Francesco Caviezel

Effects of Long‐Term Antiepileptic Therapy on the Hypothalamic‐Pituitary Axis in Man

Summary: Effects of long‐term antiepileptic therapy on the hypothalamic ‐pituitary axis were evaluated from the basal and stimulated plasma levels of growth hormone (GH) and prolactin (PRL) and from circadian adrenocorticotropic hormone (ACTH)/cortisol rhythms. Data for patients with well‐controlled epilepsy of mild‐to‐moderate severity were compared with those for normal healthy volunteers. Analysis of the effects of each antiepileptic drug (AED) and of combined AEDs revealed minor abnormalities of stimulated GH secretion in all treated patients. In epileptic men, all individual AEDs (except valproate) and AED polytherapy increased both basal and stimulated plasma levels of PRL. In epileptic women, this effect was more variable and less marked, probably because of early depletion of PRL reserves. Each AED and combined AEDs did not significantly change circadian ACTH/cortisol rhythms in epileptic patients. The effects observed seem not to be related to epilepsy per se. Clinical implications, pathways, and neurotransmitters involved and possible mechanisms of the neuroendocrine effects of long‐term AED therapy are discussed.

Diabetes and complications after cardiac surgery: comparison with a non-diabetic population

Abstract Diabetes is a well-recognized independent risk factor for mortality due to coronary artery disease. When diabetic patients need cardiac surgery, either coronary-aortic by-pass (CABP) or valve operations (VO), the presence of diabetes represents an additional risk factor for these major surgical procedures. Because of controversial data on mortality rates and post-operative complications in diabetic patients, probably due to not exactly comparable groups of patients, this retrospective study aimed to compare two homogeneous populations, which were different only for the presence or absence of diabetes. We studied 700 patients undergoing cardiac surgery: 350 with and 350 without diabetes, mean age 62 ± 9 years (67% males); 441 underwent CABP and 259 VO. Apart from the diabetes, the two groups were strictly matched for age, body mass index, concomitant pathologies and smoking habits, except for previous neurological injuries (more frequent in diabetic patients), and for a slightly lower ejection fraction in the diabetic group. Intra- and post-operative complications or events were evaluated carefully: death, number staying in post-operative intensive care unit (ICU), renal, hepatic and respiratory complications, necessity for reoperation and hemotransfusions. Anesthesia and surgical procedures (including extra-coproreal circulation techniques) remained substantially unchanged over the period of recruitment of patients (1996–1998) and applied equally to both groups of patients. All diabetic patients were treated with insulin by using standard procedures in order to optimize metabolic control. Diabetic patients in our study, did not show higher rates of mortality in comparison with non-diabetic patients, but had more total neurological complications, more renal complications, a higher re-opening rate, more prolonged ICU stay, and they needed more blood transfusions. Diabetes remains an independent risk factor for these events even in a multivariate logistic regression model analysis. In the subgroup of diabetic patients who underwent CABP a higher rate of renal dysfunction, re-opening, need for hemotransfusions and prolonged ICU stay were confirmed. In the subgroup of diabetic patients undergoing VO we found a higher rate of renal dysfunction, reopening, prolonged ICU stay and major lung complications. In conclusion, diabetes does not seem to increase the mortality rates of cardiac surgery, but diabetic patients undergoing CABP have, on the basis of the relative risk evaluation, a 5-fold risk for renal complications, a 3.5-fold risk for neurological dysfunction, a double risk of being hemotransfused, reoperated or being kept 3 or more days in the ICU in comparison with non-diabetic patients. Moreover, diabetic patients undergoing VO have a 5-fold risk of being affected by major lung complications.

