Nephrology Hypertension

Pharmacology and Toxicology: Treatment of Poisons - Methanol Intoxication

Does this patient have methanol intoxication?

Descripton of the problem

Methanol is a highly toxic alcohol that is found in a variety of commercial products, including antifreeze, windshield wiper fluid, some racing car fuels, paint thinner, and canned solid fuel for keeping food warm. There were 10 reported deaths from 1958 exposures to methanol in 2009 (Figure 1). The estimated minimum lethal dose for adults is approximately 15 – 30 ml. There are also reports of patients surviving ingestions greater than 400 ml without sequelae.

Figure 1.

Exposures and fatalities that are substantially removable by extracorporeal techniques.

Signs and symptoms

Figure 2 lists the important findings in methanol intoxication. Most of the clinical effects of methanol intoxication are due to the accumulation of formate. Before it is metabolized, methanol’s major effect is to cause central nervous system depression. This is of short duration and is followed by a latent period. The latent period, which lasts 14 to 18 hours, is due to the time it takes for alcohol dehydrogenase to metabolize methanol to formate and for formate to accumulate. The latent period will be prolonged with ethanol co-ingestion or with fomepizole treatment.

Figure 2.

Clinical effects of methanol intoxication.

The latent period is followed by a number of systemic findings as formate accumulates. The prognosis in methanol intoxication depends on the existence of the effects of the formate accumulation and patients who present with severe acidosis, seizure or coma due to the formate have an increased mortality as compared to patients without these signs on presentation. Metabolic acidosis can be severe and a pH < 7.0 has been found to be the strongest predictor of mortality. Patients with a pH < 7.0 have 20 times the mortality as compared to patients with pH > 7.0.

Central nervous system (CNS) effects in this stage can include headache, lethargy, convulsions, delirium and coma. Autopsy studies of patients who die from methanol intoxication show that the central nervous system is very susceptible to the toxic effect of methanol. Pathologic changes found on autopsy included cerebral edema, cerebral hemorrhage and hemorrhagic necrosis were found in a majority of patients. Patients who present with seizure or coma have over 10 times the mortality as patients without these symptoms. Serum methanol levels have very little prognostic value for either permanent visual changes or death.

Most of the long term morbidity due to methanol intoxication is related to the toxic effect on the retina and CNS. These pathologic changes tend to persist long after the toxic ingestion. Ocular findings can be prominent and may include photophobia, central scotoma, visual field defects, fixed pupils and difficulty with light adaptation. Pupillary dysfunction has also been shown to be a strong predictor of mortality.

The CNS effects can include bilateral hemorrhagic necrosis of the putamen with blindness, coma or death. Sudden death has occurred due to cerebral edema following hemorrhage and a number of authors have proposed that heparin used in dialysis may increase this risk. Patients that survive may develop a Parkinsonian-like syndrome or a polyneuropathy as a late sequelae of the intoxication and these consequences of intoxication are likely to persist long term. Other systemic findings can include nausea, vomiting, diaphoresis and abdominal pain. The abdominal pain may be due to pancreatitis.

What tests to perform?

Laboratory abnormalities

Fundoscopic signs can include hyperemia, disk edema and optic atrophy. The ocular findings are due to the direct cytotoxic effect of formate on the retina

Anion gap

The most prominent laboratory abnormality in methanol intoxication is an anion gap acidosis. The acidosis is due to the accumulation of formate from the metabolism of methanol and an increase in the production of lactate (see Figure 3). As stated above, a severe acidosis (i.e., pH < 7.0) suggests a late presentation of a potentially lethal ingestion and is the strongest predictor of mortality. A patient who presents early after an ingestion or later after an co-ingestion with ethanol, may have little or no acidosis making the diagnosis of methanol intoxication much more difficult. These same patients receive the most benefit from alcohol dehydrogenase inhibition since the ingested methanol still needs to be metabolized to formate to have its toxic effect. These patients tend to have a much better prognosis.

Figure 3.

Metabolism of methanol to its toxic intermediates.

Osmolar gap

Methanol also produces an osmolar gap. A serum level of 32 mg/dL increases the measured serum osmolarity by 10 mOsm/kg and the serum methanol level can be estimated by multiplying the osmolar gap by 3.2 (Figure 4). A high serum methanol level should therefore cause a gap between the calculated serum osmolarity and the measured osmolarity by freezing point depression.

