Free Carnitine Concentrations Research Articles

Effect of Short-Term Treatment with Pivalic Acid Containing Antibiotics on Serum Carnitine Concentration - A Risk Irrespective of Age

Treatment with pivalic acid containing prodrugs has been shown to cause carnitine depletion by loss of pivaloyl carnitine in urine. A 7-day standard pivmecillinam treatment of adults lead to a marked decrease of the free serum carnitine concentration (44.6 to 12.9 μmol/liter), whereas no change was seen in those given norfloxacine (40.0 to 40.5 μmol/liter). In some patients irrespective of age the free serum carnitine concentration was decreased to levels (around 10 μmol/liter) at which an impaired ketone-body production may occur. Therefore, there is reason for cautious use of this type of drug irrespective of the age of the patients.

Relationships between muscle carnitine, age and oxidative status.

Muscle carnitine levels were examined in 31 younger [mean (SD), 27 (5) years] and 27 older [49 (8) years] men. Needle biopsies were obtained from the lateral gastrocnemius or vastus lateralis muscles and assayed for free and total carnitine concentrations via a 5,5'-Dithiobis-(2-nitrobenzoic acid) DTNB-linked spectrophotometric procedure. A subgroup of subjects (n = 28) were assessed for citrate synthase (CS) and succinate dehydrogenase (SDH) activity, and type I muscle fiber composition (% type I fibers). An additional sub-group of nine subjects was assessed for free and total serum carnitine levels. No mean (SEM) differences in free [21.6 (0.7) vs 20.3 (0.9) mumol.g dry weight-1] and total [26.4 (0.6) vs 26.1 (0.9) mumol.g dry weight-1) muscle carnitine levels were found between the younger and older subjects, respectively. Correlational data revealed no significant relationships between total muscle carnitine and CS (r = -0.36), SDH (r = -0.26), or % type I fibers (r = -0.16). In addition, there was a low non-significant relationship between serum and muscle total carnitine concentrations (r = -0.44). These findings suggest that muscle carnitine levels are similar between younger and older males, and there does not appear to be any relationship between muscle carnitine and markers of muscle oxidative potential (i.e., oxidative enzymes, % type I fiber). Since serum carnitine is often used as an indicator of body carnitine status, it is noteworthy that we found a low negative relationship between blood and muscle carnitine concentrations.

Plasma Carnitine Levels in Cystic Fibrosis

SummaryPlasma carnitine concentrations were measured in 43 children and adults with cystic fibrosis (CF), and values were compared with those from normal controls. Clinically significant abnormalities of plasma carnitine concentration were not found in CF patients. The concentration of free carnitine was slightly but significantly elevated in CF patients, and the acylcarnitine concentration and acylcarnitine/free‐carnitine ratio were slightly but significantly lower. Total carnitine concentrations were similar to those of controls. The CF patients did not have abnormal urinary acylcarnitines. Altered concentrations of free and esterified carnitine were not associated with nutritional status or with liver or pulmonary function.

Plasma carnitine levels in cystic fibrosis.

Plasma carnitine concentrations were measured in 43 children and adults with cystic fibrosis (CF), and values were compared with those from normal controls. Clinically significant abnormalities of plasma carnitine concentration were not found in CF patients. The concentration of free carnitine was slightly but significantly elevated in CF patients, and the acylcarnitine concentration and acylcarnitine/free-carnitine ratio were slightly but significantly lower. Total carnitine concentrations were similar to those of controls. The CF patients did not have abnormal urinary acylcarnitines. Altered concentrations of free and esterified carnitine were not associated with nutritional status or with liver or pulmonary function.

Urinary carnitine excretion in patients with heart failure.

To evaluate the fatty acid metabolism in heart failure, the semiquantitative analysis of urinary free carnitine and acylcarnitine was made by fast atom bombardment mass spectrometry (FABMS) in 22 patients (mean age 67.3 years) with heart failure and 19 age-matched healthy controls (average age 60.4 years). Urinary excretion of free carnitine was 0.20 +/- 0.118 ratio/mg creatinine in the healthy controls and 1.32 +/- 1.170 ratio/mg creatinine in the patients with heart failure. The latter value was significantly higher (p < 0.01). Patients with heart failure were classified into two groups according to the urinary free carnitine concentration. One was the high excretion group (2.19 +/- 0.102 ratio/mg creatinine, 12 cases) and the other was the low excretion group (0.37 +/- 0.212 ratio/mg creatinine, 10 cases). In the high excretion group, urinary acetylcarnitine was also increased, but no significant abnormalities were observed in the urinary organic acid profile. In the high group, 1 patient was classified as NYHA class III and 11 as NYHA class IV. Four patients died in the hospital. In the low excretion group, five patients were classified as NYHA class III and five as NYHA class IV. Only one patient died in the hospital. In the high group, patients with severe and prolonged heart failure tended to maintain higher values of urinary free carnitine. We could not find any abnormalities in fatty acid metabolism in patients with heart failure, but it is suspected that the patients who excrete large amounts of free carnitine into the urine, namely the patients with severe heart failure, have some possibility of carnitine deficiency.

