Toxicology posts by agent
- By Dr. Hector Madariaga
Methanol kills. If you regularly read the news you may have encountered this incident that happened in Sumatra to a young British woman. In fact, Wikipedia has a list (likely not exhaustive) of methanol poisoning incidents from around the world.
The Egyptians in their embalming process used methanol. It was first isolated from boxwood in 1661 by Robert Boyle, who called it the spirit of box. It has been used since then as a solvent and chemical building block to make plastic, plywood, paint and fuel. It made its way into the Prohibition era where many people died due to wood alcohol poisoning and in recent times is associated with contamination of illicit and homemade alcohol as well as suicide attempts. It is associated with high mortality, exceeding 40% if untreated. Given the fact that Nephrology frequently gets involved in these cases, it’s good that we are informed of the latest recommendations in the management of methanol intoxication and the role of extracorporeal treatments.
Methanol has limited protein binding and a volume of distribution of 0.6–0.8L/kg. It is rapidly absorbed (less than 1 hour) and an ingestion of 30-60 mL is considered toxic. It is first metabolized by the hepatic alcohol dehydrogenase (ADH) to formaldehyde, and then to formic acid which is the toxic metabolite. It is mostly eliminated renally and has also a presumed respiratory elimination. All these processes lead to coma, seizures, new vision deficits, metabolic acidosis (pH <7.15), serum anion gap (>24 mmol/L) and if untreated, death. Hemodialysis has been used since 1960s in the treatment in methanol intoxication and given the fact that there are not randomized controls trials to prove its clinical benefit, the EXTRIP workgroup performed a systematic review on methanol intoxication and extracorporeal treatment (ECTR), specifically examining the available evidence, complications, costs and accessibility.
Methanol poisoning is eliminated (and treated) in two different ways: use of alcohol dehydrogenase inhibitors (ADH) such as fomepizole and ethanol and extracorporeal treatment. Ethanol is a competitive substrate of ADH and fomepizole is a direct inhibitor of ADH; both inhibit the formation of formic acid. Hence the early involvement of Nephrology in these cases is very important.
The EXTRIP workgroup recommended to use ECTR in the following circumstances:
1-Severe methanol poisoning: characterized by coma, seizures, new vision deficits and persistent metabolic acidosis. EXTRIP workgroup suggests to start ECTR when pH <7.15-7.2 (grade 2D recommendation) and anion gap of 20-24 (grade 2D). It was reported that a base deficit >15mmol/L did not have a role in the indication for ECTR as evidence was weak. A hemodialysis session of 4-6 hours duration is recommended and to monitor acid-base status after each session and if persistent acidemia, ECRT should be resumed.
2-Serum methanol concentration: EXTRIP workgroup recommends to start ECTR when methanol concentration is 600-700mg/mL or 18.7-21.8 mmol/L in the context of fomepizole therapy, 500-600mg/mL or 15.6-18.7 mmol/L if ethanol is being used as therapy or 400-500 mg/L or 12.5-15.6 if no alcohol dehydrogenase therapy is being considered (Grade 1D-2D). There was not good evidence for osmolar gap (OG), but it has been shown that an OG of 30 mOsm/kg h3O correlates with a methanol concentration of >900 mg/L. If methanol level is not known, an empiric treatment of 8 hours of ECTR is recommended.
3-In the setting of kidney dysfunction: Renal clearance of methanol is 5-6mL/min, following inhibition of ADH, so ECTR is recommended to accelerate methanol and formate elimination. A creatinine of >1.2 mg/dL (106 umol/L) is associated with an odds ratio of 15 for death so ECTR is indicated immediately.
Fomepizole dosing: It is given every 12 hours, EXTRIP workgroup suggests to administer a loading dose of 15mg/kg in the context of ECTR, followed by an infusion of 1–1.5mg/kg/hr, or to repeat the loading dose every 4 hours if needed.
The elimination half-life of methanol is 54 hours in the setting of ADH inhibition (2.3–13.7hr in the absence of antidote therapy). ADH inhibitors should be continued during ECTR as well as folic acid as they are dialyzable. The duration of ECTR can be predicted depending on the methanol concentration and calculating the time required to reach <200mg/mL by using an elimination half-life of 3 hours. Continued therapies such as continuous veno-venous hemofiltration (CVVH) are also recommended by the EXTRIP group although evidence is very limited with a suggested duration of at least 18 hours for toxin elimination. Using systemic anticoagulation is not recommended. ECTR can be discontinued when methanol concentration is <200 mg/L or 6.2 mmol/L.
In regards to timing of ECTR, if ADH therapy is immediately available, ECTR does not need to be initiated urgently and it can be started at a later time based on the methanol concentration and/or once patient is transferred to a facility with ECTR. There was limited evidence of the use of peritoneal dialysis.
It has yet to be proven that formic acid is eliminated through ECTR and whether it improves clinical outcomes in comparison to ADH therapy. In conclusion, the EXTRIP group supports the use of ECTR in cases of methanol poisoning, with some specific guidance provided about the timing.
About the author
Hector M. Madariaga, MD (@hecmagsmd) is currently a Transplant Nephrology Fellow at the University of Maryland in Baltimore, MD. He is a graduate of the #NSMC Internship and regularly blogs at the Renal Fellow Network