However, patients with methanol intoxication may have a normal gap (< 10 mOsm/kg) if they present late after ingestion and the methanol has been converted to formate. Formate does not contribute to the serum osmolarity because it is balanced by sodium, which is included in the calculated osmolarity. For this reason, the osmolarity gap should be used to help support the diagnosis of methanol intoxication but it is not sensitive enough to rule out intoxication when there is no gap.

Figure 4.

Osmolar contribution of various toxins and drugs.

How should patients with methanol intoxication be managed?

Diagnosis

Estimating serum levels in methanol intoxication

As discussed above, the alcohols will produce an osmolar gap when they are present in the serum in significant amounts. Although there are some cautions to be noted with its use, the osmolar gap can be used to estimate the serum concentration of the alcohols. If one keeps in mind that the osmolar gap may have fairly low specificity and sensitivity for the detection of alcohol intoxication due to variations in the normal gap in the general population, it can be helpful as a rapid way to estimate serum levels of the intoxicant. It should not be used as the sole criteria for deciding a treatment strategy in the case of a possible intoxication with one of the alcohols but it can be useful when other clinical data support the diagnosis Figure 4 describes the use of the osmolar gap to estimate the serum level of the alcohol intoxicant. An increase in the osmolar gap of 10 mOsm/L would be expected to be caused by a concentration of the drug listed in the table. For example, if methanol were to cause an increase in the osmolar gap of 10 mOsm/L then the expected concentration of methanol would be 32 mg/dL. To estimate the concentration of the agent listed, the osmolar gap divided by 10 is multiplied by the factor listed in the table for the specific alcohol.

It is important to remember that a low gap does not always imply a low risk of intoxication. First, the gap will underestimate serum levels in some people who start out with a low serum osmolarity. Secondly, the gap will fall as the alcohol is metabolized and in the case of ethylene glycol and methanol, the metabolites are toxic and therefore a patient with a low gap may still have an indication for aggressive therapy including dialysis.

Emergency management

Supportive treatment

Supportive treatment formethanol intoxication includes airway protection, circulatory support,correction of metabolic abnormalities, and control of seizures.Bicarbonate is indicated for patients with a pH < 7.3. The use offolate has not been rigorously studied in humans but has been shown toincrease the metabolism of formate to carbon dioxide and water inanimals. It can be given as a 50 mg intravenous dose every 4 hours for 5doses then once a day. Symptomatic patients should be given one dose of1 mg/kg of folinic acid intravenously.

Bicarbonate therapy

Bicarbonate based intravenous fluids should be given to all patients with acidosis due to methanol intoxication unless there is a contraindication to the volume. The use of bicarbonate based fluids may help patients in two ways. Often, patients will present with some degree of volume depletion and volume replacement will help maintain kidney function and allow for renal clearance of methanol and formate. Bicarbonate is also indicated for patients with pH < 7.3 to help correct the acidosis.

The correction of the acidosis will decrease the ratio of formic acid to formate. Formic acid likely has the greater toxic effect on mitochondrial cytochrome oxidase than formate. Therefore, in acidosis, the increased ratio of formic acid to folate contributes to the drop in serum pH by promoting lactate production. As compared to formate, formic acid also has a greater toxic effect on CNS and ocular tissue due to its ability to cross the cell membrane. A few studies have seen a correlation between improvement in ocular and CNS toxicity and correction of the acidosis in methanol intoxication.

Treatment

Ethanol

Ethanol has been used as an inhibitor of alcohol dehydrogenase in methanol intoxication for 50 years but has not been approved by the FDA. The standard loading dose of ethanol is 0.6 g/kg followed by a constant infusion to keep the blood ethanol level between 100 and 200 mg/dl. The average maintenance dose of ethanol is 100 mg/kg/hr but is significantly higher for alcoholics and must also be increased while the patient is on dialysis. Blood ethanol levels should be checked every 1 – 2 hours until a steady state has been reached and then every 2 to 4 hours (Figure 6). The potential adverse effects of ethanol include central nervous system depression, hypoglycemia, respiratory depression and aspiration.

Figure 5.

Indications for fomepizole or ethanol therapy in methanol or ethylene glycol intoxication.

Figure 6.

Ethanol dosing in methanol and ethylene glycol intoxication.

