The effect of ß-alanine supplementation on high intensity cycling capacity in normoxia and hypoxia.

The availability of dietary beta-alanine (BA) is the limiting factor in carnosine synthesis within human muscle due to its low intramuscular concentration and substrate affinity. Carnosine can accept hydrogen ions (H+), making it an important intramuscular buffer against exercise-induced acidosis. Metabolite accumulation rate increases when exercising in hypoxic conditions, thus an increased carnosine concentration could attenuate H+ build-up when exercising in hypoxic conditions. This study examined the effects of BA supplementation on high intensity cycling capacity in normoxia and hypoxia. In a double-blind design, nineteen males were matched into a BA group (n = 10; 6.4 g·d-1) or a placebo group (PLA; n = 9) and supplemented for 28 days, carrying out two pre- and two post-supplementation cycling capacity trials at 110% of powermax, one in normoxia and one in hypoxia (15.5% O2). Hypoxia led to a 9.1% reduction in exercise capacity, but BA supplementation had no significant effect on exercise capacity in normoxia or hypoxia (P > 0.05). Blood lactate accumulation showed a significant trial x time interaction post-supplementation (P = 0.016), although this was not significantly different between groups. BA supplementation did not increase high intensity cycling capacity in normoxia, nor did it improve cycling capacity in hypoxia even though exercise capacity was reduced under hypoxic conditions.

Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock.

Hemorrhagic shock depletes nicotinamide adenine dinucleotide (NAD) and causes metabolic derangements that, in severe cases, cannot be overcome, even after restoration of blood volume and pressure. However, current strategies to treat acute blood loss do not target cellular metabolism. We hypothesized that supplemental nicotinamide mononucleotide (NMN), the immediate biosynthetic precursor to NAD, would support cellular energetics and enhance physiologic resilience to hemorrhagic shock. In a rodent model of decompensated hemorrhagic shock, rats receiving NMN displayed significantly reduced lactic acidosis and serum IL-6 levels, two strong predictors of mortality in human patients. In both livers and kidneys, NMN increased NAD levels and prevented mitochondrial dysfunction. Moreover, NMN preserved mitochondrial function in isolated hepatocytes cocultured with proinflammatory cytokines, indicating a cell-autonomous protective effect that is independent from the reduction in circulating IL-6. In kidneys, but not in livers, NMN was sufficient to prevent ATP loss following shock and resuscitation. Overall, NMN increased the time animals could sustain severe shock before requiring resuscitation by nearly 25% and significantly improved survival after resuscitation (P = 0.018), whether NMN was given as a pretreatment or only as an adjunct during resuscitation. Thus, we demonstrate that NMN substantially mitigates inflammation, improves cellular metabolism, and promotes survival following hemorrhagic shock.

Quantitative relationships among plasma lactate, inorganic phosphorus, albumin, unmeasured anions and the anion gap in lactic acidosis.

BACKGROUND: Quantitative relationships among plasma [Lactate], [Pi], [Albumin], unmeasured anions ([UA]) and the anion gap (AGK) in lactic acidosis (LA) are not well defined. METHODS: A mathematical model featuring compensatory potassium and chloride shifts and respiratory changes in LA demonstrated: (1) AGK=[Lactate]+Zp×[Pi]+2.4×[Albumin]+constant1+e, where Zp is a function of pH, and e reflects unmeasured anions and cations plus pH-related variations. Eq. (1) can be algebraically rearranged to incorporate the albumin-corrected anion gap, cAGK: (2) cAGK=[Lactate]+Zp×[Pi]+constant2+e. Eq. (1) was tested against 948 data sets from critically ill patients with [Lactate] 4.0mEq/L or greater. AGK and cAGK were evaluated against 12,341 data sets for their ability to detect [Lactate]>4.0mEq/L. RESULTS: Analysis of Eq. (1) revealed r2=0.5950, p<0.001. cAGk>15mEq/L exhibited a sensitivity of 93.0% [95% CI: 91.3-94.5] in detecting [Lactate]>4.0mEq/L, whereas AGK>15mEq/L exhibited a sensitivity of only 70.4% [67.5-73.2]. Additionally, [Lactate]>4.0mEq/L and cAGK>20mEq/L were each strongly associated with intensive care unit mortality (χ2>200, p<0.0001 for each). CONCLUSIONS: In LA, cAGK is more sensitive than AGK in predicting [Lactate]>4.0mEq/L.

Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure.

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.

Rapid reversal of severe lactic acidosis after thiamine administration in critically ill adults: a report of 3 cases.

