Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Alcohol, methyl
2) Carbinol
3) Colonial spirit
4) Columbian spirit(s)
5) Methyl alcohol
6) Methyl hydroxide
7) Methylol
8) Monohydroxymethane
9) Purple lady (slang term)
10) Pyroxylic spirit
11) Wood alcohol
12) Wood naphtha
13) Wood spirit
14) CAS 67-56-1
15) COHOL METILICO (SPANISH)
16) COLUMBIAN SPIRIT
17) FORMALDEHYDE SOLUTIONS, FLAMMABLE
18) FORMALIN SOLUTION
19) METANPLO
20) METHANAL (FORMALDEHYDE)
21) METHYLENE GLYCOL (CAS 50-00-0)
22) METHYLESTER KISELINY OCTOVE (CZECH)
23) TETRAOXYMETHYLENE
24) TRIOXANE

1.2.1) MOLECULAR FORMULA
1) CH4O

Available Forms Sources

A)

1) Methanol is the simplest of the primary alcohols and is a colorless, highly polar, flammable liquid. Pure methanol has a faintly sweet odor at ambient temperatures; crude methanol may have a repulsive, pungent odor (AAR, 2000; ACGIH, 1991; Bingham et al, 2001; Budavari, 2000; Lewis, 2001; Lewis, 1998; Lewis, 2000).

B)

1) Methanol is a volatile emission product from plants and is also naturally formed during the decomposition of biological waste, sewage, and sludge. Artificially, methanol is primarily released to the environment by evaporation from its use as an industrial solvent. Lesser emission releases also occur from methanol production, end product manufacturing, storage and handling, and as a component of gas and diesel emissions (Howard, 1990).
2) Small amounts of methanol are produced endogenously by normal metabolism. Methanol occurs in, or is metabolically produced from fruits and is found in "hard" liquors (Lindinger et al, 1997; Taucher et al, 1995).
3) HOME DISTILLATION OF METHYLATED SPIRITS: A common source of methanol intoxication is home distillation of methylated spirits. Some methylated spirits contain approximately 90% ethanol and 5% methanol ("purple lady"), which can produce classical signs of severe methanol poisoning (Foley & Rogers, 1999; Meyer et al, 2000).
4) Romanian Tuica (pronounced Tsweeka), is a sweet-tasting, clear alcohol made from locally available fruits (eg; plums, apples). It has been responsible for several cases of lethal methanol toxicity. In one study, 26 of 35 Tuica samples (74%) contained detectable methanol levels (mean level, 0.66 g/dL; range, 0.06 to 8.6 g/dL) (Levy et al, 2003).
5) Chang'aa (or kill me quick) is a brewed bootleg alcohol in Kenya. Because of its methanol content, it is believed to be responsible for hundreds of deaths each year (Levy et al, 2003)
6) FIRE EATING: A man developed irreversible bilateral blindness following an accidental ingestion of small amounts of methanol during fire "eating" (Cursiefen & Bergua, 2002).
7) METHYL ACETATE IN NAIL POLISH REMOVERS

a) Many manufacturers of non-acetone nail polish removers have recently changed their formulations from ethyl acetate to methyl acetate. In acidic environments, methyl acetate is hydrolyzed to methanol and acetic acid. One retrospective study evaluated 83 cases of exposure to these methyl acetate-containing nail polish removers; 75 patients were 5 years and younger; 4 children were 6 years and older; 4 patients were adults. In most cases, the amount of nail polish remover ingested was unknown, and only 11 (13%) patients ingested more than a mouthful. Four adults ingested "a mouthful" to 150 mL of non-acetone nail polish removers. Overall, 75% (n=62) of patients were referred to a healthcare facility; 75% did not develop any effects. Minor effects developed in 25% of cases and these effects included vomiting (n=12; 14%), throat/oral irritation (n=5; 6%), drowsiness (n=1; 1.2%), abdominal pain (n=1; 1.2%), and ataxia (n=1; 1.2%). A 2-year-old boy developed mild metabolic acidosis after ingesting about 12 mL of Fung-off No Lift fungal liquid for nails. He recovered following supportive care (Minns et al, 2013).

C)

1) Methanol is widely used in paint, varnish removers and as an industrial solvent. It is also used in the manufacture of formaldehyde, acetic acid, methyl derivatives and inorganic acids; as an antifreeze, fuel anti-icing additive, and fuel octane booster; an ethanol denaturant; an extraction agent; an extractant solvent; and as fuel for picnic stoves and soldering torches. Methanol is further used as a solvent in the manufacture of cholesterol, streptomycin, vitamins, hormones, and other pharmaceuticals (ACGIH, 1991; Ashford, 2001; Bingham et al, 2001; Budavari, 2000; Lewis, 2001; Lewis, 1998).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: One of the toxic alcohols that is found in windshield wiper fluid, gas line antifreeze, fuels, photocopy fluid, solvents, carburetor cleaner, and as an adulterant in homemade ethanol distillates.
B) TOXICOLOGY: An alcohol that causes intoxication similar to ethanol and is metabolized to formaldehyde and formic acid via alcohol dehydrogenase and aldehyde dehydrogenase, respectively. Formic acid causes a metabolic acidosis and causes blindness through direct retinal toxicity. Toxicity is most common after ingestion but has been reported with inhalation and dermal exposures.
C) EPIDEMIOLOGY: Uncommon exposure that can result in significant morbidity and mortality.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Patients will initially have signs of acute intoxication, such as ataxia, sedation, and disinhibition. Patients may also complain of abdominal pain, nausea, vomiting, and headache. Acidosis or signs of visual impairment suggest a more severe poisoning.
2) SEVERE TOXICITY: Severe metabolic acidosis develops hours after exposure (if ethanol is not coingested) and may lead to multiorgan dysfunction including hypotension, tachycardia, dysrhythmias, seizures, coma, pancreatitis, and acute renal failure. Rhabdomyolysis may occur in severe poisonings. Hypomagnesemia, hypokalemia, and hypophosphatemia have also been reported. In addition, ocular toxicity may develop; manifestations include mydriasis, hyperemic optic discs, and papilledema. Visual impairment may develop, which may range from blurry/hazy vision to color vision defects to "snowfield" vision to total blindness. Permanent sequelae after severe intoxication may include basal ganglia necrosis with parkinsonian features (ie, tremor, rigidity, bradykinesia) and blindness.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Mild tachycardia is common with significant poisoning. Tachypnea secondary to metabolic acidosis is common.