BONE MINERAL DENSITY IN DIABETES MELLITUS

In the present study bone mineral content (BMC) was measured at 1/3 and 1/10 the length of the radius from the distal end in 100 adult diabetic subjects (55 females, 45 males, 54 insulin-dependent [IDD], 46 non-insulin-dependent [NIDD]), using single photon absorptiometry. Each individual BMC value in the diabetics was first compared to normal BMC values for age obtained in our laboratory from 500 non-diabetic subjects. BMC in the diabetics was within the normal range (M +/- 2 SD) with respect to sex and age. Data from IDD and NIDD males, under and over 50 years of age, and of IDD and NIDD females, pre- and postmenopausal, were compared with the respective control group data after matching each diabetic subject to a non-diabetic one of identical age and menstrual history and of comparable body mass index. In each group BMC in the diabetic subjects was found not to be statistically different from BMC in the control ones. Correlation analysis was carried out between BMC and endocrine or metabolic parameters obtained in 52 of the diabetic patients. BMC in diabetic subjects was not correlated with plasma levels of hormones (thyroid hormones, cortisol, 17-beta-estradiol, testosterone), Ca, P or alkaline phosphatase activity. It was inversely correlated with urinary Ca and P in NIDD women and with urinary Ca in NIDD men. No relationship was found between BMC and the metabolic control of diabetes (evaluated by basal glycemia, 2h-post-prandial glycemia and glycosylated hemoglobin).

Obesity and coronary artery surgery

OBJECTIVE To assess whether obesity is a risk factor for morbidity and mortality in patients undergoing elective coronary artery revascularization. DESIGN Prospective, clinical study. SETTING University hospital. PARTICIPANTS Three hundred forty-five consecutive patients who underwent elective coronary revascularization with cardiopulmonary bypass and without associated procedures. INTERVENTIONS Patients were assigned to the obese group if their body mass index was greater than 30 for men and 28.6 for women, according to the World Health Organization indications. MEASUREMENTS AND MAIN RESULTS Preoperative and intraoperative variables were collected and checked for homogeneity of the groups. Postoperative outcome was assessed on the basis of intubation time, intensive care unit (ICU) and postoperative hospital stay, mortality rate, and incidence of transfusions, reoperations, low-output syndrome, minor and major neurologic dysfunction, minor and major lung dysfunctions, renal dysfunction, and superficial and deep infections. The effect of obesity on postoperative outcome was tested with a multivariate logistic regression analysis. Obese and control patients had the same intubation time and ICU and postoperative hospital stay. Mortality and all major complications occurred with the same incidence in the two groups. Obese patients had a significantly (p < 0.05) greater rate of superficial infections and more (24.1% v 7.4%; p < 0.001) minor lung complications. Conversely, they had a significantly lower transfusion rate (27.5% v42.7%; p < 0.01). CONCLUSION Obese patients had only minor complications after coronary artery surgery. The large body surface area because of obesity protects them against the hemodilution-related transfusion risk.

The regulation of insulin and glucagon secretion by opiates: A study with naloxone in healthy humans

SummaryThe presence of β-endorphin and enkephalin in pancreatic islets suggests that opioid peptides may play a role in the regulation of pancreatic endocrine function. Since data in the literature are rather controversial, we examined the effects of different doses of naloxone on insulin and glucagon secretion in 21 healthy nonobese volunteers (6 women and 15 men) by measuring the variations of insulin and glucagon plasma levels following a 5-g i.v. glucose load before and during a 30-min naloxone infusion. Total amounts of 0.4 and 0.8 mg of naloxone failed to modify serum insulin and plasma glucose responses to glucose challenge. On the contrary, 0.2 mg/kg (i.e. 12–14 mg per subject as total amount) given to 3 women and 6 men led to a glucose-induced insulin release significantly lower than that recorded in basal conditions, with corresponding greater plasma glucose elevation. The suppressive effect of glucose on glucagon concentration was less pronounced during naloxone. Data reported here suggest that inhibition of opiate receptors in human pancreas occurs only with large amounts of naloxone. Moreover, they may indirectly support the stimulatory role of opioid peptides on insulin secretion in man, according to some experimentalin vitro andin vivo studies. In addition, naloxone seems to reduce pancreatic A-cell sensitivity to hyperglycemia.

The compliance of hypocaloric diet in type 2 diabetic obese patients: A brief term study

In studies of the effect of diets in obese type 2 diabetic patients, information about the degree of compliance or non-compliance is generally lacking or incomplete, though their poor long-term success rate is widely recognized. We have quantified the degree of short-term compliance with a personalized hypocaloric diet (800–1500 kcal) in 77 obese type 2 diabetic patients (mean age 60, mean BMI 34.4) three months after explaining their dietary schedule and its expected advantages by means of simple but essential nutritional advice lasting about 20 minutes of the type currently used for such patients attending diabetes care institutions or outpatient departments. Even though a mean 14% reduction in daily food intake was achieved, the mean daily energy intake at the interview (assessed by means of the 3-day recall method) still exceeded the prescribed diet by 40–50%. The worst compliance in terms of total excess energy intake or carbohydrate and fat intake was found in the older patients. The greater the excess of food intake, the poorer the metabolic control, as expected.