The myocardial distribution and plasma concentration of carnitine in patients with mitral valve disease.

The myocardial distribution and concentration of carnitine and its fractions was studied in 11 patients with mitral valve disease not associated with congestive heart failure (CHF). The plasma concentration of carnitine was found to be identical to the normal values documented in the literature. The left ventricular papillary muscle had the highest concentrations of total, short-acyl, long-acyl, and free carnitine, being significantly higher than those of the right ventricle, while the right atrial appendage had the lowest values of all fractions of carnitine. The proportion of long-acyl carnitine to total carnitine was significantly greater in the left ventricle than in either the right atrium or the atrial septum, and other carnitine fractions were identical in all cardiac chambers. Our results suggest that in the compensated heart with mitral valve disease, carnitine and its fractions are greatest in the left ventricle in the muscles of all cardiac chambers, and that long-acyl carnitine is most likely to be linked to the cardiac muscle demanding a higher cardiac performance.

The effect of L-carnitine on myocardial protection in cold cardioplegia followed by reperfusion.

We studied the effect of exogenous L-carnitine on myocardial viability and carnitine uptake following ischemia-reperfusion in isolated rat hearts. Hearts were subjected to hypothermic cardioplegia at 26 degrees C for 80 minutes with and without carnitine 10 mmol/L added to the perfusate and cardioplegic solution [Groups I (n = 9) and II (n = 14), respectively]. Additionally, to study myocardial carnitine uptake, hearts were subjected to global ischemia at 20 degrees C [Group III (n = 6) and IV (n = 6)] and at 37 degrees C [Group V (n = 6) and VI (n = 6)] with and without carnitine 10 mmol/L added to the perfusate. All hearts received normothermic reperfusion, and Krebs-Henseleit solution was used as the perfusate in all groups. Postischemic aortic flow, expressed as the percentage of pre-ischemic flow, morphometric scores of myocardial mitochondria, and the myocardial concentration of adenosine triphosphate at the end of reperfusion were significantly higher in Group I than in Group II. In hearts treated with L-carnitine both at 20 degrees C and 37 degrees C the myocardial concentrations of carnitine fractions (free, short-acyl, and long-acyl) increased significantly compared to those in hearts without L-carnitine treatment. The myocardial concentration of free carnitine at the end of reperfusion was significantly higher in Group III than at pre-ischemia. These results suggest that exogenous L-carnitine is incorporated into cellular metabolism, even in hypothermic cardioplegia, improving cardiac function and preserving the myocardial adenosine triphosphate concentration.

Evaluation of post-ischemic myocardial metabolism by 1H-magnetic resonance spectroscopy in the rabbit heart.

To assess myocardial metabolism during ischemia and reperfusion, 36 rabbits were divided into 4 groups; a control group (Control), an ischemia group in which the circumflex branch was ligated for 30 min (Ischemia), a 5 min reperfusion group (5-RP) and a 30 min reperfusion group (30-RP). The concentrations of metabolites (lactate, alanine and free-carnitine) in the myocardium determined by 1H-magnetic resonance spectroscopy (MRS). The concentration of free carnitine was lower in Ischemia than in Control (2.0 +/- 0.4 vs 5.2 +/- 1.4 mumol/wet.g, p < 0.01), and remained reduced in 30-RP (3.0 +/- 0.6 mumol/wet.g, p < 0.01). On the other hand, the concentration of lactate and alanine were higher in Ischemia than in those of Control (54.9 +/- 8.5 vs 8.8 +/- 0.8, 6.5 +/- 1.0 vs 2.5 +/- 0.5 mumol/wet.g, respectively; p < 0.01), and remained elevated in 30-RP. These findings indicate that recovery from an ischemia-induced disturbance in myocardial metabolism to the pre-ischemic level apparently requires a prolonged period after reperfusion, and that 1H-MRS is a useful new method for evaluating myocardial ischemia.

