valsalva, and a 5-min mental arithmetic were performed in random order. Beat-to-beat values of systolic, diastolic, and mean arterial pressure were analyzed. At rest, FIN underestimated IAP by 16.8 +/- 2.6 (SE), 10.8 +/- 1.5, and 17.5 +/- 1.6 mm Hg for systolic, diastolic, and mean arterial blood pressure, respectively (P < .05). During head-up tilt, FIN overestimated the intraarterial systolic blood pressure response by 7.2 +/- 1.6 (SE) mm Hg (P < .05). Group-averaged changes in diastolic and mean arterial IAP were followed closely by FIN. During standing, Finapres closely followed intraarterial diastolic and mean arterial pressure but the increase in systolic blood pressure was higher at the finger as compared to intrabrachial recordings, resembling the results of head-up tilt. During the Valsalva maneuver, maximal responses in systolic, diastolic, and mean arterial pressure were underestimated by FIN by 12.1 +/- 3.3 (SE), 6.8 +/- 2.7, and 7.1 +/- 1.7 mm Hg, respectively (P < .05 for all parameters). During mental arithmetic, FIN underestimated the intraarterial systolic blood pressure response by 6.1 +/- 2.7 (SE) mm Hg (P < .05), while diastolic and mean arterial pressure responses were followed correctly by FIN. It is concluded that apart from systolic blood pressure, FIN closely follows intraarterial blood pressure responses for the orthostatic maneuvers and mental arithmetic. During Valsalva, the rapid changes in blood pressure were followed in direction but not in magnitude.

Exercise cardiorespiratory function before and one year after operation for pectus excavatum

In 35 patients with pectus excavatum (aged 17.9 +/- 5.6 years) pulmonary function and maximal exercise test results were compared before and at 1 year after operation. The lower posteroanterior chest diameter on the lateral x-ray film was significantly smaller than normal (p < 0.0001) and increased significantly after operation (p < 0.0001). Preoperatively, total lung capacity (86.0% +/- 14.4%; p = 0.0001) and inspiratory vital capacity (79.7% +/- 16.2; p = 0.0001) were significantly smaller than predicted and further decreased after operation (-9.2% +/- 9.2%; p = 0.0001 and -6.6% +/- 10.7%; p = 0.0012, respectively). Arterial blood gas values displayed normal patterns with increasing exercise both before and after operation. Only the arterial pH decreased more after operation than before (p = 0.0026). After operation there was a significant increase in maximal oxygen uptake (oxygen uptake; p = 0.0002 and oxygen uptake per kilogram; p = 0.0025) and oxygen pulse (oxygen uptake/heart rate approximates an indirect parameter for stroke volume; p = 0.0333) during exercise, whereas the maximal work performed was unchanged. Efficiency of breathing (ratio of tidal volume/inspiratory vital capacity) at maximal exercise improved significantly after operation (p = 0.0005). Ventilatory limitation of exercise (defined by an increase in carbon dioxide tension during exercise) was found in 43.9% of the patients before operation. A tendency of improvement was noted (not significant) after operation (difference in carbon dioxide tension 0.6 +/- 0.4 kPa before versus 0.3 +/- 0.5 kPa after operation). However, the group with normal preoperative carbon dioxide elimination had a ventilatory limitation of exercise after operation (difference in carbon dioxide tension -0.4 +/- 0.3 kPa before versus -0.1 +/- 0.3 kPa after operation; p = 0.0128) with a significant increase in oxygen consumption (p = 0.0007). In conclusion the subjective physical improvement after operation is not explained by changes in cardiorespiratory function at exercise. The data suggest a higher work of breathing after operation.

Haemodynamic, Hormonal, and Diuretic Effects of Felodipine in Healthy Normotensive Volunteers

SummaryFelodipine and placebo were infused in a double- blind, crossover study in 10 healthy normotensive volunteers. Compared with placebo, felodipine caused a significant decrease in diastolic blood pressure and forearm vascular resistance, while there was no change in systolic blood pressure. The rises in heart rate, plasma renin activity and plasma nor- adrenaline (norepinephrine) concentration further demonstrated the vasodilating activity of felodipine. Plasma aldosterone, adrenaline (epinephrine) and antidiuretic hormone concentrations were similar after a 90- minute infusion of felodipine or placebo. The response of plasma aldosterone levels to exogenous adenocorticotrophic hormone showed evidence of a slight blunting during felodipine infusion. Felodipine had a marked diuretic effect, probably secondary to an increase in natriuresis, which might be due to a direct tubular effect of the drug.