Sleep-related growth hormone secretion in human obesity: Effect of dietary treatment

Eight obese patients (4 male, 4 female; mean age = 35.9 years) before [mean body mass index (BMI) = 37.1] and after (mean BMI = 31.4) weight loss by means of a mixed hypocaloric diet were compared with 8 lean subjects (4 male, 4 female; mean age = 37.1 years, mean BMI = 22.3) in a study of their nocturnal sleep patterns and sleep-related growth hormone (GH) secretions. Although no sleep disorders (in particular, sleep apnea and hypersomnia) were observed, GH secretion was markedly altered in obese patients that showed no sleep-related GH peaks. After weight loss, the sleep architecture in obese subjects was unchanged. On the contrary, GH peak appeared to be only partially restored and delayed until after stage III-IV of non-REM sleep. Our study on obese subjects suggests that the altered nocturnal GH secretion, probably related to a hypothalamic dysfunction, may be the result of the obesity per se.

Epidural Spinal Electrostimulatory System (ESES) in the Management of Diabetic Foot and Peripheral Arteriopathies

Epidural spinal electrostimulatory system (ESES) or dorsal column stimulation (DCS) may be used for the treatment of peripheral vascular diseases of the lower extremities. ESES has been used in our metabolic and surgical department as a way to ameliorate inadequate blood supply in patients suffering from diabetic foot (seven patients), painful chronic arterial narrowing, or inoperable occlusions (25 patients). The continuous stimulation by an implantable apparatus (Medtronic model Itrel, Medtronic, Inc., Minneapolis, MN, USA) led to a reduction or disappearance of pain, an improvement in plethysmographic curves, functional performance, and trophic lesions in about 75% of the patients. The system is safe and well‐tolerated by patients.

Ano-rectal manometry as an evaluating test for impaired ano-rectal function in diabetes mellitus

SummaryDiarrhea and/or rectal incontinence may represent a sign of autonomic neuropathy in diabetes. The present investigation was performed to study ano-rectal function and reactivity to appropriate stimuli in 20 diabetic patients with or without autonomic neuropathy (14 insulindependent diabetics; 6 non-insulin-dependent diabetics; mean age 39.2 years; mean duration of diabetes 12.6 years). Twenty-five healthy subjects (mean age 43.5 years) were studied as controls. All subjects underwent ano-rectal manometry by means of special open-ended-tip catheters connected with a 6-channel polygraph. A rectal latex balloon was inflated with 30 or 60 ml air to induce a stimulus which, under normal conditions, is apt to relax the internal sphincter and to contract the external one (ano-rectal inhibitory reflex). Eleven diabetics had symptoms and signs of autonomic neuropathy: 8 of these (73%) showed marked abnormalities of ano-rectal function (i.e. no response even to maximum stimulus or contraction of both sphincters). All non-neuropathic patients showed a normal pattern of ano-rectal manometry. A relationship between abnormal response to rectal stimulation and the presence of autonomic neuropathy involving the pelvic parasympathetic section or regional intramural plexuses may be suspected and demonstrated in diabetic neuropathic patients.

Long-term administration of acetylsalicylic acid in impaired glucose tolerance in addition to the diet: effects and limits.

SummaryThe effect of a controlled long-term oral trial with 2 g/die of acetylsalicylic acid (ASA) in addition to diet in 14 patients suffering from impaired glucose tolerance (according to WHO criteria) was compared to diet alone plus placebo (PL). All patients were randomly assigned to ASA or PL, and then submitted to cross-over scheduling procedure (30 + 30 days). Plasma glucose levels observed after an oral glucose tolerance test (OGTT, 100 g) became normal in patients receiving ASA for 30 days (p<0.01 at χ2 analysis). No change of abnormal OGTT data was observed when patients were treated with PL. Insulin secretion after OGTT and after i.v. glucose tolerance test (IVGTT, 5 g) was unmodified by ASA. Basal glucose levels and plasma glucose disappearance rate after IVGTT also remained unchanged after ASA. Only two subjects had to stop ASA treatment because of gastric discomfort. The oral administration of 2 g of ASA might possibly interfere with intestinal glucose absorption. The well known influence of ASA on prostaglandin synthesis and on insulin secretion could not be relevant in our own pharmacological approach.