0.2.20)

A) Methanol, together with other solvents, has been linked with birth defects of the central nervous system in humans (Holmberg, 1979), but methanol cannot be considered a human reproductive hazard, because of mixed or poorly documented exposures.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Obtain a methanol level, serum chemistry, and a serum pH. A thorough visual exam should be performed, including visual acuity. An elevated osmolar gap suggests the presence of methanol or another alcohol but cannot be used to rule out a significant exposure. If a methanol concentration is readily available (results known within 2 hours) and the patient is asymptomatic, then alcohol dehydrogenase (ADH) inhibition can be delayed until the methanol concentration is available. Patients with a methanol concentration of more than 25 mg/dL or metabolic acidosis should be treated with ADH inhibition. If methanol concentrations cannot readily be measured, patients with a history of a potentially toxic ingestion, symptomatic patients, and those with suspected methanol intoxication with an anion gap metabolic acidosis or an osmolal gap greater than 10 mOsm should be treated with ADH inhibition. Folate should also be intravenously administered to patients requiring ADH inhibition. In patients who receive ADH inhibition who have a significant methanol concentration, consider hemodialysis since the apparent half-life of methanol under these circumstances is quite prolonged.

B) MANAGEMENT OF SEVERE TOXICITY

1) Patients presenting with severe acidosis, signs or symptoms of visual changes, or depressed level of consciousness should be started immediately on an ADH inhibitor and intravenous folate. Hemodialysis should be initiated and should be continued until the methanol concentration is undetectable and the serum pH is normal. Treat seizures with benzodiazepines.

C) DECONTAMINATION

1) PREHOSPITAL: There is no role for prehospital decontamination.
2) HOSPITAL: In general, gastrointestinal decontamination is not very useful because methanol is rapidly absorbed and binds poorly to activated charcoal. Insertion of a nasogastric tube to aspirate gastric contents may be useful in rare patients who present shortly after large ingestions.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation may be necessary in patients with significant CNS or respiratory depression. Extreme care must be taken to increase minute ventilation sufficiently to prevent severe acidemia in intubated patients.

E) ANTIDOTE

1) Treat patients with either fomepizole or ethanol to prevent the production of formate. Indications include documented plasma methanol concentration greater than 20 mg/dL (greater than 200 mg/L) OR documented recent history of ingesting toxic amounts of methanol and osmolal gap greater than 10 mOsm/L OR history or strong clinical suspicion of methanol poisoning with at least 2 of the following criterion: arterial pH less than 7.3; serum bicarbonate less than 20 mEq/L; osmolol gap greater than 10 mOsm/L.

a) FOMEPIZOLE VS ETHANOL: Fomepizole is easier to use clinically, requires less monitoring, does not cause CNS depression or hypoglycemia, and may obviate the need for dialysis in some patients. Ethanol requires continuous administration and frequent monitoring of serum ethanol and glucose levels and may cause CNS depression and hypoglycemia (especially in children). The drug cost associated with ethanol use is generally much lower than with fomepizole; however, other costs associated with ethanol use (eg, continuous intravenous infusion, hourly blood draws, nursing costs, and ethanol levels, possibly greater use of hemodialysis) may make the costs more comparable.
b) FOMEPIZOLE: Fomepizole is administered as a 15 mg/kg loading dose, followed by 4 bolus doses of 10 mg/kg every 12 hours. If therapy is needed beyond this 48-hour period, the dose is then increased to 15 mg/kg every 12 hours for as long as necessary. Fomepizole is also effectively removed by hemodialysis; therefore, doses should be repeated following each round of hemodialysis.
c) ETHANOL: Ethanol is given to maintain a serum ethanol concentration of 100 to 150 mg/dL. This can be accomplished by using a 5% or 10% ethanol solution administered intravenously through a central line. Intravenous therapy dosing, which is preferred, is 0.8 g/kg as a loading dose (8 mL/kg of 10% ethanol) administered over 20 to 60 minutes as tolerated, followed by an infusion rate of 80 to 150 mg/kg/hr (for 10% ethanol, 0.8 to 1.3 mL/kg/hr for a nondrinker; 1.5 mL/kg/hr for a chronic alcoholic). During hemodialysis, either add ethanol to the dialysate to achieve 100 mg/dL concentration or increase the rate of infusion during dialysis (10% ethanol, 2.5 to 3.5 mL/kg/hr). Oral ethanol may be used as a temporizing measure until intravenous ethanol or fomepizole can be obtained, but it is more difficult to achieve the desired stable ethanol concentration. The loading dose is 0.8 g/kg (4 mL/kg) of 20% {40 proof}) ethanol diluted in juice administered orally or via nasogastric tube. Maintenance dose is 80 to 150 mg/kg/hr (20% {40 proof}) ethanol; 0.4 to 0.7 mL/kg/hr for a nondrinker; 0.8 mL/kg/hr for a chronic alcoholic). Concentrations greater than 30% (60 proof) ethanol should be diluted. For both modalities, blood ethanol levels must be monitored hourly and adjusted accordingly, and both require patient monitoring in an ICU setting.
d) FOLATE: Folate increases the metabolism of formate. Either folic acid or leucovorin (folinic acid) may be used. In symptomatic patients (anion gap acidosis, visual disturbances) and asymptomatic patients with known or suspected methanol intoxication, administer intravenous folic acid 1 to 2 mg/kg every 4 to 6 hours for the first 24 hours, and continue until methanol is cleared and acidosis resolved. Folate is removed by hemodialysis so in patients undergoing hemodialysis, administer one dose prior to and another at the completion of hemodialysis.