BACKGROUND: Thiamine plays a critical role in energy metabolism. Critically ill patients may have thiamine deficiency and increased mortality due to potentially irreversible consequences. The aim of this study was to show the impact of thiamine deficiency in a series of patients and the rapid response to thiamine replacement, showing the changes in clinical and metabolic conditions over time. METHODS: We described 3 cases of hospitalized patients who had received parenteral nutrition (PN) without vitamin supplementation. All the patients were admitted to the ICU between 2010 and 2011 with a severe form of lactic acidosis, an unstable circulatory state, and a different neurological disorder (a lethargic state, a severe form of impaired near-coma consciousness, and Wernicke encephalopathy). RESULTS: Intravenous (IV) administration of thiamine was associated with a rapid and marked restoration of acid-base balance, hemodynamic stability and the disappearance of neurological disturbances, and normalization of the clinical and biochemical conditions of all the patients within the following hours. CONCLUSIONS: The 3 cases demonstrated the rapidity of the reversal of severe thiamine deficiency, achieved by appropriate replacement in different hospitalized patients. The regression of clinical and biochemical disorders requires a prompt diagnosis and treatment based on the IV administration of thiamine and magnesium sulfate. In hospitalized patients at risk, thiamine deficiency is prevented by the integration of thiamine supplementation into PN and other forms of nutrition support.

Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.

The causes of Reye-like syndrome are not completely understood. Dihydrolipoamide dehydrogenase (DLD or E3) deficiency is a rare metabolic disorder causing neurological or liver impairment. Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical form of the disease. Here, we report a consanguineous family of Algerian origin with DLD deficiency presenting without suggestive clinical laboratory and anatomopathological findings. Two children died at birth from hepatic failure and three currently adult siblings had recurrent episodes of hepatic cytolysis associated with liver failure or Reye-like syndrome from infancy. Biochemical investigation (lactate, pyruvate, aminoacids in plasma, organic acids in urine) was normal. Histologic examination of liver and muscle showed mild lipid inclusions that were only visible by electron microscopy. The diagnosis of DLD deficiency was possible only after genome-wide linkage analysis, confirmed by a homozygous mutation (p.G229C) in the DLD gene, previously reported in patients with the same geographic origin. DLD and pyruvate dehydrogenase activities were respectively reduced to 25% and 70% in skin fibroblasts of patients and were unresponsive to riboflavin supplementation. In conclusion, this observation clearly supports the view that DLD deficiency should be considered in patients with Reye-like syndrome or liver failure even in the absence of suggestive biochemical findings, with the p.G229C mutation screening as a valuable test in the Arab patients because of its high frequency. It also highlights the usefulness of genome-wide linkage analysis for decisive diagnosis advance in inherited metabolic disorders.

Lactic acidosis following intentional overdose by inhalation of salmeterol and fluticasone.

Salmeterol, a long-acting ß2-adrenergic receptor agonist used for the treatment of asthma and chronic obstructive pulmonary disease, has an adverse effects profile that is similar to that of salbutamol and other ß2-agonists. We report a sympathomimetic syndrome with metabolic acidosis and hyperlactatemia after intentional inhalation of salmeterol in a suicide attempt. A 16-year-old female patient was admitted to the emergency department approximately 2 hours after having inhaled 60 puffs of a combination of salmeterol xinafoate 25 µg and fluticasone propionate 50 µg. She presented in an anxious state with complaints of palpitations and chest pain. The electrocardiogram demonstrated sinus tachycardia and ST-segment depression in the inferior and anterolateral leads. Laboratory findings showed hypokalemia, hypophosphatemia, and lactic acidosis. Cardiac troponin I and creatine kinase MB remained within the normal range. Treatment was supportive and included intravenous fluids and cautious potassium supplementation. The next day, electrocardiographic and laboratory findings returned to normal. We hypothesize that stimulation of ß2-adrenergic receptors by inhalation of salmeterol caused this patient's lactic acidosis. This observation is consistent with the hypothesis that the hyperlactatemia observed during asthma attacks is due in part to the administration of high doses of ß2-agonists. Salmeterol overdose by inhalation appears to be sufficient to cause lactic acidosis.

[Lactic acidosis and accumulation of glutamate in the blood of neonates following treatment with calcium levulinate for hypocalcaemia]. / Lactaatacidose en glutamaatophoping in het bloed van neonaten na behandeling met calciumlevulaat wegens hypocalciëmie.

