P.-H. Althoff

Plasma Renin Aktivität und Aldosteronverhalten bei kritisch kranken Patienten

To investigate the influence of critical illness on plasma renin activity and aldosterone levels and to examine potential inhibitory effects of dopamine therapy on aldosterone responsiveness, we measured plasma renin activity, and potassium and creatinine in serum, as well as the responses of aldosterone, cortisol and prolactin levels to TRH 200 micrograms i.v. + Synacthen 0.25 mg i.v. in 63 unselected, critically ill patients (32 females, 31 males, aged 18-84 years). Of the patients 19 received dopamine treatment (3-13 micrograms/kg/min i.v.); 21 of the patients died in the further course of their disease. Plasma renin activity was increased in 66.7% of the patients and aldosterone levels were elevated in 90.5% of the patients. There were correlations (P less than 0.05) of lethality with plasma renin activity and cortisol levels and correlations (P less than 0.01) of aldosterone concentrations with plasma renin activity and cortisol levels. Whereas dopamine treatment had no inhibitory effect on aldosterone levels before and after stimulation, prolactin stimulation was decreased in dopamine-treated patients. Thus, dopamine does not generally lose its potency of hormone inhibition in critically ill patients, but has no influence on the secondary aldosteronism developing regularly in the early phase of critical illness, which is apparently mainly due to the stimulatory effect of ACTH (or ACTH-related pituitary peptides) and is considered an epiphenomen of the stress mechanisms acting upon the patients in this condition.SummaryTo investigate the influence of critical illness on plasma renin activity and aldosterone levels and to examine potential inhibitory effects of dopamine therapy on aldosterone responsiveness, we measured plasma renin activity, and potassium and creatinine in serum, as well as the responses of aldosterone, cortisol and prolactin levels to TRH 200 µg i.v. + Synacthen 0.25 mg i.v. in 63 unselected, critically ill patients (32 females, 31 males, aged 18–84 years). Of the patients 19 received dopamine treatment (3–13 µg/kg/min i.v.); 21 of the patients died in the further course of their disease. Plasma renin activity was increased in 66.7% of the patients and aldosterone levels were elevated in 90.5% of the patients. There were correlations (P<0.05) of lethality with plasma renin activity and cortisol levels and correlations (P<0.01) of aldosterone concentrations with plasma renin activity and cortisol levels. Whereas dopamine treatment had no inhibitory effect on aldosterone levels before and after stimulation, prolactin stimulation was decreased in dopamine-treated patients.Thus, dopamine does not generally lose its potency of hormone inhibition in critically ill patients, but has no influence on the secondary aldosteronism developing regularly in the early phase of critical illness, which is apparently mainly due to the stimulatory effect of ACTH (or ACTH-related pituitary peptides) and is considered an epiphenomen of the stress mechanisms acting upon the patients in this condition.

Bromocriptine treatment over 12 years in acromegaly: effect on glucose tolerance and insulin secretion

SummaryIt is not known whether the beneficial effect of bromocriptine on glucose homeostasis in acromegaly is limited by a certain duration of therapy. To elucidate this problem, oral glucose tolerance tests were performed in 12 acromegaly patients before bromocriptine medication, under therapy (15.0 ± 6.8 mg/day for 12 ± 3 years), and during a 2-week drug withdrawal after long-term treatment. Initially altered glucose tolerance was normalized in 4 of 5 patients under bromocriptine therapy. During drug withdrawal the mean fasting glucose level and the mean glucose concentration at 120 min after oral glucose load increased from 5.05 ± 0.61 to 5.77 ± 0.78 mmol/1 and from 5.61 ±2.05 to 7.55 ± 3.05 mmol/1, respectively. A deterioration in glucose homeostasis was observed in 9 patients, and impaired glucose tolerance was ameliorated (but not to normal range) in 2 when bromocriptine was withdrawn. The proportion of alterations in glucose tolerance during drug withdrawal corresponded to that before the beginning of long-term bromocriptine treatment. Impaired glucose tolerance, observed in 2 patients under bromocriptine treatment, seemed to be compensated because a distinct elevation of glycosylated hemoglobin A1c was not observed. Bromocriptine led to a significant decrease in basal as well as glucose-stimulated insulin levels, and growth hormone secretion during oral glucose load was reduced in all 12 patients. Similarly to the increased growth hormone secretion after drug withdrawal in 11 patients, a rise in glucose-stimulated insulin secretion was found in all patients; hereby, the mean insulin levels at 0 and 120 min during oral glucose load rose significantly from 7.5 ± 2.6 to 12.1 ± 5.1 mU/1 (P<0.01) and from 71.3±52.1 to 101.4±50.7 mU/1 (P<0.02), respectively. A direct relationship between disturbance in glucose homeostasis and degree of hypersomatotropism was not observed. Our data confirm that the beneficial effect of bromocriptine therapy on glucose homeostasis in selected patients with acromegaly is still present after dopaminergic treatment over a mean period of 12 years. Compared with the published rates on improved glucose homeostasis under octreotide, the effect of bromocriptine seems to be more favorable.

