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The aim of the article. The aim of this study was to evaluation of the effectiveness of standard antidote therapy and dimephosphon administration in rats with acute ethylene glycol poisoning. The tasks of the study included modeling acute ethylene glycol poisoning in rats, conducting experimental therapy with ethanol antidote in combination with sodium bicarbonate and dimephosphon therapy, comparing the effectiveness of drugs in relation to indicators of acid-base state impairment and renal function.
Materials and methods. Ethylene glycol (EG) was administered per os to Wistar male rats (190-210 g b.w.) at a single dose of 6 mL / kg b.w. through an atraumatic gastric tube. The animals were divided into 4 groups of 6 individuals each: intact (negative control), EG poisoning (positive control), EG + standard antidote therapy, EG + dimephosphon therapy. Experimental therapy was carried out for first 24 hours using standard antidote therapy: ethanol (30% solution 2 mL / kg b.w. i.p. after 1, 4, 6, 12, 18 hours) and sodium bicarbonate (4% solution 6 mL / kg b.w. i.p. 3 times on the first day), as well as administration of dimephosphon (150 mg / kg i.p. 3 times on the first day, 450 mg / kg b.w. per day). Daily urine on day 3 after poisoning was collected in metabolic cages. Creatinine concentration in urine and blood serum samples were measured, and creatinine clearance was calculated. After 24 hours of therapy, the pH, level of sodium, potassium, calcium, magnesium, chlorides, bicarbonates, lactate, d-3-hydroxybutyrate, albumin, urea and creatinine (measured parameters) were determined in venous blood samples. Anion gap, ∆рН, ∆AG, ∆HCO3, ∆AG/∆HCO3 and ∆Gap were calculated. The mechanism of death was determined for the dead animals. Data processing was performed using GraphPad Prism 6.0.
Results. Acute poisoning of rats with ethylene glycol leads to the development of toxic encephalopathy and nephropathy, acid-base abnormalities, high anion gap metabolic acidosis due to the presence of metabolites, as well as lactate-ketoacidosis due to depression of the central nervous system and hunger. 100% of the EG-treated (12 mL / kg b.w.) animals died within 3 days. Metabolic acidosis in combination with hypermagnesemia had provided a cardiodepressive effect, which with direct nephrotoxic and neurotoxic effects contributed to the development of a mixed variant of thanatogenesis and death. Death comes from toxic encephalopathy and nephropathy, high anion gap metabolic acidosis caused by direct nephrotoxic and neurotoxic effects of EG and its metabolites. The standard antidote therapy with ethanol in combination with sodium bicarbonate prevented a pH shift, lactic acidosis and ketoacidosis, an increase in urea, but did not affect the level of bicarbonate (p=0.048), creatinine and its clearance (p=0.037) and the anion gap (p=0.033). The dimephosphon therapy prevented a decrease in creatinine clearance and blood bicarbonate level, limited the increase in lactate dehydrogenase activity, had a more pronounced effect on the AG and ∆AG (p=0.042), but did not affect the hypocalcemia (p=0.0076) and hypoalbuminemia (p=0.021).
Conclusion. Acute ethylene glycol poisoning leads to the development of a mixed variant of thanatogenesis with damage to the central nervous and urinary systems, as well as the heart. Autopsy and histopathology confirmed the cause of animal death. In the model at a dose of 6 mL / kg of EG the dimephosphon therapy was more conducive to the correction of the main markers of high anion gap metabolic acidosis (HAGMA) than standard antidote therapy (both measured and calculated, p0.05). The dimephosphon therapy prevented a decrease in creatinine clearance. A comparative analysis of two methods for the correction of high anion gap metabolic acidosis in rats in acute poisoning with ethylene glycol showed that dimephosphon therapy vs. standard antidote therapy had a stronger effect on markers of metabolic acidosis and renal impairment.
Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis
