Halothane alters the oxygen consumption-oxygen delivery relationship compared with conscious state

The authors' objectives were as follows: 1) to characterize for the first time the relationship between whole body O2 delivery (DO2) and O2 consumption (VO2) in adult conscious dogs; and 2) to asses the effects of the inhalational anesthetic, halothane, on that relationship. DO2 was varied over a wide range in chronically instrumented dogs by gradual inflation and deflation of a hydraulic occluder implanted around the thoracic inferior vena cava to alter venous return and cardiac output. VO2 was measured at different values of DO2 in dogs in the fully conscious state and again during halothane anesthesia. A "binning" technique indicated that halothane decreased VO2 (P less than 0.01) at any given value of DO2 over a broad range of VO2. A two-line piecewise linear regression analysis technique indicated that halothane decreased (P less than 0.01) the critical O2 delivery (COD) from 20 +/- 3 to 10 +/- 1 ml.kg-1.min-1 and increased (P less than 0.01) O2 extraction at COD from 31 +/- 3 to 40 +/- 2%. However, the DO2-VO2 plots measured in both conscious and halothane-anesthetized dogs did not exhibit a discrete discontinuity but rather were closely fit (correlation coefficient = 0.98) by an exponential equation of the following form: O2 extraction = B1.(1 - exp (-DO2/B2))/DO2, where B1 is the delivery-independent estimate of VO2 and B2 is the "delivery constant," i.e., the DO2 associated with a VO2 equal to 63% of B1. Halothane decreased B1 (P less than 0.01) from 5.3 +/- 0.1 to 3.9 +/- 0.1 ml.kg-1.min-1 and decreased B2 (P less than 0.01) from 5.6 +/- 0.3 to 3.6 +/- 0.3 ml.kg-1.min-1 compared with that measured in conscious dogs. Thus, compared with the conscious state, halothane anesthesia alters the fundamental relationship between DO2 and VO2 and may have a beneficial effect on tissue oxygenation at low values of DO2.     

Physiology and pathophysiology of organic acids in cerebrospinal fluid

Summary Concentrations of organic acids in cerebrospinal fluid (CSF) appear to be directly dependent upon their rate of production in the brain. There is evidence that the net release of short-chain monocarboxylic acids from the brain is a major route for removing these products of cerebral metabolism. Concentrations of organic acids in blood and CSF are largely independent of each other. Quantitative reference values for the concentrations of organic acids in CSF and plasma as well as ratios of individual organic acids between CSF and plasma were determined in 35 pairs of samples from paediatric patients. Over 25 organic acids were quantifiable in all or in the majority of CSF and/or plasma specimens (limit of detection 1 µmol/L). There were substantial differences in the CSF/plasma ratios between subgroups of organic acids. Metabolites related to fatty-acid oxidation were present in CSF in substantially less amounts than in plasma. Organic acids related to carbohydrate and energy metabolism and to amino acid degradation were present in CSF in the same amounts as or slightly smaller amounts than in plasma. Finally, some organic acids were found in substantially higher amounts in CSF than in plasma, e.g. glycolate, glycerate, 2,4-dihydroxybutyrate, citrate and isocitrate.Studies of organic acids in CSF and plasma samples are presented from patients with cerebral lactic acidosis, disorders of propionate and methylmalonate metabolism, glutaryl-CoA dehydrogenase deficiency andl-2-hydroxyglutaric acidura. It became apparent that derangements of organic acids in the CSF may occur independently of the systemic metabolism. Quantitative organic acid analysis in CSF will yield new information on the pathophysiology in the central nervous system (CNS) of these disorders and may prove necessary for successful monitoring of treatment of organoacidopathies, which present mainly with neurological disease. For example, in glutaryl-CoA dehydrogenase deficiency the urinary excretion of glutarate appears to be an inadequate parameter for monitoring the effect of dietary therapy, without plasma and CSF determinations. Inl-2-hydroxyglutaric aciduria the elevation ofl-2-hydroxyglutarate was found to be greater in CSF than in plasma. In addition, some other organic acids, glycolate, glycerate, 2,4-dihydroxybutyrate, citrate and isocitrate, were also elevated in the CSF of the patients out of proportion to normal levels in plasma and urine. High concentrations of an unknown compound, which was tentatively identified as 2,4-dihydroxyglutarate, were found in the CSF of patients withl-2-hydroxyglutaric aciduria. Quantitative determination of organic acids in CSF and plasma should aid the monitoring of treatment of patients with organic acid disorders, allow investigations of metabolites in known disorders, and detect neurometabolic diseases in which the diagnostic metabolites accumulate preferentially in CSF.     