Impaired renal responsiveness to human atrial natriuretic peptide (hANP) in normotensive patients with type 1 diabetes mellitus.

SummaryPotential impairment of the efficacy of human atrial natiuretic peptide (human ANF-(99-126), hANP), the most potent endogenous natriuretic agent in healthy subjects, was examined in eight male normotensive patients with uncomplicated type 1 diabetes mellitus (aged 22–37 years). After giving informed consent, patients and eight male control subjects (aged 22–28 years) received in a random double-blind study design i.v. bolus injections of 100 µg hANP (Bissendorf peptide) or placebo. At base-line, patients differed from controls in elevated creatinine clearance (P<0.05) and in mild postprandial hyperglycemia. Whereas the responses of urinary cyclic guanosine monophosphate, the second messenger of hANP, were found to be normal in patients, the diuretic and natriuretic effects of hANP were grossly impaired when compared to controls (P<0.01); hANP resulted in increased plasma protein concentrations only in controls (P<0.05 vs patients). In both groups, creatinine clearance remained uninfluenced by hANP. There were similar decreases in plasma renin activity, aldosterone, levels, and blood pressure (systolic more than diastolic) in both groups (P<0.05 vs placebo). Heart rate and blood glucose remained unchanged. Thus, there is evidence for a decreased responsiveness to hANP exclusively of renal fluid, sodium, and chloride excretion in uncomplicated type 1 diabetes mellitus. The mechanisms responsible for this phenomenon remain obscure, neither a down regulation at the hANP receptor sites nor an hANP-induced shift from intra- to extravascular fluid volume are likely to be involved in its probably diabetes-specific pathogenesis.

Gallstones in acromegalic patients undergoing different treatment regimens.

SummaryThe frequency of gallstones during longterm treatment with the somatostatin analogue octreotide reported in different studies varies from 0% to 50%, the reason for this variation being unknown. Therefore, we examined 58 acromegalic patients undergoing different treatment regimens for the frequency of gallstones. Thirteen were treated with octreotide, 20 with bromocriptine, and 25 had no medical treatment after successful neurosurgery. Also, 58 patients without known gallbladder disease served as controls. The postprandial gallbladder contraction was also investigated in 27 acromegalic patients (10 with octreotide, 10 with bromocriptine, and 7 with no medical therapy). Ten of the 58 acromegalic patients were found to have gallstones, 4 of 25 receiving no medical treatment, 4 of 20 treated with dopamine agonists, and 2 of 13 treated with octreotide. In 9 of the 58 control patients, gallstones were detected. Although in the octreotide group the gallstones were newly formed under therapy, there was no difference in gallstone prevalence between the different treatment regimens and the control group. However, the postprandial gallbladder contraction was significantly more often inhibited during octreotide therapy, and this effect was most pronounced during the first hours following injection. Differences in the timing of injections therefore may be an explanation of the variable incidence of cholelithiasis in the different studies.

PREVALENCE OF HLA-DQ BETA CHAIN NON-ASP ALLELES IN TYPE I (INSULIN-DEPENDENT) DIABETICS WITH YOUNG AND OLDER AGES OF ONSET

SummaryParticular HLA-DQβ chain alleles were reported as immunogenetic markers of type I diabetes mellitus with young onset of the disease. In a homogenous German population, we studied HLA-DR specificities and HLA-DQβ chain alleles in young-onset (<21 years of age;n=185) and adult-onset (>40 years of age;n=48) insulin-dependent diabetics. In both cohorts of type I diabetics, the HLA-DR3 and -DR4 specificities were significantly increased. The presence of an HLA haplotype with an amino acid other than aspartic acid at position 57 of the DQβ chain was significantly associated with type I diabetes in both cohorts (etiologic fraction:93% and 73%). We conclude that the presence of DNA sequences coding for an amino acid other than aspartic acid at the 57th position of the DQβ chain provides a molecular risk marker for type I diabetes of both and adult onset.