F) ENHANCED ELIMINATION

1) Methanol and its metabolites (formaldehyde and formic acid) are readily removed by hemodialysis. Emergent hemodialysis is indicated in any methanol-intoxicated patient with an anion gap metabolic acidosis (pH less than 7.3), visual disturbances, or CNS depression. Because methanol is cleared very slowly once ADH inhibitors are administered, hemodialysis should also be considered in patients with methanol concentrations greater than 50 mEq/L, even in the absence of acidosis or severe symptoms.

G) PATIENT DISPOSITION

1) OBSERVATION CRITERIA: Intentional ingestions should be evaluated in a health care facility. Potential serum levels can be calculated using methanol percentage, amount ingested, and patient weight and all levels potentially greater than 25 mg/dL should be evaluated in a health care facility.
2) ADMISSION CRITERIA: Patients who are acidotic, have visual symptoms, or have serum methanol concentrations above 25 mg/dL should be admitted.
3) CONSULT CRITERIA: Consult a poison center or medical toxicologist in cases of severe poisonings, in cases where a methanol level is not readily available, or in cases where the ingestion is uncertain. Consult a nephrologist for any patient who may require hemodialysis.

H) PITFALLS

1) Depending on the timing of the presentation, an increased osmolar gap or an increased anion gap may not always be present. An increased anion gap will not be present in patients presenting early, and an increased osmol gap may not be present in patients presenting late. When calculating osmolarity, the ethanol level needs to be taken into account in the calculation. A normal osmolal gap does not rule out the possibility of methanol intoxication. Patients who are ethanol intoxicated will have a later presentation of their acidosis, as the ethanol is effectively blocking the metabolism of the methanol.

I) PHARMACOKINETICS

1) Methanol is rapidly and readily absorbed. The apparent half-life of methanol is approximately 8 to 28 hours. The volume of distribution is approximately 0.6 L/kg. It is not protein bound.

J) TOXICOKINETICS

1) When alcohol dehydrogenase inhibitors are being used, the apparent half-life is increased to approximately 50 hours.

K) DIFFERENTIAL DIAGNOSIS

1) Exposure to other alcohols, such as ethanol, ethylene glycol, isopropyl alcohol, and other glycol ethers. A broad variety of other toxins and medical causes can also result in a metabolic acidosis.

0.4.3)

A) Intentional inhalational exposures can result in significant methanol levels and should be treated similarly to oral ingestions.
B) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) Rarely has repeated dermal exposure resulted in severe methanol toxicity. It should be treated similarly to an ingestion exposure.
2) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) MILD TO MODERATE TOXICITY: Patients will initially have signs of acute intoxication, such as ataxia, sedation, and disinhibition. Patients may also complain of abdominal pain, nausea, vomiting, and headache. Acidosis or signs of visual impairment suggest a more severe poisoning.
2) SEVERE TOXICITY: Severe metabolic acidosis develops hours after exposure (if ethanol is not coingested) and may lead to multiorgan dysfunction including hypotension, tachycardia, dysrhythmias, seizures, coma, pancreatitis, and acute renal failure. Rhabdomyolysis may occur in severe poisonings. Hypomagnesemia, hypokalemia, and hypophosphatemia have also been reported. In addition, ocular toxicity may develop; manifestations include mydriasis, hyperemic optic discs, and papilledema. Visual impairment may develop, which may range from blurry/hazy vision to color vision defects to "snowfield" vision to total blindness. Permanent sequelae after severe intoxication may include basal ganglia necrosis with parkinsonian features (ie, tremor, rigidity, bradykinesia) and blindness.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Mild tachycardia is common with significant poisoning. Tachypnea secondary to metabolic acidosis is common.

3.3.2)

A) WITH POISONING/EXPOSURE

1) Tachypnea secondary to metabolic acidosis is common (Bennett, 1953; Carpentieri et al, 2003; Adanir et al, 2005).

3.3.3)

A) WITH POISONING/EXPOSURE

1) Hypothermia may develop in patients with prolonged coma and exposure to a cold environment (Figueras Coll et al, 2008).

3.3.4)

A) WITH POISONING/EXPOSURE

1) Blood pressure usually remains within normal limits until the terminal state is reached, when refractory hypotension occurs.
2) Trauma patients with other causes of hypotension should have a serum methanol level performed if acidemia persists after correction of hypotension or if acidemia appears to be out of proportion to the degree of hypotension (Saxena et al, 1987).
3) CASE REPORT: Hypotension (90/60 mmHg) was reported in a 52-year-old woman following percutaneous methanol absorption resulting from frequent topical application, to her extremities, of methanol-containing cologne and spirits (Adanir et al, 2005).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Mild tachycardia is common with significant poisoning (Figueras Coll et al, 2008; Carpentieri et al, 2003; Adanir et al, 2005).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) TRANSIENT ABNORMALITIES: Transient visual abnormalities that develop during acute methanol intoxication may include blurred or double vision, changes in color perception, constricted visual fields, spots before the eyes, and sharply reduced visual acuity (Ingemansson, 1984; Kinney & Nauss, 1988).

a) INCIDENCE

1) CASE SERIES: In a chart review of methanol poisonings (n=113) reported to a poison center, visual symptoms were reported in 24 cases (21.2%) (Kalkan et al, 2003).
2) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, 62% of patients had blurred vision with blindness in 10.5%. Normal fundus examination was observed in 34.3% of patients. Bilateral hyperaemia of discs, bilateral disc pallor, and papilledema were found in 52.8%, 8.4%, and 4.5% of patients, respectively. Overall, these patients had higher mean methanol concentrations (121.1 +/- 32.2 mg% versus 70.1 +/- 23.2 mg%, p =0.032) than patients with normal fundus examination (Jarwani et al, 2013).

b) CASE REPORT: A 6-month-old infant experienced temporary blindness with pale optic discs after long-term inhalation exposure to methanol from a lamp next to the crib. After the lamp was removed, the child recovered fully (Posner, 1975).
c) Temporary concomitant ocular defects are peripapillary edema, hyperemia of the optic disc, diminished pupillary light reactions, and central scotomata (Grant & Schuman, 1993).

