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Basic Clin Pharmacol Toxicol. 2018 Dec;123(6):749-755. doi: 10.1111/bcpt.13074. Epub 2018 Jul 23.

The Hypothesis of Circulus Hypoxicus and Its Clinical Relevance in Patients With Methanol Poisoning - An Observational Study of 35 Patients.

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Department of Acute Medicine, Division of Medicine, Oslo University Hospital, Oslo, Norway.
University of Oslo, Oslo, Norway.
Toxicological Information Center, Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
Norwegian CBRNE Centre of Medicine, Department of Acute Medicine, Division of Medicine, Oslo University Hospital, Oslo, Norway.


Methanol mass poisoning is a global problem with high fatality rates and often severe sequelae in survivors. Patients typically present late to the hospital with severe metabolic acidosis followed by a rapid deterioration in their clinical status. The hypothesis 'Circulus hypoxicus' describes the metabolic acidosis following methanol poisoning as a self-enhancing hypoxic circle responsible for methanol toxicity. We wanted to test the validity of this hypothesis by an observational study based on 35 patients from the methanol outbreaks in Norway (2004) and the Czech Republic (2012). Comprehensive laboratory values, including S(serum)-methanol, S-formate, S-lactate, arterial blood gases, anion and osmolal gaps, were used in the calculations. Laboratory values and calculated gaps were compared to each other using linear regression. S-lactate and S-formate correlated better with the increased base deficit and anion gap than did S-formate alone. Base deficit rose to about 20 mmol/L and S-formate rose to 12 mmol/L prior to a significant rise in S-lactate - most likely caused by formate inhibition of mitochondrial respiration (type B lactacidosis). The further rise in S-lactate was not linear to S-formate most likely due to the self-enhancing pathophysiology, but may also be associated with hypotension in critically ill patients and variable ethanol drinking habits. Our study suggests that the primary metabolic acidosis leads to a secondary lactic acidosis mainly due to the toxic effects of formate. The following decline in pH will further increase this toxicity. As such, a vicious and self-enhancing acidotic circle may explain the pathophysiology in methanol poisoning, namely the 'Circulus hypoxicus'.

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