Lactic acidosis with tissue hypoxia

Contraindications to the use of metformin have been debated (34), in relation to the reduced number of cardiovascular events seen in the obese patients treated with metformin in the UK prospective diabetes study (UKPDS) (35). The authors stated inter alia that lactic acidosis is rare (1-5 cases per 100 000) and that in the absence of renal insufficiency accumulation of metformin is rare. Moreover, the authors of a Cochrane systematic review concluded that treatment with metformin was not associated with an increased risk of lactic acidosis (36). Tissue hypoxia is often the trigger for metformin accumulation. Many physicians do not comply with the official British contraindications. The author suggested the following necessary precautionary measures ... 

Cardiovascular and septic shock, with resultant tissue hypoperfusion, are the most common causes of lactic acidosis. Poor tissue perfusion and hypoxia influence enzymatic pyruvate and lactate metabolism to stimulate anaerobic glycolysis and to decrease lactate utilization. This leads to hyperlactatemia and lactic acidosis. The mortality rate of this type of lactic acidosis may be as high as 80% and correlates with the degree of hyperlactatemia. 

Cyanide is one of the least toxic of the lethal CWAs. The inhalational LCtso values for AC and CK have been estimated to be 2,500-5,000 and 11,000 mg min/m respectively (Simeonova, 2004). The cyanide ion (CN ) is the toxic moiety, mediated primarily by its great affinity for the heme as moiety of cytochrome c-oxidase in mitochondria, a key component in oxidative respiration. This interaction blocks the last stage in the electron transfer chain, resulting in cellular hypoxia and a shift of aerobic to anaerobic cellular respiration, leading to cellular ATP depletion and lactic acidosis. Therefore, tissues with high metabolic demands, such as neurons and cardiac cells, are key targets for toxicity. At lethal doses, death occurs within 6-8 min (Sidell et al., 1997). 

Lack of oxygen in blood or tissues. Tissue hypoxia can be caused by injury, inflammation, or tumor growth, due to disruption of blood supply. Tissue hypoxia is normally associated with acidosis, as anaerobic metabolism leads to production of lactic acid. 

DKA is a positive anion gap metabolic acidosis associated with the accumulation of P-hydroxy-butyrate and acetoacetate. Lactic acidosis secondary to cardiac or renal failure, hypoxia, poor tissue perfusion, shock, or sepsis may also contribute to the anion gap in DKA. A normal anion gap (AG) is 12 2 mEq/L.The anion gap (AG) is calculated using the following formula AG = ([Na+ + K+] - [Cl- + HCO,]). In our illustrative case, the anion gap was 28, indicating severe metabolic acidosis. 

Type 1 lactic acidosis occurs in hypoxic subjects and is due to an excessive production of lactate by peripheral tissues. Hypoxia is not a feature of type II lactic acidosis which is probably caused by the impaired metabolism of lactate in the liver. Both are chtuacterized by an extreme metabolic acidosis ((H above 100 nmol/1). There is a high anion gap with low or absent ketones, and high blood lactate concentrations. 

Additionally, hypoxia results in anaerobic metabohsm in tissues with a resulting lactic acidosis. While respirations normally are increased to buffer the metabolic acidosis, damage to the lungs reduces or removes this mechanism from availabihty. 

Tissue ischemia may result from many causes in general, hypoperfusion leads to hypoxia of cells, which results in anaerobic metabolism with the attendant accumulation of organic (mainly lactic) acids. The kidneys (and brain) are especially sensitive to hypoperfusion, such that acute renal failure often is a contributing factor m the high anion gap metabolic acidosis associated with global tissue ischemia (as may occur in major trauma). 

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