2) SNOWFIELD BLINDNESS EFFECT: Visual abnormalities may be delayed in onset for several hours or days following acute ingestion. A whiteness in the visual field, "like stepping out into a snowfield" has been described (Becker, 1981; Williams et al, 1997).
3) IRRITATION: Direct methanol eye contact produces mild, reversible irritation, assuming treatment is initiated promptly (Grant & Schuman, 1993).
4) PERMANENT DEFECTS: Permanent ocular abnormalities may include pallor of the optic disc, attenuation and sheathing of retinal arterioles, a diminished pupillary light reaction, reduced visual acuity, central scotomata, and defects of optic nerve fiber bundles (Naeser, 1988; Sharma et al, 1999).

a) Permanent blindness due to toxic effects of the methanol metabolite on the retina and optic nerve may occur. Fixed, dilated pupils on initial presentation following ingestions are an ominous sign of severe vision loss (Sullivan-Mee & Solis, 1998). Permanent blindness may ensue. Pupillary status may provide prognostic information for both morbidity and mortality. In 1 fatal case of methanol intoxication, electrophysiologic and morphologic changes showed evidence that the human retina is a site of direct toxicity (Treichel et al, 2004).
b) INCIDENCE: The incidence of permanent visual defects is directly correlated with the degree of metabolic acidosis, with the volume of methanol consumed, delay in treatment, the pupillary response at presentation (Dethlefs & Naraqi, 1978; Liu et al, 1998; Yang et al, 2005), and the concentration of formate (Martin-Amat et al, 1978).
c) ELECTRORETINOGRAPHIC STUDIES: In 2 cases of human methanol poisoning with visual disturbance, normal pupil response, and normal color plate response revealed generally depressed retinal sensitivity, cone flicker response, and alpha- and beta- waveforms (McKellar et al, 1997).
d) MECHANISM: The pathologic consequences in the eye may be caused by formate inhibition of cytochrome oxidase in the optic nerve (Becker, 1981; Haines, 1987; Sullivan-Mee & Solis, 1998). Cytotoxic effects of formate within the retrolaminar optic nerve, retina, or both are usually apparent 24 hours postinsult (Sullivan-Mee & Solis, 1998).

1) Inhibition of formate formation using disulfiram prevents retinal toxicity in rats (Garner et al, 1995).

e) CASE REPORT: A 28-year-old man developed blurred vision and motor dysfunction including rigidity and hypokineses approximately 10 hours after ingesting methanol. Five months after presentation, he still experienced visual and extrapyramidal symptoms. Neurological and eye examinations of another patient with methanol poisoning (a 50-year-old man) showed extrapyramidal signs and diminished reflexes, and 6/36 vision. Fundus examination revealed a blurred disc margin and hyperemic spots on the retina (Arora et al, 2007).
f) CASE REPORT: A 19-year-old man developed irreversible bilateral blindness following an accidental ingestion of small amounts of methanol during fire "eating" (Cursiefen & Bergua, 2002).
g) Hayasaka et al (2000) reported NO significant differences in serum methanol levels (range, 0.12 to 3.86 mcg/mL) between patients (n=127) without optic nerve head disease and serum methanol levels (less than 3.86 mcg/mL) in patients (n=71) with optic neuritis, Wolfram syndrome, Leber hereditary optic neuropathy at late stage, retinitis pigmentosa, and primary open-angle glaucoma. The authors suggest that accumulation of formate may be responsible for optic neuropathies (Hayasaka et al, 2000).
h) CASE REPORT: Total blindness occurred in a 21-year-old male following an ingestion of methanol. He had no motor deficit in any extremities (Yu et al, 1995).
i) CASE REPORT: Severe bilateral optic neuropathy, with significant vision loss, complicated by an intraocular hypertension, is reported at 4-month follow-up in a 35-year-old man who had a 1-week history of binge alcohol drinking that included windshield wiper fluid. A persisting bilateral mydriasis and loss of red color vision were also notable (Sullivan-Mee & Solis, 1998).
j) CASE REPORT: Severe methanol-induced visual impairment (initial visual acuity less than 20/800 with retinal edema on fundoscopy; methanol level 97 mg/dL), described as end-organ retinal toxicity, was reversed following administration of intravenous fomepizole (15, 10, then 5 mg/kg) and hemodialysis. By day 14, the patient recovered 20/20 vision with normal fundoscopy (Sivilotti et al, 2001).
k) CASE REPORT: A healthy 37-year-old man who drank industrial alcohol (75% methanol, 25% ethanol) 100 mL/day for 4 days developed total blindness 7 days after the initial methanol ingestion. Serum methanol concentration on admission was 12.8 mg/dL. Peripapillary nerve fiber swelling and accumulation of intraretinal fluid were observed by optical coherence tomography (OCT) during the acute phase. Two years after the ingestion, his visual acuity was 6/200 OD and 4/100 OS, his optic discs were totally atrophic, and his retinal thickness was diffusely decreased (Fujihara et al, 2006).