Renal adaptation to dietary carnitine in humans

Carnitine homeostasis in humans is maintained by dietary carnitine intake, a modest rate of endogenous carnitine synthesis, and efficient conservation of carnitine by the kidney. To assess the effect of dietary carnitine on the efficiency of carnitine reabsorption in humans, rates of carnitine excretion and reabsorption, indexed to the glomerular filtration rate, were determined over a range of plasma free and total carnitine concentrations in 12 strict vegetarians before and after dietary carnitine supplementation (0.248 mmol/d). This amount of dietary carnitine supplementation did not significantly increase plasma carnitine concentration and did not alter the glomerular filtration rate. At normal physiological plasma carnitine concentrations, the rate of carnitine excretion was increased and the rate of carnitine reabsorption was decreased by carnitine supplementation. We conclude that the kidney adapts to carnitine intake by reducing the efficiency of carnitine reabsorption.

Relationship of Carnitine and Carnitine Precursors Lysine, ɛ-N-Trimethyllysine, and γ-Butyrobetaine in Drug-Induced Carnitine Depletion

Plasma concentrations and rates of urinary excretion of carnitine and some of its precursors were studied in three groups of children receiving drugs known to cause carnitine depletion. Patients in group A received pivampicillin and a molar equivalent of carnitine for 7 d. Patients in group B received pivampicillin with a 5.8-fold molar excess of carnitine for 1 wk. Patients in group C were treated chronically with valproic acid and received a molar equivalent (to valproic acid) of carnitine for 14 d. Patients in group A had markedly increased (16-fold) urinary carnitine ester excretion concomitant with diminished urinary free carnitine and gamma-butyrobetaine output and lower plasma free carnitine concentration. Supplementation with one molar equivalent of carnitine (to pivampicillin) was ineffective in preventing the reduction of plasma carnitine concentration observed with pivampicillin treatment alone. For group B patients, administration of excess carnitine resulted in a further increase (35-fold) of urinary carnitine ester output with no decrease of plasma carnitine concentration, urinary gamma-butyrobetaine, or free carnitine excretion. For patients in group C, the initially low plasma free and total carnitine concentrations and urinary output of carnitine and carnitine esters markedly increased with carnitine supplementation, but urinary excretion of gamma-butyrobetaine remained unchanged. The plasma concentrations and urinary output of L-lysine and epsilon-N-trimethyllysine remained unchanged within each group before and after treatment. A positive linear correlation was found between urinary epsilon-N-trimethyllysine and 3-methylhistidine output, indicating that the rate of epsilon-N-trimethyllysine excretion correlates with the amount of 3-methylhistidine liberated by protein turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Branched chain amino acids chronic treatment and muscular exercise performance in athletes: a study through plasma acetyl-carnitine levels

In relation to energy request during physical exercise, muscular tissue Branched Chain Amino Acids (BCAA) are metabolized particularly when the oxidation rises. But in the whole-human body, it is difficult to estimate, in a quantitative sense, the role played by BCAA in sustaining exercise. During a BCAA treatment, made on a group of athletes kept under observation, it was observed, through Conconi's test, that this treatment influenced physical performance. Aim of present work is to investigate if BCAA chronic treatment effect on physiological trial is confirmed on blood circulating biochemical energy parameters and in particular on acetyl-carnitine, since acetyl-linked compounds may be an important biochemical factor.Fourteen athletic well trained male subjects, were randomly divided into two subgroups; a first group was submitted to a chronic treatment (n = 7) of BCAA (oral intake was 0.2 g/Kg die) and a second group, as controls (n = 7), assumed oral placebo. Conconi's test demonstrated a significant difference (p < 0.005) in the exercise performance of the two sub-groups, comparing the measurements of ratios of deflection velocity (V d ), before and after the treatment. Therefore we studied the athletes performing a muscular exercise test (40 Km/h, cycle race, for 90 min) after one month of treatment. During this treatment period the subjects followed a well standardized diet. Samples of blood were drawn before, at the end and during the recovery (60 min) to study if traditional biochemical parameters varied and confirmed the observed differences in Conconi's test. The measurements of concentrations of FFA, KB, free carnitine, acetyl-carnitine and BCAA were performed. Plasma BCAA levels did not demonstrate variations either before or after the exercise performance, or between the two groups. The biochemical factors, substrates and hormones, KB, FFA, lactate, insulin and growth hormone plasma levels did not demonstrate significant differences from the patterns present in literature. Plasma free and acetyl-carnitine followed the well known variations, but only acetyl-carnitine levels demonstrated, at the end increase in acetyl-carnitine levels could be related to a minor fatigue situation and to a larger energy supply availability perhaps present in BCAA treated athletes (Sahlin et al., 1990; May et al., 1989). Both mentioned hypothesis seem in concordance with a smaller acetyl-CoA substrate accumulation, or better for present study, is even more successful with athletes who give a better physical performance. In fact Conconi's test in the two sub-groups of athletes seems to suggest that BCAA treated athletes were able to give a better performance, furthermore out of curiosity we point out that the athletes treated with BCAA won more races than the untreated.We would also like to add in conclusion that although confirming the difficulties of studies in the whole-body, our work gives an interesting clue about the possibility to use acetyl-carnitine plasma levels to understand the biochemical importance of the BCAA as substrate able to influence physical performance, but further research is needed.The phenomenon presence might be showed better perhaps by studying untrained groups during prolonged exercise and with physical performance at exhaustion. If treatment were able to help the physical performance and to shift the fatigue, then confirmation might be a less raised plasma acetyl-carnitine level. In effect blood ammonium levels in present study did not demonstrate any variation in and between sub-groups; this latter observation could be caused by the quantity of work load, and training state of the athletes (Ji et al., 1987; Kirkendall, 1990). Moreover, as observed by Hageloch et al. (1990), the ammonia increases less during prolonged endurance exercise, and in fact the athletes of present study were all middle distance racing cyclists, and the physical performance was a prolonged endurance exercise.