Fomepizole

Fomepizole should be given at a loading dose of 15 mg/kg followed by 10 mg/kg every 12 hours for 48 hours. After 48 hours, the dose should be increased to 15 mg/kg every 12 hours. Fomepizole should be continued until the serum methanol level is < 20 mg/dl and the patient is asymptomatic with a normal serum pH. Fomepizole is removed with dialysis and therefore needs to be dosed every 4 hours during dialysis (Figure 7).

Conclusions

Figure 7.

Fomepizole dosing in methanol and ethylene glycol intoxications.

Inhibition of alcohol dehydrogenase – ethanol and fomepizole

The main objective oftreatment of methanol intoxication is to limit the accumulation offormate. This is achieved by inhibiting alcohol dehydrogenase witheither ethanol or fomepizole. Both have been shown to slow themetabolism of methanol to formate. One of these two antidotes should beused as soon as possible to prevent the production of formate.Indications for the use of either ethanol or fomepizole include a serumlevel > 20 mg/dL, a high osmolar gap after ingestion of methanol or ahigh index of suspicion for methanol intoxication in a critically illpatient (Figure 5).

The dose of both inhibitors of alcohol dehydrogenase has to be increased during dialysis.

Fomepizole may be the preferred antidote in methanol intoxication because levels do not need to be followed, it has fewer side effects, does not cause further sedation and it has a much simpler dosing scheme both with and without concurrent dialysis. Finally, because of the low side effect profile, some patients treated with fomepizole may not need observation in an intensive care unit if they are otherwise stable without significant acidosis. Other studies have found an increase in cost with the use of fomepizole and recommend the use of ethanol when feasible. With either antidote, the treatment should be continued until the methanol level is undetectable or both symptoms and acidosis resolve and the level is < 20 mg/dL.

Hemodialysis

Methanol like the rest of the alcohols, (e.g, ethyl alcohol, ethylene glycol, and isopropyl alcohol) all have drug characteristics that allow for rapid removal with hemodialysis. They all have low molecular weights, are hydrophilic, have small Vd and rapidly equilibrate with the intravascular space. The drug characteristics of these compounds are listed in Figure 8. Ethanol toxicity usually does not require hemodialysis because most patients will recover with supportive measures alone.

Figure 8.

Characteristics of drugs and toxins that are amenable to removal with extracorporeal therapy.

Estimating dialysis time

Like all of the alcohols, methanol has a small Vd and rapid equilibration with the vascular space, its elimination therefore closely follows first order kinetics during dialysis.

The elimination of all the alcohols will follow the formula for first order kinetics:

C1/C0 = e-kt/V

If we determine a final concentration C1 that we want to achieve, we can solve for the time required for dialysis to achieve this final concentration:

t (min) = - ln (C1 /C0) x Vd(L) / k (L/min)

As an example, if a 100 Kg man has an methanol ingestion with a level of 80 mg/dL and we want to perform dialysis with a membrane that can deliver a k = 0.3 L/min until his level is less than 20 mg/dL then

t = - ln ( 20/80) 60 L / 0.3 L/min = 277 min = 4 hrs 37 min

It is important to note that this estimation does not take into account endogenous clearance of the alcohol and therefore will overestimate the time needed if the patient has significant renal clearance.

Indications

Hemodialysis will remove both methanol and formic acid efficiently and will help correct the acidosis seen in methanol intoxication. It should be considered in any patient with severe acidosis or other refractory metabolic disturbance, high formate levels, seizures, visual changes, funduscopic abnormalities or mental status changes (Figure 9). The traditional indication for dialysis was a methanol level > 50 mg/dL. However, with the availability of fomepizole, a less toxic antidote as compared to ethanol and since the serum methanol level has not been linked to permanent visual changes or death, some authors have argued that a high methanol level alone is no longer an indication for dialysis if no other indication for dialysis is present. Withholding dialysis in patients with a high methanol level should only be considered if all of the following conditions are met:

Figure 9.

Indications for dialysis in patients with ethylene glycol intoxication.

Hemodialysis can hinder the maintenance of adequate ethanol levels and a number of authors have described the use of ethanol enriched dialysate solutions. Hemodialysis should be continued until the serum methanol level is undetectable or the patient has a normal serum pH and a level < 20 mg/dL. If a rapid method for determining the methanol level is not available, the osmolar gap can be used as a surrogate level and in that case, dialysis should be performed until the gap drops to normal.

