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

Pw, Stacpoole; Ec, Wright; Tg, Baumgartner; Rm, Bersin; Buchalter, Scott E.; Sh, Curry; Ca, Duncan; Em, Harman; Gn, Henderson; Jenkinson, S. G.

doi:10.1056/nejm199211263272204

Cited by 300 publications

(131 citation statements)

References 23 publications

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“…In a second patient, Figure 4 illustrates the expected change in plasma drug clearance. In sharp contrast to our prior studies in adults with acquired causes of lactic acidosis (14,15) or in healthy volunteers, both Table 2 and Figure 4 demonstrate that repeated dosing in children appears to lead to progressive increases in Cmax. Figure 5 illustrates the plasma metabolism of an oral 12.5 mg/kg dose of DCA (1:1 isotope ratio) in a child with CLA.…”

Section: Introductioncontrasting

confidence: 89%

Clinical Pharmacology and Toxicology of Dichloroacetate

Stacpoole¹,

Henderson²,

Yan³

et al. 1998

Environmental Health Perspectives

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Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and industrial chemicals. Its accumulation in groundwater and at certain Superfund sites is considered a potential health hazard. However, concern about DCA toxicity is predicated mainly on data obtained in inbred rodent strains administered DCA at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of DCA induces hepatotoxicity and neoplasia. Ironically, the DCA doses used in animal toxicology experiments are very similar to those used clinically for the chronic or acute treatment of several acquired or hereditary metabolic or cardiovascular diseases. As a medicinal, DCA is generally well tolerated and stimulates the activity of the mitochondrial pyruvate dehydrogenase enzyme complex, resulting in increased oxidation of glucose and lactate and an amelioration of lactic acidosis. By this mechanism, the drug may also enhance cellular energy metabolism. DCA is dehalogenated in vivo to monochloroacetate and glyoxylate, from which it can be further catabolized to glycolate, glycine, oxalate, and carbon dioxide. It remains to be determined whether important differences in its metabolism and toxicology exist in humans between environmentally and clinically relevant doses. -Environ Health Perspect 106(Suppl 4):989-994 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-4/989-994stacpoole/abstract.html

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Section: Introductioncontrasting

confidence: 89%

Clinical Pharmacology and Toxicology of Dichloroacetate

Stacpoole¹,

Henderson²,

Yan³

et al. 1998

Environmental Health Perspectives

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“…Prior human studies have explored dichloroacetate, a medication that inhibits the conversion of active PDH to inactive PDH, in the treatment of patients with lactic acidosis. In one randomized, controlled trial, administration of dichloroacetate significantly reduced lactate levels and improved pH, but was not associated with a difference in hemodynamics or mortality (12). This study was done more than 20 years ago, however, and there have been considerable changes to critical care since.…”

Section: Brief Communicationmentioning

confidence: 98%

Pyruvate Dehydrogenase Activity is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis: A Prospective Observational Trial

Nuzzo¹,

Berg

Andersen

et al. 2015

Annals ATS

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Rationale: Rodent studies have shown that pyruvate dehydrogenase (PDH) levels are low in sepsis. This may cause cells to shift to anaerobic metabolism, resulting in increased lactate production. Alterations in PDH during sepsis have never been studied in humans.Objectives: The objective of this pilot study was to measure PDH activity and quantity in patients with severe sepsis. Methods:We conducted a pilot case-control study at a single urban tertiary care center. We compared PDH activity and quantity between patients with severe sepsis admitted to the intensive care unit and healthy control subjects. PDH activity and quantity were measured in isolated peripheral blood mononuclear cells. We measured PDH activity and quantity in control subjects at baseline and in patients with sepsis at 0 (baseline), 24, 48, and 72 hours. Measurements and Main Results:We enrolled 56 patients with sepsis and 20 control subjects with at least one blood sample being drawn from each patient. PDH activity and quantity in the sepsis group were significantly lower than the control group (P , 0.001). In multivariable linear regression adjusting for age, race, sex, and assay plate, the difference remained significant. Patients with sepsis who died had significantly lower PDH activity compared with those who survived (P = 0.03).Conclusions: PDH activity and quantity is decreased in peripheral blood mononuclear cells of humans with severe sepsis when compared with healthy control subjects, and may be associated with mortality. Whether decreased PDH activity plays a role in lactate metabolism or whether pharmacologic modification of PDH activity may improve outcomes remains unknown.

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“…It is the trend rather than any single measurement that is associated with a high mortality [122]. However, therapies that have been aimed directly at lowering serum lactate have failed to produce a significant impact on this mortality rate [123]. Lactate has been cited as a marker of tissue hypoxia for over 30 years [124].…”

Section: Significance Of Lactic Acidosismentioning

confidence: 99%

Anions and the anaesthetist

2002

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SummaryAnions are the negative components of most chemical structures and play many important physiological and pharmacological roles that are of interest to the anaesthetist. Their relevance is reviewed with a particular emphasis on the inorganic anions (halides, bicarbonate, phosphate and sulphate) and the significance and limitations of the anion gap. Organic anions (albumin, lactate) are also discussed, albeit briefly. The suitability of anions for their role in neurotransmission and acid2base balance is outlined.

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

Abstract: Dichloroacetate treatment of patients with severe lactic acidosis results in statistically significant but clinically unimportant changes in arterial-blood lactate concentrations and pH and fails to alter either hemodynamics or survival.

Cited by 300 publications

References 23 publications

Clinical Pharmacology and Toxicology of Dichloroacetate

Clinical Pharmacology and Toxicology of Dichloroacetate

Pyruvate Dehydrogenase Activity is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis: A Prospective Observational Trial

Anions and the anaesthetist

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