Technical mishaps as easily avoidable causes of treatment failure when using pumps for pulsatile administration of gonadotropin-releasing hormone

SummaryA patient (19 years old) with Kallmanns syndrome was treated with gonadotropin-releasing hormone (2.5–16 µg) administered subcutaneously every 2 h using a portable infusion pump. During 42 weeks of treatment testosterone levels and testicular size did not increase sufficiently although no reasons for this insufficient response were detectable. Therefore the regime of controlling and changing the catheter system was intensified. By this means partial occlusions of the catheter were detected and could be corrected. Afterwards testosterone levels increased immediately and persistently to normal values.

Heart Size Reduction in Acromegalic Patientes Treated with the Long-Acting Somatostatin-Analogue SMS 201–995 (Somatostatin®)

Cardiomegaly by hypertrophy of the heart in acromegalic patients — prevalence 85% in our patients with acromegaly [1] — is often complicated by complex arrhythmias and gradual cardiac-insufficiency [1, 3, 8]. The aim of the study was to evaluate the extend of heart size reduction in acromegalic patients under longterm-treatment with the long-acting somatostatin-analgoue SMS 201–995 (Sandostatin®, Sandoz) [2, 5, 7]. All patients had been treated before SMS 201–995 therapy by neurosurgery and/or radiation and medical treatment with bromocriptine (Pravidel®), so that hypersomatotropism before SMS 201–995 therapy was only moderate (s. Table la).

[Bromocriptine in patients with idiopathic edema (author's transl)].

SummaryThe diuretic therapy of patients with idiopathic edema is known to induce a secondary aldosteronism, which perpetuates edema formation and exacerbates the clinical symptoms. The observation of a decreased excretion of dopamine in these patients suggests that a treatment with the orally active dopamine agonist bromocriptine might be beneficial.Nine patients with typical symptoms of idiopathic edema, which had been present for several years, were treated with bromocriptine (Pravidel®) 2 × 2.5 mg/die. The response to therapy was assessed clinically by the normalization of diurnal weight gain and general well-being. Seven patients showed a good response to bromocriptine, in one patient the response was only modest, and in one patient the medication had to be stopped because of nausea. Bromocriptine normalized diurnal weight gain without inducing weight loss.Both without therapy and during bromocriptine treatment electrolytes in serum, blood pressure, plasmareninactivity and aldosterone are within the normal range.From the present pilot study it can be concluded that bromocriptine is an effective alternative to the traditional diuretic therapy in some patients with idiopathic edema. It remains unclear, whether the beneficial effect of bromocriptine reveals a dopamine deficiency, or whether bromocriptine is only a symptomatic treatment.ZusammenfassungDie Therapie idiopathischer Ödeme mit Diuretica ist problematisch, da sie die Symptome nicht beseitigt, sondern einen sekundären Hyperaldosteronismus induziert, der die Ödembildung unterhält. Die Beobachtung einer verminderten Dopaminausscheidung bei Patientinnen mit idiopathischen Ödemen läßt einen Behandlungsversuch mit dem oral wirksamen Dopaminagonisten Bromocriptin als sinnvoll erscheinen.Wir behandelten daher neun Patientinnen mit idiopathischen Ödemen mit typischer Symptomatik und mehrjähriger Anamnese mit 2 × 2,5 mg/die Bromocriptin (Pravidel®). Der Therapieerfolg wurde nach der Normalisierung der circadianen Gewichtsschwankungen und dem subjektiven Befinden beurteilt. Sieben Patientinnen zeigten einen guten, eine nur einen unsicheren Therapieerfolg, und eine Patientin brach die Therapie wegen Nausea ab.Vor und während Bromocriptinbehandlung sind Serumelektrolyte, Blutdruck, Plasmareninaktivität und Aldosteron normal. Bromocriptin normalisiert die circadianen Gewichtsschwankungen, ohne das morgendliche Körpergewicht zu senken. Die Ergebnisse der vorliegenden Pilotstudie legen nahe, daß Bromocriptin bei einigen Patientinnen mit idiopathischen Ödemen eine wirksame Alternative zur herkömmlichen diuretischen Therapie sein kann. Es bleibt offen, ob die Bromocriptinwirkung durch einen Dopaminmangel zu erklären ist, oder ob Bromocriptin eine rein symptomatische Behandlung darstellt.