5) CASE REPORT: Bilateral optical disc atrophy was reported in a 52-year-old woman following percutaneous methanol absorption resulting from frequent topical application, to her extremities, of methanol-containing cologne and spirits. A CT scan revealed frontal subcortical necrosis and bilateral lentiform nuclei hypodensity (Adanir et al, 2005).
6) CASE REPORT: A 54-year-old woman developed nausea and vomiting after wrapping her feet with methylated spirit-soaked materials (10% methanol) for 6 to 7 hours for pain relief. Two days later, she presented comatose with dilated pupils with an absent light reflex and was diagnosed with methanol toxicity. Following supportive care, she was discharged 6 days later with progressive vision loss. Two months later, fundoscopy revealed bilateral total optic atrophy. A CT scan showed symmetrical putaminal necrosis and generalized cortical atrophy (Iscan et al, 2013).
7) CASE REPORT: A 27-year-old man presented with acute headache, vomiting, abnormal behavior, and bilateral blindness 3 days after ingesting an unknown amount of methanol. A month later, he had no light perception in either eye and fundoscopy revealed bilateral optic atrophy. An MRI of the brain revealed bilateral hemorrhagic putaminal necrosis. On 4-month follow up, his vision was improved to perception of hand movements at 30 cm (Singh et al, 2013).
8) CASE REPORT: Total blindness occurred in a 49-year-old man several hours after drinking an unknown amount of homemade herbal wine. Four days following ingestion, the patient's blood methanol level was 811 mg/dL. Initial fundoscopy of both eyes revealed moderately swollen, hyperemic optic disc and dilated, unresponsive pupillary reflex. A brain MRI performed approximately 15 days postingestion showed multifocal necrosis in the bilateral putamen and frontal and occipital subcortical white matter areas as well as vasogenic brain edema. Despite aggressive supportive care, bilateral total blindness persisted. A repeat fundoscopy, 2 months postingestion, showed bilateral optic atrophy and a glaucomatous-like cupping of the optic disc indicative of extensive loss of retina ganglion cells (Yang et al, 2005).
9) CASE REPORT: Optic neuritis was reported in a 32-year-old man who consumed a large quantity of alcohol containing methanol. A CT brain scan showed bilateral lesions of the putaminal regions of the basal ganglia, as well as brain edema. With supportive treatment, the patient's visual acuity improved to 20/30; however, 6 weeks after intoxication, his distant visual acuity deteriorated to 20/200, and bilateral fundoscopy revealed bilateral pallor of the optic nerve heads. On hospital discharge, the patient's distant visual acuity was 9/200 bilaterally, and he developed optic atrophy (Bitar et al, 2004).
10) NYSTAGMUS: Vertical and rotatory nystagmus were described in 1 patient with a methanol level of 163 mg/dL (Riggs et al, 1987).
11) ANIMAL STUDIES: Hayreh (1989) studied experimental methanol poisoning in rhesus monkeys and found that the most common ocular defect was development of toxic optic neuropathy. No vascular lesions were seen in the optic nerves studied (Hayreh, 1989).

a) Electroretinographic analyses of retinas from methanol-intoxicated rats revealed a significant early deficit in beta-wave amplitude and a lesser reduction in alpha-wave amplitude. Generalized retinal edema and vacuolation in the photoreceptors and retinal pigment epithelium were reported. Swelling of the mitochondria of the photoreceptor inner segments, optic nerve, and retinal pigment epithelium was seen on ultrastructural examination (Murray et al, 1991).

Cardiovascular

3.5.2)

A) SINUS TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) Mild tachycardia is common in patients with significant poisoning (Airas et al, 2008; Vara-Castrodeza et al, 2007; Carpentieri et al, 2003; Adanir et al, 2005).
b) INCIDENCE: Early in the course of methanol poisoning, tachycardia was observed in 7 of 323 cases in 1 series (Bennett, 1953).

B) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) In fatal methanol poisoning cases, marked sinus bradycardia may develop with widening of the pulse pressure (Bennett, 1953; Kinoshita et al, 1998).

C) HEART FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe reversible cardiac failure with left ventricular dysfunction and diffuse T-wave abnormalities were described in severe methanol poisoning (Cavalli et al, 1987).
b) CASE REPORT: A patient presented to the ED 1 to 2 days postingestion of moonshine with methanol toxicity and with complaints of feeling unwell, and progressed to cardiac arrest (Smyth et al, 1997).

D) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Blood pressure usually remains within normal limits until the terminal state is reached, when refractory hypotension occurs. Severe hypotension, requiring fluid and vasopressor therapy, occurs terminally in severe methanol intoxications (Cao et al, 2016; Williams et al, 1997; Foster & Schoenhals, 1995; Kinoshita et al, 1998).
b) CASE REPORT: Hypotension (90/60 mmHg) was reported in a 52-year-old woman following percutaneous methanol absorption resulting from frequent topical application, to her extremities, of methanol-containing cologne and spirits (Adanir et al, 2005).
c) CASE REPORT: A 51-year-old woman developed severe methanol toxicity (coma, high-anion-gap metabolic acidosis, hypotension [80/60 mmHg], methanol level of 3.3 mg/dL) after repeated dermal application of methanol ("spirit") to her head. The patient's relatives denied oral ingestion of methanol-containing substances. Despite supportive treatment and hemodialysis, she died after 4 days of hospitalization (Soysal et al, 2007).

Respiratory

3.6.2)

A) DYSPNEA

1) WITH POISONING/EXPOSURE

a) Dyspnea may occur during the early stages of methanol poisoning, but is unusual (Bennett, 1953).

