Thomas G. Baumgartner

A Controlled Clinical Trial of Dichloroacetate for Treatment of Lactic Acidosis in Adults

Abstract Background. Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. Methods. We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of ≥5.0 mmol per liter and either an arterial-blood pH of ≤7.35 or a base deficit of ≥6 mmol per liter. The mean (±SD) arterial-blood lactate concentrations before treatment were 11.6±7.0 mmol per liter in the dichloroacetate-treated patients and 10.4±5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24±0.12 and 7.24±0...

Treatment of lactic acidosis with dichloroacetate.

We administered dichloroacetate, which prevents or reverses hyperlactatemia in animals and lowers plasma lactate levels in human beings, to 13 patients with lactic acidosis of various causes. All had hypotension, and their acidemia had resisted treatment with sodium bicarbonate. The metabolic effects of dichloroacetate were evaluated in 11 patients. In seven dichloroacetate significantly reduced the level of arterial blood lactate (P less than 0.005) from the base-line value and raised the levels of arterial blood bicarbonate (P less than 0.02) and arterial pH (P less than 0.005). In six of these seven, the acidemia resolved completely with therapy. In 10 of the 13 patients systolic blood pressure increased by 10 to 40 mm Hg, and 4 patients had a 21 per cent increase in cardiac output (P less than 0.02). Despite improvement in their lactic acidemia, all patients but one died of their underlying disease. No serious drug-related toxicity occurred. We conclude that dichloroacetate is a safe and effective adjunct in the treatment of patients with lactic acidosis, although the ultimate prognosis may depend on the underlying disease.

Natural history and course of acquired lactic acidosis in adults

Abstract study objective: To determine the pathogenesis and clinical course of lactic acidosis in adults receiving standard medical care. design: Placebo arm of a 5-year prospective, randomized, blinded study comparing placebo and dichloroacetate as specific lactate-lowering therapy. Each patient received intravenous saline placebo in addition to conventional therapy. setting: Intensive care units of 10 tertiary care hospitals in North America. patients: One hundred twenty-six patients with lactic acidosis, defined as arterial blood lactate greater than or equal to 5 mmol/L and either arterial pH of less than or equal to 7.35 or base deficit greater than 6mmol/L. Patients were followed for up to 6 months. measurements and main results: Mean ± SD demographic entry data for 126 patients included: age 56 ± 17 years, lactate 10.4 ± 5.5 mmol/L, pH 7.24 ± 0.14, calculated base deficit 14.1 ± 5.4, arterial systolic blood pressure 103 ± 29 mm Hg, Glasgow Coma score 7.9 ± 4.9, and APACHE II score 19.2 ± 8.1. Despite fluids and pressors, 32% of patients had systolic blood pressures of less than or equal to 90 mm Hg in association with sepsis (59%), cardiac failure (18%), or hemorrhage (18%). The most common causes of lactic acidosis in the absence of shock were sepsis (49%), liver disease (15%), and respiratory failure (12%). The median survival was 38.5 hours. Survival at 24 hours was 59%. Arterial pH predicted 24-hour survival better than base deficit or bicarbonate level. Percent survival was 41% at 3 days and 17% at 30 days. Only 21% of patients survived to leave the intensive care unit, and 17% were discharged from the hospital. In patients receiving sodium bicarbonate, neither acid-base nor hemodynamic status improved. conclusions: In this first prospective study of the clinical course of acute lactic acidosis in adults, nearly all subjects had both hemodynamic and nonhemodynamic (metabolic) underlying causes, many of which independently predicted survival and most of which were refractory to standard care.