The data from 5 clinics concerning 8 infants, who had developed severe lactic acidosis and hyperglutamic acidaemia were reviewed. Blood-lactate levels were up to 15 mmol/l (reference level: < 2) and plasma-glutamate levels up to 1632 pmol/l (reference level: 14-78), and there was no concomitant hyperglutaminaemia (levels up to 1032 micromol/l (reference level: 333-809)). A positive correlation between the amount of calcium levulinate administered and the degree of hyperglutamic acidaemia was found. Replacement of the calcium levulinate by another calcium salt caused a reversal of the biochemical abnormalities of the patients. Two of the infants had a 22q11 microdeletion. This development of severe acidosis in infants who had been given a calcium supplement in the form of calcium levulinate may be related to genetic predisposition. The paradoxal hyperketonaemia and generalized aminoaciduria in 4 other patients suggested disturbed function ofthe mitochondrial respiratory chain. The hypothesis of the occurrence of an underlying defect of the mitochondrial respiratory chain was tested in the muscle tissue of one 22q11 patient, but this showed no abnormalities. Excessive accumulation of glutamate because of dysfunction ofglutamine synthetase, which forms glutamate from glutamine seems unlikely because of the relatively low values of plasma glutamate compared to the glutamine plasma levels. Calcium levulinate should no longer be used in neonates as it may lead to lactic acidosis.

[Lactic acidosis: a complication of spinal cord injury in multiple trauma]. / Laktatazidose: eine Komplikation beim querschnittgelähmten Polytrauma.

Large-dose methylprednisolone has been advocated to lessen neurologic deficits in spinal cord injury for nearly a decade despite confounding statistical results in the Second National Acute Spinal Cord Injury Study (NASCIS-2). Recent retrospective studies found lack of significant functional improvement, increases in the incidence of infectious complications and an increase in ventilated and intensive care days in steroid-treated groups. We report on five cases with severe hyperglycemia and nonketotic metabolic acidosis in otherwise non-diabetic patients with multiple blunt injuries and an associated spinal cord injury. Those adverse effects were induced by epinephrine and aggravated by methylprednisolone. We conclude that high-dose methylprednisolone should be avoided in multiple injured or otherwise compromised patients potentially needing catecholamine support.

Lactic acidosis caused by thiamine deficiency in a pregnant alcoholic patient.

BACKGROUND: Metabolic acidosis from accumulation of lactic acid is a relatively common condition, whereas its causation by thiamine deficiency is not. METHODS: We studied a pregnant alcoholic patient who presented with hyperemesis and a high anion gap acidosis. RESULTS: Lactic acidosis and thiamine deficiency were confirmed. The patient's symptoms and acidosis resolved with thiamine administration. CONCLUSIONS: Lactic acidosis caused by thiamine deficiency must be suspected when pregnant patients at risk for thiamine deficiency present with a high anion gap acidosis. A large dose of thiamine must be administered immediately.

Review of the literature: severe hyperphosphatemia.

A patient with a markedly elevated serum phosphorus level (23.9 mg/dL) is described, followed by a brief review of severe hyperphosphatemia. Elevated serum phosphorus levels may be artifactual or true. True hyperphosphatemia is usefully subdivided according to (a) whether phosphorus is added to the extracellular fluid from a variety of exogenous or endogenous sources, or (b) whether the urinary excretion of phosphorus is reduced from either decreased glomerular filtration or increased tubular reabsorption. Severe hyperphosphatemia, defined herein as levels of 14 mg/dL or higher, is almost invariably multifactorial--usually resulting from addition of phosphorus to the extracellular fluid together with decreased phosphorus excretion. The hyperphosphatemia of the patient described herein appeared to result from a combination of dietary phosphorus supplementation, acute renal failure, acute pancreatitis, and ischemic bowel disease, complicated by lactic acidosis.

Determination of lactate threshold by respiratory gas exchange measures and blood lactate levels during incremental load work.

OBJECTIVE: The purpose of this investigation was the determination of the lactate threshold (LT) by selected respiratory gas exchange measures and venous blood lactate levels during incremental load work on a mechanically braked cycle ergometer. DESIGN: Repeated measures design. SETTING: Human Performance Laboratory. PARTICIPANTS: Eight healthy trained soccer players (mean age 21.9 +/- 3.0 yr, mean VO2max = 59.2 +/- 3.6 ml.kg.min-1). OUTCOME MEASURE: Subjects conducted two incremental load work tests. Incremental load work was increased by 1 kilopond (kp) every third minute at 60 rpm until voluntary exhaustion. Blood samples from a forearm vein were collected during the second trial (T2) only and analyzed for lactic acid [LA-]. RESULTS: One-way analysis of variance (ANOVA) with repeated measures indicated no statistically significant difference between the two tests for maximal oxygen uptake (VO2max), maximal carbon dioxide production (VCO2max), maximal heart rate (HRmax), maximal pulmonary ventilation (VEBTPSmax) and lowest ventilatory equivalent of oxygen (VE/VO2), respectively; however, there was a significant difference among the oxygen uptake (VO2) values at the LT for the four determination methods. In our subjects, the measured (mean +/- SD) VE/VO2 in relation to VO2 for the first trial (T1) of 22.9 +/- 1.9 occurred at VO2 of 1.27 +/- 0.8 l.min-1. The lowest VE/VO2 and the onset of [LA-] accumulation calculated from individual exponential equations relating VE to VO2 yielded VO2 values of 1.77 +/- 0.18 and 1.74 +/- 0.25 l.min-1 for the T2. Utilizing natural log for lactate ln [LA-] to natural log for ln (VO2) equations, the LT for T2 occurred at VO2 of 1.30 +/- 0.70 l.min-1. CONCLUSION: LT was best predicted by the measured lowest VE/VO2 and the plot of the ln [LA-] to ln VO2 relationship. The methods used in this study provide a valid estimate of the LT and support the use of measured lowest VE/VO2 as an indirect measure of the LT.