B) TACHYPNEA

1) WITH POISONING/EXPOSURE

a) Tachypnea secondary to metabolic acidosis is common (Vara-Castrodeza et al, 2007; Bennett, 1953; Carpentieri et al, 2003). (Adanir et al, 2005)

C) RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) Respiratory arrest may develop with severe poisoning (Bennett, 1953; Williams et al, 1997) and is a strong prognostic indicator of poor outcome if present on hospital admission (Hovda et al, 2005).
b) CASE REPORT: A 49-year-old man presented unconscious 2.5 hours after ingesting 152 g of ethanol and 20 mL of methomyl pesticide containing methanol (exact amount unknown) as a solvent in a suicide attempt. On presentation, he became semicomatose and developed respiratory failure and was treated with supportive care. At this time, he didn't have any cholinergic symptoms and his cholinesterase concentrations were within normal range; however, laboratory results revealed rhabdomyolysis, high anion gap metabolic acidosis, blood ethanol concentration of 74.8 mg/dL, urine methanol concentration of 55.6 mg/dL, and urine ethanol concentration of 22 mg/dL. He underwent 4 hours of hemodialysis and his condition improved gradually. He was extubated the next day and was discharged on day 7 (Gil et al, 2012).

D) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Severe pulmonary edema, seen at autopsy and histological examination, in 2 fatalities, was reported following estimated methanol ingestions of 97 g and 107 g, respectively (Kinoshita et al, 1998).

E) PULMONARY ABSORPTION

1) WITH POISONING/EXPOSURE

a) INHALATION exposure to methanol-containing substances may cause severe toxicity (Frenia & Schauben, 1992). Tachypnea (as well as visual, neurologic, and metabolic toxicity) has been reported in deliberate inhalational abusers of methanol-containing products (Frenia & Schauben, 1992).

1) Serum methanol levels of 16 and 23 mg/dL developed in 2 members of firefighting/HAZMAT crews who were exposed via inhalation and dermal contact (Aufderhyde et al, 1993).

F) INHALANT ABUSE

1) WITH POISONING/EXPOSURE

a) In a retrospective study of 22 patients with inhalational exposure to methanol-containing carburetor cleaners (mean serum methanol concentration of 28 mg/dL obtained at a mean of 3.5 hours postexposure; range 0 to 34), 14 (63.6%) presented with vomiting, and all patients developed neurologic abnormalities (ataxia, lethargy). Overall, significant toxicity (eg, acidosis, visual disturbance) was rare, with symptoms improving without aggressive care (dialysis, alcohol dehydrogenase blockade). Neither visual disturbances nor neurological sequelae developed in any patient (LoVecchio et al, 2004).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Signs and symptoms of acute methanol intoxication may include lethargy, intoxication, confusion, muscular weakness, abdominal cramps with excruciating pain and tenderness, changes in the sensorium, lethargy, and stupor. Hyperactivity of the deep tendon reflexes may also appear.
2) Neurologic symptoms of methanol intoxication can mimic those of an ethanol "hangover" and may include general malaise, headache, dizziness, vertigo, neuritis, and weakness (Proctor & Hughes, 1978).

b) INCIDENCE

1) CASE SERIES: In a chart review of methanol poisonings (n=113) reported to a poison center, central nervous system symptoms were reported in 51 cases (45.1%) (Kalkan et al, 2003).
2) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, giddiness, sedation, altered sensorium, seizures, and coma developed in 24, 32, 20, 12, and 12 patients, respectively. Four patients had bilateral putaminal necrosis with delayed onset neuropathy and axonopathy. Bilateral 7th and 8th cranial nerve palsies were observed in 2 patients (Jarwani et al, 2013).
3) CASE REPORT: A 40-year-old woman presented with dysarthria, disorientation, and smelling of alcohol after ingesting an unknown amount of a methanol-containing product. She developed severe agitation, tachypnea, tachycardia, generalized hypertonia, and a hypertensive crisis 5 hours postadmission. Laboratory analysis revealed severe metabolic acidosis with increased anion and osmol gaps. A CT scan, 12 hours postadmission, revealed a hypodense practically-symmetrical bilateral diffuse lesion of the supratentorial white matter and lentiform nuclei, without mass effect on the lateral ventricles or median line. The MRI and diffusion-weighted MRI (DWI) performed 2 days later revealed an extensive symmetrical bilateral lesion of the supratentorial white matter, sparing the subcortical association fibers, with hypointensity in T1-weighted sequences, and hyperintensity in T2-weighted and fluid attenuated-inversion recovery (FLAIR) sequences, with restricted diffusion. The lateral and posterior regions of both putamina had increased necrosis-related diffusion. The patient died of gastrointestinal hemorrhage 33 days after exposure (Vara-Castrodeza et al, 2007).
4) CASE REPORT: A 27-year-old man presented with acute headache, vomiting, abnormal behavior, and bilateral blindness 3 days after ingesting an unknown amount of methanol. A month later, he had no light perception in either eye and fundoscopy revealed bilateral optic atrophy. An MRI of the brain revealed bilateral hemorrhagic putaminal necrosis. On 4-month follow up, his vision was improved to perception of hand movements at 30 cm (Singh et al, 2013).

c) RISK FACTORS

1) A retrospective study of 30 patients poisoned by methanol reported that the occurrence of neurologic signs was significantly increased with greater amounts of methanol ingested, greater time between ingestion and beginning of treatment at the hospital, and decreased blood pH. Risk factors for permanent neurologic sequelae and death were decreased blood pH and greater delay in treatment (Anderson et al, 1989).