Treatment Of Acute Rejection Of Cadaveric Renal Allografts With Rabbit Antithymocyte Globulin

In a prospective randomized single-blind trial, we compared the effectiveness of rabbit antithymocyte globulin (RATG) in the treatment of acute renal graft rejection with the results of treatment by high oral doses of prednisone. Twenty recipients of cadaveric kidneys were included in each group. In the RATG group, the prednisone dose was not increased and a dose-by-rosette protocol was used to keep T cell levels between 50 and 150/mm3. In this group 15 of the 20 patients responded to the treatment. One of these patients lost her kidney afterward because of a technical failure. In five patients rejection was irreversible despite a subsequent course of high-dose prednisone orally. In the prednisone group, 13 patients showed a good response, but 3 of them only after a subsequent course of RATG. The remaining seven patients underwent nephrectomy before a course of RATG could be given. One patient in this group died of septicemia. In either group there were six second rejection episodes, but they developed 2.2 months later in the RATG group. All second rejection episodes were treated with the alternative regimen and all patients responded to this treatment. Renal function after 6 months was similar in both groups. Less infections occurred in the RATG group. Prior to rejection, there were no differences in concentrations of peripheral T cells between both groups. Treatment of acute rejections with RATG is an effective and safe procedure which is steroid sparing.

Diagnostic performance of biopsy-based methods for determination of Helicobacter pylori infection without a reference standard

Endoscopic biopsy-based tests are considered to be the reference method for diagnosing Helicobacter pylori infection and monitoring antibiotic treatment, but unbiased data on their diagnostic performance is lacking. In this study we evaluated the diagnostic performance of culture, histology and rapid urease testing of antral biopsies separately and in combination. Antral biopsies were taken from consecutive patients undergoing upper gastrointestinal endoscopies at a single center between January 1995 and May 1997. The biopsies were examined for culture, histology, and CLOtest. The diagnostic performance, i.e., the sensitivity and specificity of the tests was estimated with 7 non-linear equations in 7 unknowns. To determine sources of heterogeneity that may have biased the results, data were stratified for age, gender, and whether they were taken before or after anti-Helicobacter antibiotic treatment. During the study period 631 patients underwent 869 upper gastrointestinal endoscopies. In 122 (14%) of the antral specimens the test results of culture, histology and CLOtest differed. Based on the nonlinear regression techniques we estimated that in 347 tests (40%) H. pylori infection was present. Overall sensitivity, specificity, positive and negative predictive value for each test were as follows: culture 91.4%, 96.3%, 94.2%, 94.4%, respectively; histology 90.3%, 97.8%, 96.4%, 93.8%, respectively; CLOtest 94.9%, 96.7%, 95.0%, 96.6%, respectively. In combination, the three tests provided the definitive diagnosis, either non-infected or infected, in 862 out of the 869 tests. Sensitivity of gastric antral histology was 64.9% (95% CI: 38-86) in females who did and 84.5% (95% CI: 77-90) in females who did not have had recent antibiotic therapy to cure the infection. Approximately 5-10% of H. pylori infected patients, were mis-diagnosed with a single biopsy-based test taken from the gastric antrum. Only a combination of bacterial culture, histological examination and the CLOtest represents an appropriate reference standard for research purposes to identify infected patients.