In cases of very high methanol levels treated with high-efficiency dialysis, there may be a small rebound (< 20 mg/dL). For this reason, the alcohol dehydrogenase inhibitor should be continued for a few hours after the termination of dialysis and the methanol level should be rechecked. See estimating dialysis time for alcohol intoxication above for an example of how to approximate the necessary dialysis time.

1. The patient is receiving fomepizole.

2. The patient is clinically stable, awake and alert.

3. The patient has normal kidney function.

4. The serum bicarbonate and anion gap are normal.

5. There is no evidence of end organ damage such as visual or fundiscopic changes.

Patients with a high methanol level that are not treated with dialysis should be watched closely for the development of acidosis or vision changes that would indicate the need for urgent dialysis.

Details on the dialysis prescription

Clearance constants with high efficiency membranes have been as high as 250 ml/min for both formate and methanol. The dose of both ethanol and fomepizole need to be increased during hemodialysis.

Complications

There are a couple of important possible complications of hemodialysis in methanol intoxication. The most drastic complication is brain hemorrhage. This risk may due to the combination of the bilateral cerebral ischemia of the basal ganglia that can arise from formate toxicity and the use of heparin during dialysis. It is not clear whether avoidance of heparin during dialysis would decrease the risk of brain hemorrhage but caution is warranted in the use of heparin in methanol intoxication.

Hypophosphatemia is a fairly common complication of prolonged hemodialysis for methanol intoxication. Phosphate can be given peripherally or a phosphate enriched dialysate may be used. As stated above, hemodialysis can lead to inadequate alcohol dehydrogenase inhibitor levels if the dose of the antidote is not increased during therapy.

What is the evidence?

Abramson, S, Singh, AK. "Treatment of the alcohol intoxications: ethylene glycol, methanol and isopropanol". Current Opinion in Nephrology & Hypertension,. vol. 9. 2000. pp. 695-701.

Kraut, JA, Kurtz, I. "Toxic alcohol ingestions: clinical features, diagnosis, and management". Clinical Journal of The American Society of Nephrology:CJASN. vol. 3. 2008. pp. 208-225.

Lynd, LD, Richardson, KJ, Purssell, RA, Abu-Laban, RB, Brubacher, JR, Lepik, KJ, Sivilotti, ML. "An evaluation of the osmole gap as a screening test for toxic alcohol poisoning". BMC Emergency Medicine. vol. 8. 2008. pp. 5.

Hunderi, OH, Hovda, KE, Jacobsen, D. "Use of the osmolal gap to guide the start and duration of dialysis in methanol poisoning ". Scandinavian Journal of Urology & Nephrology. vol. 40. 2006. pp. 70-74.

Singh, A, Samson, R, Girdha, A. "Portrait of a methanol-intoxicated brain". American Journal of Medicine,. vol. 124. 2011. pp. 125-127.

Barceloux, DG, Bond, GR, Krenzelok, EP, Cooper, H, Vale, JA. "The American Academy of Clinical Toxicology Ad Hoc Committee on the Treatment Guidelines for Methanol, P: American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning". Journal of Toxicology - Clinical Toxicology. vol. 40. 2002. pp. 415-446.

Brent, J. "Fomepizole for ethylene glycol and methanol poisoning". New England Journal of Medicine. vol. 360 . 2009. pp. 2216-2223.

Bronstein, AC, Spyker, DA, Cantilena, LR, Green, J, Rumack, BH, Heard, SE. "2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS)". Clin Toxicol (Phila). vol. 45. 2009. pp. 815-917.

Paasma, R, Hovda, KE, Hassanian-Moghaddam, H, Brahmi, N, Afshari, R, Sandvik, L, Jacobsen, D. "Risk factors related to poor outcome after methanol poisoning and the relation between outcome and antidotes--a multicenter study". Clinical Toxicology: The Official Journal of the American Academy of Clinical Toxicology & European Association of Poisons Centres & Clinical Toxicologists. vol. 50. 2012. pp. 823-31.

A more recent review of cases with severe methanol intoxication that examined the risk factors for a poor outcome. It supported earlier studies that a low serum pH remains the marker with the strongest correlation with morbidity and mortality.
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