Lactic acidosis associated with high-dose niacin therapy.

We have reported a case of lactic acidosis induced by ingestion of sustained-release nicotinic acid. Prompt recovery followed treatment with glucose-containing fluids and discontinuation of nicotinic acid therapy.

Diets enriched with N-3 fatty acids ameliorate lactic acidosis by improving endotoxin-induced tissue hypoperfusion in guinea pigs.

The effect of 6 weeks dietary lipid manipulation on the acute physiologic response to 7-hour continuous endotoxin infusion in guinea pigs was examined. One diet was enriched with N-3 fatty acids, whereas the other contained N-6 fatty acids, primarily linoleic acid. Animals fed N-6 fatty acids developed significant lactic acidemia, microvascular muscle hypoperfusion, and pulmonary infiltrates in response to endotoxin infusion. N-3 fatty acid-fed animals demonstrated improved lactate levels, microvascular muscle perfusion, and lung morphology compared to N-6 fatty acid-fed animals after endotoxin infusion. There was no significant change in cardiac output, PaO2, or mean arterial blood pressure at the end of the endotoxin infusion in either group. Pretreatment with indomethacin, or BM 13505, a specific thromboxane A2 receptor blocker, ameliorated the development of metabolic acidosis in N-6 fatty acid-fed animals, demonstrating a role for prostanoids in the sequelae of endotoxemia. The ability of dietary pretreatment with N-3 fatty acids to influence favorably the physiologic response to endotoxin represents a novel nutrient-metabolic interaction with potential therapeutic implications.

Severe metabolic acidosis and "muti" (traditional herbal medicine) ingestion in young children.

Twenty infants and young children admitted with severe metabolic acidosis and a positive history of 'muti' ingestion were investigated. All had accompanying gastroenteritis and significant dehydration. Biochemical data was diagnostic of high anion/gap metabolic acidosis in the majority (70 per cent). Further biochemical data indicated that lactic acidosis and pre-renal azotaemia resulting from severe hypovolaemia were likely causes of the high anion GAP metabolic acidosis. There was no evidence to suggest that the ingested muti per se was associated directly with the acidosis or acute renal failure seen in these children.

Lactic acidosis in theophylline overdose.

An 18-year-old man with theophylline overdose developed an increased anion gap metabolic acidosis. Serum lactate levels were markedly elevated. A direct correlation was found between the increasing theophylline level, clinical hyperadrenergic state, and the worsening acidosis. Early hemoperfusion reversed the acidosis, the elevated serum theophylline level, and the hyperadrenergic state. This case substantiates the role of lactate accumulation in the metabolic acidosis associated with isolated theophylline toxicity.

Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia.

A 2-day-old girl developed a severe lactic acidosis with a normal lactate/pyruvate ratio and hyperammonaemia. Plasma arginine and citrulline levels were below the limit of detection. In muscle total pyruvate dehydrogenase complex (PDHC) and pyruvate decarboxylase (E1) activities were reduced to a fraction of lower control values. The acute neonatal period was bridged with peritoneal dialysis, dichloroacetate therapy, supplements of arginine and branched chain amino acids, a complete vitamin B complex and lipoic acid. Lactate homeostasis responded to pharmacological supplements of lipoic acid. At age 1 year the child was hypotonic, showed severe developmental retardation, optic atrophy and cranial dysmorphism. She died aged 1 year 8 months with signs of respiratory paralysis but with normal lactate levels under assisted breathing. Pathological findings at autopsy were suggestive of Leigh syndrome, interstitial pneumonia and extensive fatty infiltration of hepatocytes. Regression analysis of data from 187 plasma amino acid determinations from the patient over a period of 1 year 8 months revealed a persistent-imbalance involving alanine, glutamic acid, glutamine, proline, citrulline and branched chain amino acids. Aspects of acute and long-term therapy in this patient and some implications of the imbalances in plasma amino acids are discussed.