B) COMA

1) WITH POISONING/EXPOSURE

a) In severe methanol intoxication, profound coma and seizures may develop. When coma or seizures and severe acidosis are present on admission to the ED, prognosis is poor (Vara-Castrodeza et al, 2007; Hovda et al, 2005; Adanir et al, 2005; Bitar et al, 2004; Liu et al, 1998; Williams et al, 1997; Foster & Schoenhals, 1995; Salzman, 2006).
b) CASE REPORT: Coma lasting 4 days and resolving after hemodialysis was reported in a 21-year-old man with methanol intoxication (Yu et al, 1995).
c) CASE REPORT: Persistent coma was seen in a 50-year-old woman after severe methanol intoxication. At the time of the case report, the patient had been in a vegetative state for 1 year (Kuteifan et al, 1998).
d) CASE REPORT: A 51-year-old woman developed severe methanol toxicity (coma, Glasgow coma scale score of 3; high-anion-gap metabolic acidosis, hypotension, methanol level of 3.3 mg/dL) after repeated dermal application of methanol ("spirit") to her head. The patient's relatives denied oral ingestion of methanol-containing substances. Despite supportive treatment and hemodialysis, she died after 4 days of hospitalization (Soysal et al, 2007).
e) CASE REPORT: A 24-year-old man presented unconscious (Glasgow Coma score 10) about 2 hours after ingesting about 100 mL of methanol and 50 g of sodium ferrocyanide. His vital signs included a blood pressure of 78/34 mmHg, heart rate of 56 beats/min, irregular respiratory rate, and pulse oxygen saturation of 65%. Laboratory results revealed increased leukocytes, respiratory failure, acute kidney injury, and metabolic acidosis. Serum concentrations of sodium ferrocyanide, methanol, and its product formic acid at 2 hours postingestion were 361.2 mg/L, 1244.1 mg/L, and 728.6 mg/L, respectively. Following supportive care, including endotracheal intubation and mechanical ventilation, gastric lavage, sodium bicarbonate, ethanol, plasmapheresis (plasma exchange), and continuous renal replacement therapy (CRRT), his condition gradually improved and he was discharged on day 6 without further sequelae (Liu et al, 2015).
f) CASE REPORT: A 54-year-old woman developed nausea and vomiting after wrapping her feet with methylated spirit-soaked materials (10% methanol) for 6 to 7 hours for pain relief. Two days later, she presented comatose with dilated pupils with an absent light reflex and was diagnosed with methanol toxicity. Following supportive care, she was discharged 6 days later with progressive vision loss. Two months later, fundoscopy revealed bilateral total optic atrophy. A CT scan showed symmetrical putaminal necrosis and generalized cortical atrophy (Iscan et al, 2013).
g) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, coma developed in 12 patients (Jarwani et al, 2013).
h) CASE REPORT: A 49-year-old man presented unconscious 2.5 hours after ingesting 152 g of ethanol and 20 mL of methomyl pesticide containing methanol (exact amount unknown) as a solvent in a suicide attempt. On presentation, he became semicomatose and developed respiratory failure and was treated with supportive care. At this time, he didn't have any cholinergic symptoms and his cholinesterase concentrations were within normal range; however, laboratory results revealed rhabdomyolysis, high anion gap metabolic acidosis, blood ethanol concentration of 74.8 mg/dL, urine methanol concentration of 55.6 mg/dL, and urine ethanol concentration of 22 mg/dL. He underwent 4 hours of hemodialysis and his condition improved gradually. He was extubated the next day and was discharged on day 7 (Gil et al, 2012).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures have been reported (Cao et al, 2016; Jarwani et al, 2013; Liu & Daya, 1997).
b) In a retrospective study, patients presenting with coma or seizures following methanol ingestions had higher fatality rates (85%) than those with minor neurological impairments (4%). Poor prognostic indicators were coma or seizures on presentation or an initial pH less than 7 (Liu & Daya, 1997).
c) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, seizures developed in 12 patients (Jarwani et al, 2013).

D) EXTRAPYRAMIDAL DISEASE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 28-year-old man developed blurred vision and motor dysfunction including rigidity and hypokineses approximately 10 hours after ingesting methanol. Five months after presentation, he still experienced visual and extrapyramidal symptoms. Neurological and eye examinations of another patient with methanol poisoning (a 50-year-old man) showed extrapyramidal signs and diminished reflexes, and 6/36 vision (Arora et al, 2007).
b) Case reports of permanent Parkinson-like syndrome following acute methanol intoxication have been described, usually as a late onset sequelae (several months to 2 years after poisoning) (Airas et al, 2008; Ley & Gali, 1983; LeWitt & Martin, 1988) Indakoetzea et al, 1990; (Davis & Adair, 1999; Quartarone et al, 2000). Patients may benefit from treatment with anti-Parkinson medications (Airas et al, 2008).
c) CASE REPORT: Plastic-type rigidity, intention tremor, and masked facies were seen in a 13-year-old girl 8 months after methanol ingestion (Guggenheim et al, 1971).
d) CASE REPORT: A 28-year-old woman who ingested 200 mL of methanol was treated with IV ethanol, sodium bicarbonate, and hemodialysis and was discharged with no apparent neurological impairment.

1) She presented 2 years later with a Parkinson-like syndrome, dysarthria, expressionless face, limb bradykinesia, and abnormal postural reflexes.
2) Tests of motor skills and dyspraxia showed impairment. A CT scan showed bilateral hypodensity in the putamen (Mozaz et al, 1991).

e) CASE REPORT: A 32-year-old man who ingested a large quantity of alcohol containing methanol developed parkinsonism, characterized by bradykinesia, resting tremors, moderate cogwheel rigidity, a shuffling gait, and impairment of postural reflexes. Initially, the patient had extreme difficulty walking only a few steps; however, his condition improved significantly 4 weeks after beginning amantadine therapy, and he was walking with support following hospital discharge (Bitar et al, 2004).

E) CEREBELLAR INFARCTION

1) WITH POISONING/EXPOSURE

a) BASAL GANGLIA INFARCTION: Infarcts and necrosis of the basal ganglia, particularly the putamina, may occur after severe methanol poisoning (Friedman, 1987; (Anderson et al, 1987; Rosenberg, 1987; Vickers & Revenas, 1987; Yu et al, 1995; Kuteifan et al, 1998; Roberge et al, 1998).
b) CT/MRI FINDINGS: Symmetrical areas of necrosis in the putamina of the brain are a classic finding in cases of acute lethal methanol toxicity (Aquilonius et al, 1980; Hantson et al, 1997; Faris et al, 2000; Deniz et al, 2000); however, these findings are also present in other conditions, such as Wilson disease and Leigh disease and are not pathognomonic for methanol poisoning. Injury to the putamen is likely a selective toxic effect and may be potentiated by poor venous drainage. Long-term survivors may show cystic cavities within the putamen, and some of these patients may exhibit a Parkinson-like syndrome (Feany et al, 2001).

