Birger Fagher

Carnitine and left ventricular function in haemodialysis patients

Left ventricular function was non-invasively studied in 28 randomly selected haemodialysis patients before and after administration of L-carnitine, 2 g i.v. three times per week or saline in a double blind designed study over a six-week period. Cardiac function variables showed no relationship to muscle (vastus lateralis) and plasma carnitine concentrations. No apparent deficiency in muscle carnitine was found, whereas total plasma carnitine was lower in female patients than in female controls, p less than 0.002. The echocardiographic left ventricular end-diastolic diameter was initially increased in about one third and the ejection fraction was depressed in about one fifth of the patients. An increased A:H ratio was found in 15%. Systolic time intervals were deranged in 30% of the patients. After carnitine administration, marked increases of muscle and plasma carnitine levels were found, p less than 0.01, but no effects were recorded in any of the cardiac tests. Muscle carnitine increased from 14.6 mmol/kg dry weight to a median of 23.7 mmol/kg. We found no support for the hypothesis that carnitine depletion is responsible for cardiac dysfunction in haemodialysis patients.

L-carnitine and haemodialysis: double blind study on muscle function and metabolism and peripheral nerve function

Twenty-eight haemodialysis patients were randomized to L-carnitine, 2 g i.v. three times a week, and saline over a 6-week period. No obvious deficiency of carnitine was found in vastus lateralis with a median value of 12.9 mmol/kg dry weight; range 6.2-21.4. Female patients had lower total plasma carnitine compared to female controls, p less than 0.002, whereas no decrease was found in males. No relationship was found between muscle and total plasma carnitine. After carnitine administration the muscle carnitine level increased about 60%, p less than 0.01, and the total plasma carnitine level more than tenfold, whereas the initially high degree of acylation decreased, p less than 0.02. Maximum dynamic muscular strength was reduced with a mean value of 44% compared with healthy controls. Total metabolic activity of isolated skeletal muscle fibres, measured as heat production with a new technique using a perfusion microcalorimeter, showed a median value of 0.40 mW/g, 25% lower than normal, p less than 0.02. Carnitine administration had no effect on several different tests of muscular function. Neurophysiologically, discrete improvements in the temperature responses were recorded, but no changes in sensory and motor nerve conduction velocities or in vibration thresholds were noted. No symptomatic improvement was observed even in patients with the lowest carnitine levels prior to treatment. Our data do not support the hypothesis that carnitine deficiency contributes to muscle and nerve dysfunction in patients on chronic haemodialysis.

Plasma lipoproteins, liver function and glucose metabolism in haemodialysis patients: lack of effect of L-carnitine supplementation

The effects of L-carnitine administration (2 g i.v. three times weekly for 6 weeks) were studied in a double blind trial comprising 2 X 14 patients on regular haemodialysis treatment. The initial plasma carnitine concentrations were normal in the male, but slightly lowered in the female participants and rose more than ten-fold in the patients receiving active treatment. The majority (15/28) of patients had moderate hypertriglyceridaemia, whereas plasma HDL cholesterol levels were normal. Activities of hepatic and lipoprotein lipase were decreased and fat tolerance impaired. The S-triiodothyronine and/or thyroxine levels were subnormal in 11 patients. Four patients had fasting hyperinsulinemia, and 6 demonstrated abnormal B-glucose patterns after a peroral glucose load. The galactose elimination rate demonstrated moderately impaired hepatocyte function in four patients. No effects of carnitine treatment on any of the variables could be detected.

Effect of erythropoietin on muscle metabolic rate, as measured by direct microcalorimetry, and ATP in hemodialysis patients

Ten anemic hemodialysis patients were treated for 6-14 months with human recombinant erythropoietin (EPO). The mean hemoglobin level significantly increased by 42%. Pretreatment skeletal muscle heat production rate at rest, as determined by direct microcalorimetry, was lower than normal (p < 0.03), indicating decreased metabolic activity. ATP levels in muscle were inversely correlated (rs = -0.66, p < 0.05) with the heat production values. The latter significantly increased by about 40% and were almost normalized by the therapy, whereas a decline in the mean ATP level was seen, from 14.8 to 13.2 mumol g-1 of muscle (p = 0.06). We hypothesize that the lowered ATP concentration in muscle after treatment might have been due to an enhanced ATP consumption in parallel with improved muscle strength. Alternatively, since acidosis prior to treatment might have altered the equilibrium state of the creatine kinase reaction towards ATP production, it is possible that the improved oxygenation after EPO had increased pH in the muscle and catalyzed the transfer of phosphate from ATP to PCr. It is concluded that EPO treatment can almost normalize the decreased muscle metabolic rate in hemodialysis patients, and that the anemia per se seems to be an important cause of the deranged metabolism in striated muscle.