Carnitine in adolescents

Carnitine, abundant in muscle and other tissues, is normally synthesized from lysine. Its major metabolic role is transport of long-chain fatty acids into muscle where β oxidation takes place. Normative data are available for carnitine levels, but few studies define carnitine of specific age groups. This report provides data on normal male and female adolescents in relationship to age and pubertal status. The population consisted of adolescents between 10 and 18 years, seen either for routine health maintenance or minor illnesses. Concentrations of carnitine in plasma were determined by radioisotype enzyme assay. The overall mean was 45.3 ± 8.9 μmol/L for free carnitine. There was a trend of decreasing free carnitine with increasing Tanner stage. Among the females, there was a statistically significant correlation with both age and Tanner stage. In contrast, the data for males indicated no statistically significant correlation. The data provided standards for the evaluation of carnitine status in normal adolescents. Total carnitine in plasma ranged from 43.2 to 55.9 μmol/L and was virtually all free carnitine. The significant negative correlation of concentration of free carnitine with age and pubertal stage in females was interesting, although not of clinical importance. It suggests the possibility of female hormonal influence associated with puberty.

Muscle carnitine repletion by long-term carnitine supplementation in nephropathic cystinosis.

The renal tubular Fanconi syndrome of children with nephropathic cystinosis causes plasma and muscle carnitine depletion. L-Carnitine replacement therapy for up to 18 mo has previously been shown to normalize plasma but not muscle carnitine levels. We treated six cystinosis patients, aged 1 to 4 y, with a mean dosage of 92 mg L-carnitine/kg/d given every 6 h for an average of 62 mo. Despite fractional excretions of free carnitine ranging from 55 to 108%, plasma-free and total carnitine concentrations were maintained at or above normal levels. At the end of the carnitine replacement period, the six children had muscle-free carnitine values ranging from 16.0 to 28.0 nmol/mg noncollagen protein compared with values of 3.0 to 11.4 for cystinosis children not supplemented with carnitine [normal, 22.7 +/- 5.0 (SD) nmol/mg protein]. Total muscle carnitine values were also normalized by L-carnitine replacement. The monthly increase in total body creatinine production, a measure of muscle mass, was higher (p = 0.036) in children with normal plasma free carnitine concentrations (3.4 +/- 0.9 mg/d) than in children with low plasma free carnitine (2.3 +/- 0.7 mg/d). No serious side effects, such as severe diarrhea, were observed. We conclude that oral L-carnitine replacement can normalize muscle carnitine content in children with cystinosis.

Carnitine status and safety after administration of S-1108, a new oral cephem, to patients.