Hypophosphatemic rickets/osteomalacia in linear sebaceous nevus syndrome: a variant of tumor-induced osteomalacia

A severe form of vitamin D-resistant rickets is associated with the linear sebaceous nevus syndrome. We investigated the pathophysiology underlying defective bone mineralization in two individuals and examined the effects of 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol) therapy on the clinical and biochemical abnormalities. Both patients had fasting hypophosphatemia, markedly diminished TmP/GFR, and elevated alkaline phosphase activity in the presence of normocalcemia. Before treatment with calcitriol, serum 1,25(OH)2D concentrations were reduced but serum 25-hydroxyvitamin D (25(OH)D) concentrations were normal. Administration of calcitriol increased serum 1,25(OH)2D concentrations and led to an increase in TmP/GFR and serum phosphorus levels and to a decrease in alkaline phosphatase activity. However, the renal tubular maximum for reabsorption of inorganic phosphate, normalized according to glomerular filtration rate, and serum phosphorus levels remained abnormally low even in the patient who also received phosphate supplementation. Bone histomorphologic studies in the adult patient showed extreme osteomalacia, which partially improved with calcitriol. These data demonstrate that the putative skin lesion-derived factor results in both a renal tubular defect in phosphate reabsorption and in 1,25-(OH)2 D deficiency. The vitamin D-resistant rickets of linear sebaceous nevus syndrome is a variant of tumor-induced osteomalacia.     

Non-ketotic hyperglycinaemia in a family with an unusual phenotype

A 10-year-old girl, one of three affected sisters, with non-ketotic hyperglycinaemia is described. In contrast to other reported cases, the course of the disorder was comparatively mild in this family. The only clinical signs were mental retardation and abnormalities in the EEG; blood glycine levels were 2–3 times normal. In the propositus, the formation of¹⁴CO₂ from glycine-1-¹⁴C and of FH ₄ ¹⁴ CH₂OH from glycine-2-¹⁴C were impaired, shown by the decreased¹⁴CO₂ content of expired air and diminished labelling of carbon 3 of serine. However, the biochemical defect was no less than that seen in patients with much more severe clinical effects.     

Tetrahydrobiopterin in intestinal lumen: Its absorption and secretion in the small intestine and the elimination in the large intestine

Summary  In treating hereditary deficiency of tetrahydrobiopterin (BH₄), supplementation with BH₄ might be the ultimate choice of therapy. Oral administration of BH₄ has been believed to be inefficient owing to poor absorption of BH₄ in the intestine. In this study, we found a considerable amount of BH₄ as well as its oxidized pterins in the ingredients of intestinal lumen of mice when they were served food that did not contain significant amounts of biopterin. Ligation of the biliary duct led to significant decrease in luminal biopterin. Supplementation of BH₄ either by intraperitoneal administration of sepiapterin or of 6RBH₄ ((6R)-l-erythro-5,6,7,8-tetrahydrobiopterin) increased the BH₄ content in the intestinal lumen with a slight delay after the rise of blood BH₄. In these mice, biopterin appeared in the large intestine, caecum and colon, 2 h after the administration. The appearance of BH₄ in the large intestine was accompanied by a large amount of pterin (2-amino-4-hydroxypteridine). The amounts of biopterin + pterin that appeared in the large intestine after intraperitoneal administration of BH₄ were not greater than those found after oral administration at the same dose. When the mice were treated with a large dose of antibiotics prior to the BH₄ administration, the amount of biopterin increased in the caecum but the amount of pterin decreased greatly. These results suggested that a large proportion of BH₄ administered moved to the large intestine, where most biopterin was decomposed presumably by enteric bacteria. Nonetheless, most of the orally administered biopterin was taken up by the small intestine and the amount of biopterin reaching the large intestine was almost the same as that which appeared after direct injection of 6RBH₄ into the peritoneal cavity. Competing interests: None declared References to electronic databases: Phenylalanine hydroxylase: EC 1.14.16.1. Tyrosine hydroxylase: EC 1.14.16.2. Tryptophan hydroxylase: EC 1.14.16.4. NO synthase: EC 1.14.13.39. Presented at the International Conference on Tetrahydrobiopterin, PKU, and NOS, 23–28 March 2008,St Moritz, Champfér, Switzerland.     