Lack of influence of short-term treatment with propranolol and terbutaline on metabolism and energy expenditure of the Na-K pump in human erythrocytes evaluated by microcalorimetry

SummaryA double blind placebo-controlled study was conducted of the effects of oral propranolol (β1β2-adrenoceptor antagonist) and terbutaline (β2-adrenoceptor agonist) on erythrocyte heat production, measured by direct microcalorimetry under static conditions at 37°C and pH 7.4. Propranolol 80 mg and terbutaline slow-release 7.5 mg were randomly administered twice daily for one week to 15 healthy males, using a cross-over design.No thermogenic difference was detected. Serum potassium was significantly decreased by terbutaline but was only slightly increased by propranolol, but no relationship was found between changes in the extra- and intracellular levels. In the placebo group, 10% of total cell energy was consumed by the Na-K pump, as assessed by ouabain inhibition, and this value was not significantly affected by the treatments. Thus, it seems unlikely that there is a clinically relevant influence on the Na-K pump in erythrocytes during continuous terbutaline or propranolol medication.It is concluded that short term medication with propranolol and terbutaline in therapeutic doses has almost no thermal or metabolic effect on human erythrocytes. The results indirectly imply that no clinically relevant β-adrenoceptor effects are mediated in erythrocytes and this may also be true with regard to the ‘membrane effect’ of propranolol.

Felodipine in Patients with Organic Solvent-Induced Chronic Toxic Encephalopathy

AbstractObjective: The aim of this investigation was to study the effect of felodipine extended release (ER) 5 and 10mg once daily compared with placebo on performance in psychometric testing and Target Complaints in patients with toxic encephalopathy (TE). Design: The study was conducted as a double-blind, crossover study with each treatment given for 6 weeks. The patients were examined on five occasions, using semistructured interviews (Target Complaints), questionnaires [Psychological General Well-Being Index (PGWB)] and psychometric tests of visuo-spatial capacity and memory functioning. Patients: Twelve male patients with organic solvent-induced chronic TE and a median age of 47 years. All were skilled workers who had been exposed to organic solvents for a median of 26 years (range 9 to 39 years). The baseline examinations revealed severe symptoms such as memory impairment, sleep disturbance and personality change. Impaired test performance and reduced cerebral blood flow were also noted. Because of the severity of the symptoms only 3 patients were able to work (part-time). Results: No difference was observed between felodipine treatment and placebo in the psychometric testing and the PGWB index. However, in the Target Complaints a statistically significant (p < 0.05) reduction of the severity of the symptoms was noted when the patients were treated once daily with felodipine ER 5mg compared with placebo. This reduction was especially pronounced in five of the patients, the so-called responders. Conclusion: The findings indicate that felodipine can be used in the treatment of TE patients to reduce their symptoms.

Reduced thermogenesis in muscle and disturbed lipoprotein metabolism in relation to thyroid function in haemodialysis patients

Muscle thermogenesis, measured by direct calorimetry on resting biopsy samples, was studied in 28 haemodialysis patients and related to thyroid function variables, plasma lipoprotein concentrations and post-heparin lipase activities. The heat production was decreased in about 40% of the patients and significantly correlated with total thyroxine and free thyroxine index. In addition to a slight to moderate hypercholesterolaemia comparable to that found in subclinical hypothyroidism, the patients had also hypertriglyceridaemia in combination with low lipoprotein lipase activity and impaired fat tolerance. The latter abnormalities were related to the lowered muscle heat production values. The pattern of changes may represent a biological adaptation to the systemic illness for conservation of energy.