The metabolism and clinical safety of the pivalic acid-containing antibiotic S-1108, an orally active pro-drug cephalosporin, were investigated to assess the clinical effects, with special emphasis on the influence of carnitine consumption in 15 patients with various infectious diseases receiving S-1108 three times a day at a 300- or 600-mg total daily dose for 3 to 7 days. The free carnitine concentrations in plasma were greatly reduced to approximately 65% of pretreatment levels, and the plasma pivaloylcarnitine (the main metabolite of pivaloyloxymethyl ester) concentrations were increased during the 200-mg (three times a day) regimens but returned to the pretreatment levels within 3 to 5 days after the cessation of treatment. In three elderly patients with declining renal function (creatinine clearance rate, 31 to 50 ml/min), the acylcarnitine/free carnitine ratio increased from 0.1 to 0.4 up to 0.7 to 1.5 at day 5 during the 7-day treatment, showed a tendency to decrease, and then returned to the pretreatment ratio 4 days after discontinuation of the drug. The degree of free carnitine reduction and increase of the acylcarnitine/free carnitine ratio depended mostly on the dose and the duration of S-1108 treatment. The increased acylcarnitine/free carnitine ratio in elderly patients was due to reduction of the free carnitine concentration in plasma and mainly to the retardation of nontoxic pivaloylcarnitine excretion. This study indicated that there was a decrease in free carnitine levels in plasma, but there were no clinical symptoms or adverse effects associated with carnitine reduction in patients during the 7-day multiple administration of S-1108.

Plasma carnitines: reference values in an ambulatory population.

Carnitine was determined radioenzymatically in the plasma of 415 hospital employees involved in a screening programme for prevention of major cardiovascular risks. A reference population (N = 340) was extracted after excluding subjects with hypertension, diabetes mellitus or treatment for hypercholesterolaemia. This population showed a Gaussian distribution for total and free carnitine concentrations both in females and males but not for acyl carnitine or the acyl/free ratio. Females had lower total and free carnitine concentrations but a higher ratio of acyl/free carnitine than males. These differences were not detectable in older subjects (35 years for the acyl/free ratio, 45 years for total and free carnitine concentrations). Females with a body mass index > 28 had a lower acyl/free ratio than their respective controls. The differences in carnitine concentrations indicate that sex and age should be matched in patients or experimental groups and controls in studies involving carnitine plasma concentrations.

Preferential elimination of pivalate with supplemental carnitine via formation of pivaloylcarnitine in man.

1. To evaluate the effectiveness of carnitine administration in aiding the elimination of pivalate liberated from pivampicillin, studies were undertaken on seven paediatric patients treated for 7 days with combined pivampicillin and molar excess of carnitine. 2. A 22-fold increase occurred in urinary carnitine ester excretion on the last day of treatment (2967 +/- 604 versus 134 +/- 50 mumol/day, p < 0.05); the pivaloylcarnitine was identified with 13C-n.m.r. Only pivalate was detected in the urinary carnitine ester g.l.c. profile, the amount of this ester was equal to 92% of the daily pivalate intake. 3. The renal clearance rate of carnitine esters significantly exceeded that of creatinine indicating that the carnitine ester was eliminated by active transport. 4. The plasma concentration and urinary output of free carnitine were not changed significantly by the treatment, and the free and esterified carnitine concentrations in red cells remained unchanged indicating that carnitine deficiency was prevented.

THE EFFECT OF VALPROIC ACID ON FATTY ACID OXIDATION BEFORE AND AFTER L-CARNITINE SUPPLEMENTATION

Urinary metabolites and 13CO2-production from 13C-octanoic acid were studied in 12 patients (3-19 y.o.) with seizure disorders before and during valproic acid (VPA) therapy without and with L-carnitine supplementation. Only one patient had a decreased plasma level of free carnitine (FC) during VPA. Urinary FC concentrations were positively correlated with serum VPA levels (p<0.01) indicating a dose-related effect of VPA on the tubular reabsorption of FC. Urinary dicarboxylic acid concentrations relative to plasma β-OH-butyrate and urinary hexanoyl- and butyrylglycine concentrations (stable isotope dilution method) increased during VPA. Changes in cumulative excretion of 13CO2 in breath were inconsistent. L-carnitine administration had no significant effect. 11/12 patients excreted octanoylearnitine (OC) in excess of octenoylearnitine during VPA. Quantitation of OC by radioisotopic exchange/HPLC showed urinary concentrations of OC comparable to those found in asymptomatic patients with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (x 0.71; R 0.09-14.6 vs. × 0.38; R 0.10-4.21 mmoles/mole creatinine). Gas chromatographic/mass spectrometric analysis revealed that the predominant saturated 8-carbon acylcarnitine in urine was OC with valproylcarnitine being only a minor metabolite. Conclusion: VPA therapy results in an inhibition of β-oxidation partly at the level of MCAD. L-carnitine has no consistent effect.