Metabolism of branched-chain amino acids in fibroblasts from patients with maple syrup urine disease and other abnormalities of branched-chain ketoacid dehydrogenase activity

The metabolism of branched-chain amino acids was studied in cultured fibroblasts from patients with branched-chain ketoacid dehydrogenase deficiency using 1-14C- and UL-14C-leucine and valine. The formation of 14CO2 from 1-14C-valine or 1-14C-leucine was 1-3% of normal. In fibroblasts of patients with associated lactic acidemia the values were 4-29% of control. Analysis of organic acid products revealed that in both patients and controls the amount of labeled alpha-ketoisovalerate recovered after incubation with 1-14C-valine was one-third of the amount of alpha-ketoisocaproate recovered after incubation with 1-14C-leucine. Very little alpha-hydroxyisocaproate was produced, while the amount of alpha-hydroxyisovalerate was about 10% of the alpha-ketoisovalerate. Unexpectedly beta-hydroxyisobutyrate was found to be the major metabolic product of UL-14C-valine in normal fibroblasts. Large accumulations of beta-hydroxyisovalerate were found in normal fibroblasts using UL-14C-leucine. There were little or no conversions to these compounds in fibroblasts of patients with branched-chain ketoacid dehydrogenase deficiency. There were substantial conversions in the patients in whom dehydrogenase deficiency was associated with lactic acidemia.     

Oxidation of [U-14C]succinic semialdehyde in cultured human lymphoblasts: measurement of residual succinic semialdehyde dehydrogenase activity in 11 patients with 4-hydroxybutyric aciduria

The oxidation of [U-14C]succinic semialdehyde to 14CO2 has been investigated in cultured lymphoblasts to develop a whole cell assay for succinic semialdehyde dehydrogenase. We have previously demonstrated deficiency of this enzyme in extracts of white cells derived from 13 patients with 4-hydroxybutyric aciduria. Major goals were the demonstration of greater residual succinic semialdehyde dehydrogenase activity in patient cell lines and the better representation of physiology in vivo. In 18 control lymphoblast lines, the conversion of [U-14C]succinic semialdehyde to 14CO2 was 1579 +/- 310 dpm. The mean value in lymphoblasts derived from 11 patients with deficiency of succinic semialdehyde dehydrogenase was 112 +/- 36 dpm approximating 7% of the mean control value. Analysis of organic acids produced from [U-14C]succinic semialdehyde in control lymphoblasts indicated that 14CO2 emanated from the tricarboxylic acid cycle; the major metabolic products were succinic and lactic acids. In the presence of 5mM malonic and 2-propylpentanoic (valproic) acids, 14CO2 production in a control lymphoblast line was decreased by 68 and 45%, respectively. The whole cell assay is less laborious than our previously described assay employing cell extracts, and the general trend was the demonstration of higher residual levels of activity for lymphoblasts derived from patients.     

6-pyruvoyl tetrahydropterin synthase deficiency: a case report

A 5 day old girl screened positive for hyperphenylalaninemia on routine newborn screening. Initial diagnostic work-up showed elevated blood phenylalanine of 1100 mmol/L and low tyrosine. Limited protein diet and phenylalanine-free formula were prescribed. Further investigation revealed a defect in biopterin metabolism. Urine had no detectable biopterin (BH4) and an elevated level of neopterin at 24.31 mmol/mole Cr. Enzymatic assay showed zero level of 6-pyruvoyl tetrahydropterin synthase. The activity in the mother was 3.5 or 19.9% of controls consistent with heterozygosity. The concentrations of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid were below the reference ranges. A treatment regimen of BH4 tablets, 5 hydroxytryptophan and DOPA was initiated. The diagnostic evaluation, management and follow-up of patients with this disorder will be outlined. This is the first reported case of a Filipino with a defect in biopterin metabolism.     

Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father

BACKGROUND: Autosomal recessive inborn errors of metabolism often present as life-threatening disease in infancy and have adverse effects on the nervous system. Parents are usually heterozygotes. This is true of most disorders of fatty acid oxidation, which are rare and present with hypoketotic hypoglycemia. However, the gene for medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency is common in white people, raising the possibility that a parent may be homozygous. OBJECTIVE: To document the occurrence of MCAD deficiency in a 12-month-old boy and his father, both of whom were homozygous for the A985G mutation. DESIGN: Clinical observations and definitive biochemical testing. SETTING: Children's hospital and university laboratory. PARTICIPANTS: One child and one adult. INTERVENTIONS: Diagnosis and treatment. MAIN OUTCOME MEASURES: Clinical outcome; analysis results of plasma and urine for carnitine and organic acids. RESULTS: An infant admitted with an acute illness requiring intensive care was found to have carnitine deficiency and dicarboxylic aciduria; MCAD deficiency was diagnosed by assay of his DNA for the common mutation. Test results of the father revealed him also to be homozygous. CONCLUSION: In MCAD deficiency, as opposed to the usual rare autosomal recessive metabolic disease, a parent may also be an affected homozygote.