Improved patient and graft survival after treatment of acute rejections of cadaveric renal allografts with rabbit antithymocyte globulin

In a prospective randomized trial, we compared the effectiveness of trabbit antithymocyte globulin (RATG) in the treatment of acute renal allograft rejection with the results of treatment by high oral doses of prednisone. Firfty recipients of cadaverric kidneys were included in each grop. In the RATG group, the prednisone dose was not increased and a dose-by-rosette protocol was used to keep T cell levels between 50 and 150/mm3. The three-month and one-year graft survival rates in the RATG group were 84% and 78%, and were significantly higher than those in the prednisone group (64% and 50%). A significant difference in patient survival could also be detected. In the RATG group the three-months and one-year patient survival rates were 100% and 98%, and patient survival rates in the prednisone group were 91% and 84%, respectively. The percentage of second rejections was higher in the prednisone group and 70% of these patients showed a good response to subsequent RATG treatment. Renal function after six months was similar in both groups. No serious side effects were encountered in the RATG group. The incidence of infections was the same in both groups. Treatment of acute rejections with RATG is preferable to prednisone treatment. It improves long-term graft and patient survival and is steroid-sparing.

Treatment of Raynaud's syndrome with adrenergic alpha-blockade with or without beta-blockade.

In a double blind placebo-controlled cross-over trial of 24 weeks 31 patients with Raynauds syndrome were treated with the alpha-blocker phenoxybenzamine (10-20 mg daily) and with the combination of the alpha-blocker phenoxybenzamine (10-20 mg daily) and the beta-blocker sotalol (40-80 mg daily). A favourable effect on recovery of finger temperature after finger cooling was demonstrated after alpha-blockade as com pared to the before treatment situation. This favourable effect was not different when the group received the combined alpha- and beta-blockade. The blood pressure was not influenced by either of the 2 medications. Fluid retention appeared with alpha-blockade and was absent with combined alpha- and beta-blockade. Decrease of heart rate oc curred with alpha- plus beta-blockade and was absent with alpha-blockade alone. Clinical symptoms of Raynauds syndrome equally were alleviated by the two medica tions. Common, and equally frequent side effects of the two medications were nasal congestion, disturbed ejaculation and potence, dry mouth, exercise-induced and ortho- static dizziness. We conclude that alpha-blockade is beneficial in Raynauds syndrome and that additional beta-blockade counteracts the alpha-blocker side-effect fluid retention, re duces the heart rate and thus may prevent alpha-blocker induced tachycardia, and that it does not cause hypotension.

Risk Factors in Asymptomatic Patients with a Carotid Bruit

A consecutive series of 369 asymptomatic patients with a carotid bruit was prospectively followed with Ocular Pneumoplethysmography (OPG). The aim of the study was to identify those patients most prone to cerebrovascular ischemia and/or progression of obstructive carotid disease. During follow-up 13 patients developed a stroke of which six were fatal (two thrombo-embolic and four haemorrhagic strokes). TIAs occurred in 15 patients, including eight patients with amaurosis fugax. TIAs occurred more frequently on the side of a haemodynamically significant stenosis (9% = 9/95) than on the side of a normal, OPG (2% = 6/274). There was no difference in the strokelocated side. The occurrence of symptoms and/or signs of cerebrovascular disease was 4% at two years and 10% at five years. The left hemisphere was affected twice as often as the right. The development of a haemodynamically significant carotid stenosis, according to OPG, was equal for the right and the left carotid arteries, being 18% at two years and 56% after 5 years of follow-up. The major risk factors for progression of obstructive disease were systolic blood pressure above 160 mmHg independent of age, diabetes mellitus and the presence of ischaemic heart and peripheral arterial obstructive disease. This study supports the contention that in a group of patients with an asymptomatic carotid bruit, a group of patients at risk from cerebrovascular accidents can be filtered out by a simple non-invasive test in combination with a complete physical examination.

Crossover Trials with a Binary Response: A Powerful Method Despite the Carryover Effect

The two‐period crossover trial has the evident advantage that, by use of within‐patient comparisons, the usual large between‐patient variability is not used as a measure to compare treatments. A prerequisite, however, is that the order of the treatments does not substantially influence the outcome of the treatment. Crossover studies with a binary response (such as yes/no or present/absent), although widely used for initial screening of new compounds, have not previously been studied for such order effects. This study uses a mathematical model based on standard statistical tests to study to what extent such order effects, here identical to carryover effects, may reduce the power of detecting a treatment effect. It is concluded that, despite large carryover effects, the crossover study with a binary response remains a powerful method and that testing for carryover effects makes sense only if the null hypothesis of no treatment effect cannot be rejected.