A Child With Valproic Acid-Associated Carnitine Deficiency and Carnitine-Responsive Cardiac Dysfunction

Valproic acid enhances renal losses of carnitine esters and leads to decreased plasma free carnitine concentrations in many patients receiving valproic acid therapy. However, decreased serum carnitine levels are of unclear pathologic significance, and most children manifest no symptoms of carnitine deficiency. We report a child with valproic acid-associated carnitine deficiency who had severe cardiac dysfunction develop that resolved with carnitine replacement therapy.

The measurement of carnitine and acyl-carnitines: Application to the investigation of patients with suspected inherited disorders of mitochondrial fatty acid oxidation

We describe an improved radio-enzymatic method for the measurement of carnitine, short-chain acyl-carnitine and long-chain acyl-carnitine in plasma and tissue. An internal standard, hexadecanoyl-[CH 3- 3H]-carnitine was synthesised and used to improve the determination of long-chain acyl-carnitine. The between and within batch precisions were 10.4 and 7%, respectively. Control data for neonates, infants, children and adults in the fed and fasted state are documented. In addition we confirm the hypocarnitinaemia associated with pregnancy. Patients with medium-chain acyl-CoA dehydrogenase deficiency were studied during episodes of hypoglycaemia. In both fasted controls and patients there were high concentrations of short-chain acyl-carnitine, however in the latter group there were also low concentrations of free carnitine. We suggest that the monitoring of plasma carnitine and its derivatives is a useful adjunct to the investigation of children suspected to suffer from inherited disorders of mitochondrial β-oxidation. We also describe a sample preparation procedure suitable for high performance liquid chromatographic analysis of specific acyl-carnitines from urine, plasma and tissue homogenates. The recoveries of acetylcarnitine, octanoyl-carnitine and hexadecanoyl carnitine from urine were 101.5, 95 and 91% and from plasma 99.5, 91.5 and 85.5%, respectively. Acyl-carnitines (C2-C16) were analysed as their p-bromophenacyl derivatives by reverse-phase high performance liquid chromatography using a ternary gradient of acetonitrile/water/ triethylamine phosphate. We report ten patients who excreted octanoyl-carnitine, hexanoyl-carnitine and in some cases a small amount of decanoyl-carnitine. In most of these cases suberylglycine and dicarboxylic acids were also detected by GC/MS. We had access to cultured fibroblasts from five of these patients and were able to demonstrate medium-chain acyl-CoA dehydrogenase deficiency by direct enzyme assay.

Prevalence of carnitine depletion in critically ill patients with undernutrition

The aim of this study was to evaluate to what extent secondary carnitine deficiency may exist based on the prevalence of subnormal carnitine status in patients with critical illness and abnormal nutritional state. Healthy control patients (n = 12) were investigated and compared with patients with possible secondary carnitine deficiency, ie, patients with overt severe protein-energy malnutrition (PEM, n = 28), postoperative long-term (> 14 days) parenteral glucose feeding (250 g glucose/d, n = 7), severe liver disease (n = 10), renal insufficiency (n = 7), and sustained septicemia with increased metabolic rate (n = 8). Nutritional status, energy expenditure, creatinine excretion, and blood biochemical tests were measured in relationship to free and total carnitine concentrations in plasma and skeletal muscle tissue, as well as urinary excretion of free and total carnitine. The overall mortality rate was 48% within 30 days of the investigation in study patients with the highest mortality in liver disease (90%). The hospitalization range was 14 to 129 days in study patients. Most study patients had lost weight (4% to 19%) and had abnormal body composition. Patients with liver disease, septicemia, renal insufficiency, and those on long-term glucose feeding had significantly higher than predicted metabolic rate (+25% ± 3%), while patients with severe malnutrition had decreased metabolic rate compared with controls. Patients with liver disease had increased plasma concentrations of free (96 ± 16 μmol/L) and total (144 ± 27 μmol/L) carnitine compared with controls (45 ± 3,58 ± 7 μmol/L, respectively). No other differences among the groups were seen in plasma or muscle carnitine concentrations as compared with control patients, although some patient groups (liver disease, sever PEM, long-term glucose feeding) showed indices of increased free and total carnitine excretion. There was no correlation between muscle and plasma carnitine concentrations. The present study demonstrates that the overall prevalence of statistically significant carnitine depletion was less than 5% in a large heterogeneous group of patients suffering from critical illness and abnormal nutritional state.