Plasma concentrations and metabolic effects of intravenous sodium dichloroacetate

Eleven healthy subjects received five doses of intravenous sodium dichloroacetate (DCA) at 2‐hr intervals. Determinations of DCA in plasma and of lactate and glucose in blood were made at various times until 24 hr after starting the first infusion. Twenty‐four–hour urinary oxalate excretion was also measured. DCA levels rose and fell during and after each dose, with higher levels induced by higher doses. Lactate levels fell as the result of DCA treatment, with greater falls after higher doses, and returned to normal after 24 hr at the two lower dose levels but not at the level of 50 mg/kg. Lactate levels did not change parallel to changes in DCA levels. Only the doses of 50 mg/kg prevented postprandial rises in lactate levels. Blood glucose levels were not altered. The mean DCA t½ after the initial doses was 63.3 min (range 15.0 to 112.2 min), while that after the final doses was 374.0 min (range 37.8 to 1386.0 min). The AUC and the DCA‐induced increase in urinary oxalate excretion were linearly related to dose. Mean DCA apparent volume of distribution was 0.30 l/kg (range 0.09 to 0.60 l/kg).

Further studies of a technique for total parenteral nutrition in the mouse

Abstract A method for total parenteral feeding in mice has undergone further evaluation in our laboratory. The procedure involved cannulation of the inferior vena cava, partial immobilization by tail restraint and continuous infusion of a solution containing 40% dextrose plus 4.3% amino acids. In previous studies with this method (1,14), no evidence of restraint stress was noted, although adrenal function was not assessed. This report demonstrates that, in tail-restrained mice, urinary excretion of corticosteroids and catecholamines is not increased, thus indicating that this form of immobilization does not stimulate the hypothalamo-adrenocortical system. The technique of parenteral feeding was further evaluated in a group of female Swiss mice that were fully supported by parenteral infusions at maintenance levels for seven days. No changes in body weight were found. The weights of the spleen, kidneys, lungs and heart were normal when compared with controls. Liver weight declined, although protein and fat concentrations were normal. Carcass water, fat and nitrogen content were also normal. Hepatocellular enzyme activities were slightly altered. However, a group of mice given the parenteral solution to drink showed similar changes in enzyme activities, indicating that diet composition and not route of feeding was the responsible factor. Plasma protein and albumin levels were normal in parenterally-fed mice, whereas glucose decreased 28% with no detectable rise in insulin level. No evidence of immobilization-induced stress was found. Mice infused at NAS/NRC (2) levels of energy and nitrogen appeared to show normal utilization of the nutrients. A comparison of these results with those reported in parenterally-fed rats indicates that mice show fewer metabolic and compositional alterations associated with parenteral nutrition. This study further validates our technique of parenteral feeding in the mouse.

Cost Containment Using Cysteine HCl Acidification to Increase Calcium/ Phosphate Solubility in Hyperalimentation Solutions

The purpose of this study was to determine if (1) the calcium/phosphate insoluble product was inversely related to pH [when cysteine HC1 (CH) was added as neonatal supplementation at 0.5 mM/kg/day to hyperalimentation (HAL) solutions] and (2) the potential cost savings to the hospital. The pH of the HAL solutions was adjusted by adding various amounts of CH to the HAL solution. HAL solutions containing 27 mEq of calcium/liter and 30 mEq (15 mM) of phosphate/liter were compounded. Ten-milliliter aliquots were analyzed at 0, 12, 24, and 48 hr. All samples (n = 56) were filtered (0.22 mu), viewed with 7-10,000 X magnification scanning electron microscopy, and qualitatively analyzed with a Philips Energy Dispersive X-Ray Analysis System equipped with a SW9100 Microprocessor. Calcium/phosphate insoluble product was present in the 0-, 12-, 24-, and 48-hr samples from the CH-free solutions. The solutions containing 759 mg (4.17 mM)/liter of CH however, remained free of precipitant. This investigation demonstrated that addition of CH to HAL can foster significant cost containment (projected

The effect of energy substrate manipulation on tumor growth and metastasis and intermediary metabolism in the parenterally fed mouse

82,000/yr tangible hospital savings) by the elimination of current calcium/phosphate separation procedures for neonates on parenteral nutrition.

Total Parenteral Nutrition in the Mouse: Body Composition and Plasma Chemistries

The effect of N-free energy substrate manipulation on tumor growth and metastasis, host maintenance, and intermediary metabolism was studied in parenterally fed Swiss mice bearing subcutaneously implanted Lewis lung carcinoma. Non-N energy was provided from dextrose (CHO), lipid emulsion (FAT), or a 75:25 balanced (BAL) solution, infused from day 14 through day 22 postimplant. Control mice were offered equivalent energy and N from a balanced, casein-based solid diet (CAS). Tumor-doubling time was significantly prolonged in the CHO group compared to FAT and CAS. Pulmonary metastatic nodules were decreased in number in all parenterally fed mice compared to CAS, suggesting that the route of administration altered pulmonary physiology in such a way that the transmissability and/or growth of the tumor cells was inhibited. Tumor-free body weight was maintained in the CHO (+ 1.3%) and BAL (+ 0.3%) groups. However, significant weight loss occurred, despite equal intake, in the FAT (-4.7%) and CAS (-7.5%) groups. The energy appeared to be channeled into nonoxidative pathways, reflected by an increase in hepatic and adipose tissue lipogenesis and hepatic glycogen content. During the period studied, parenteral dextrose/amino acid infusion in this host-tumor system resulted in a decrease in primary tumor growth and optimal host maintenance compared to fat-based TPN and enteral feeding of a balanced, solid diet. Tumor metastasis was decreased in all parenterally fed mice, a phenomenon related to the route of administration and apparently independent of energy substrate.

Development of an Oral Drug Formulation for Dichloroacetate and Thiamine

Mice that were maintained in energy and nitrogen (N) balance by total parenteral nutrition (TPN) for 12 days were analyzed for changes in organ weight, carcass and liver N and fat, and plasma glucose, urea N, and total protein. The results are compared with two other groups: (1) PO, which consisted of mice that were given the TPN solution per os in amounts equivalent to the TPN group, and (2) AL, which consisted of mice allowed to consume a stock diet ad libitum. In comparison with group AL, the TPN-fed mice had normal liver, kidney, and lung weights but heavier spleens and hearts. Group PO had an increase in liver weight only. Hepatic lipid content declined in group TPN but increased markedly in PO-fed mice. The latter group also demonstrated a 35% increase in carcass fat whereas it was unchanged in the TPN group. No differences were found in plasma urea N and total protein among the groups but plasma glucose increased 2-fold in group PO. It appears that our technique of parenteral feeding in mice maintains fairly normal body composition and plasma chemistries. However, mice drinking the TPN solution (group PO) exhibited the greatest number of alterations. These results are discussed in relation to differences in route of feeding, diet composition, feeding pattern, and the possible influence of circadian rhythms. The dilemma of choosing appropriate control groups in TPN studies is also discussed.

Nutritional Support by Intraperitoneal Dialysis in the Rat: Maintenance of Body Weight with Normal Liver and Plasma Chemistries

Dichloroacetate (DCA) is an investigational drug for the treatment of several metabolic and cardiovascular disorders. Hitherto, it has been used mostly in intravenous, short term treatment regimens. Chronic administration of the drug may be toxic, due in part to the depletion of tissue thiamine stores. We therefore developed a stable liquid preparation of the sodium salt of DCA and thiamine HCl suitable for chronic oral administration. The DCA-thiamine mixture is formulated as a palatable solution containing glycerol, sodium benzoate and aspartame in phosphate buffer at pH 3.5. A thermally accelerated decomposition study of the oral DCA formulation revealed a shelf-life of about 5 years at 4°C and about 156 days at 25°C. The stability was also followed for 1 year at its storage condition of 4°C and it was found to be stable at least for 1 year, which is its current recommended storage time. A new high performance liquid chromatographic method was developed to quantitate DCA, thiamine, aspartame and sodium...