1) CASE REPORT: A brain CT scan revealed bilateral necrosis of caudate nuclei, putamina, insular cortex, and parasagittal cortex of anterior cerebral artery territories with a small hemorrhage in the left putamen in a 21-year-old man following methanol intoxication. CT and MRI confirmed a diagnosis of bilateral basal ganglion lesions (Yu et al, 1995).
2) CASE REPORT: Anderson et al (1997) report contrast-enhancing lesions in the caudate nuclei, putamina, hypothalamus, and subcortical white matter seen on MRI in an adult male 2 weeks after ingestion of an unknown amount of methanol.
3) CASE REPORT: A brain CT scan 36 hours after presentation in a 46-year-old man with severe methanol poisoning (serum methanol level 570 mg/dL) revealed bilateral putamen infarcts and subcortical white matter destruction (Salzman, 2006).

c) Patients who survived severe acute methanol toxicity also have been reported to have brain lesions on CT scans. Aquilonius et al (1980) demonstrated bilateral areas of low attenuation in the putamen of one such patient.
d) CASE REPORT: Chen et al (1991) reported putaminal and bilateral cerebellar cortical lesions seen on CT and MRI in a woman with neurologic signs 7 years after a severe methanol poisoning.
e) CASE REPORT: A 40-year-old woman who ingested 1 L methylated spirits was examined with CT scanning 5 days after intoxication and MRI 3 weeks after intoxication (Pelletier et al, 1992).

1) Although treated within several hours of ingestion and treated with 4-MP (fomepizole) and sodium bicarbonate, residual clinical signs included bilateral blindness, moderate bilateral sensory neuropathy, and extrapyramidal syndrome.
2) CT scan revealed bilateral areas of low density in the basal ganglia. MRI showed a core lesion on the putamen, surrounded by a large hyperintensity suggestive of edema.

f) CASE REPORT: Oromandibular dystonia, with jaw clenching, has been reported in a patient with bilateral putaminal necrosis about 1 year following methanol poisoning. The patient additionally was noted to have Parkinson-like signs and polyneuropathy (Quartarone et al, 2000).
g) CASE REPORT: A 30 year-old man developed sudden visual loss after consuming ethanol adulterated with methanol. Although his vision initially improved after hemodialysis, vision loss was biphasic, with permanent blindness resulting. MRI scan revealed bilateral lenitform nuclear degeneration(Dutta et al, 2003) .

F) CEREBRAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Methanol toxicity involving the optic nerve and brain may result in basal ganglia hemorrhage, evidenced on CT scan (Askar & Al-Suwaida, 2007; Ganguly et al, 1996). Abrupt onset of blindness and loss of consciousness may occur with basal ganglia bleeding (Ganguly et al, 1996). Bilateral basal ganglia hemorrhagic infarction does not normally occur following ethanol intoxication but is distinct in methanol poisonings. A bilateral hemorrhagic necrosis of the putamen, not limited to the deep grey matter, but also involving the subcortical white matter can occur (Blanco et al, 2006). Feany et al (2001) reported a methanol fatality with massive cerebral edema and widespread, multifocal hemorrhagic necrosis of subcortical white matter with smaller areas of hemorrhage noted in the putamen. White matter lesions are considered less specific of methanol poisoning (Feany et al, 2001).
b) CASE SERIES: In a series of 21 severely methanol-intoxicated patients who had CT scans, brain hemorrhage was documented in 6. Heparinization during hemodialysis was felt to be a contributing factor (Phang et al, 1988).
c) CASE REPORT: A 15-year-old patient developed massive bilateral basal ganglia hemorrhage and transtentorial herniation from methanol toxicity (Harchelroad & Wilson, 1993c).
d) CASE REPORT: A 26-year-old man with methanol intoxication developed bilateral primary optic atrophy. Two months later, a CT scan of the brain revealed either a bilateral basal ganglia hematoma or bilateral hemorrhagic infarction (Ganguly et al, 1996).
e) CASE REPORT: A 35-year-old man presented comatose 12 hours after ingesting methanol (serum methanol 66.61 mg/dL). A head CT scan revealed widespread brain edema and hemorrhages localized in the supratentorial region of the temporal lobe in the white matter surrounding the capsula externa and extending to the periventricular white matter and occipital lobes. Heparinization during hemodialysis, metabolic and lactic acidosis, or formate may have been the contributing factors for developing intracranial hemorrhage. Despite supportive care, including hemodialysis, he died on day 9 (Sebe et al, 2006).
f) CASE REPORT: A 27-year-old man presented with acute headache, vomiting, abnormal behavior, and bilateral blindness 3 days after ingesting an unknown amount of methanol. A month later, he had no light perception in either eye and fundoscopy revealed bilateral optic atrophy. An MRI of the brain revealed bilateral hemorrhagic putaminal necrosis. On 4-month follow up, his vision was improved to perception of hand movements at 30 cm (Singh et al, 2013).

G) HEMATOMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 26-year-old man with methanol intoxication developed bilateral primary optic atrophy. Two months later, a CT scan of the brain revealed either a bilateral basal ganglia hematoma or bilateral hemorrhagic infarction (Ganguly et al, 1996).
b) CASE REPORT: A 34-year-old woman presented with high anion gap metabolic acidosis and confusion after inadvertently ingesting an unknown amount of methanol. Lesions in putamen and cerebral deep white matter were observed in a CT scan. She developed coma and cardiorespiratory arrest about 16 days after methanol exposure. A massive unilateral intraparenchymatous insular hematoma was observed in a second CT scan. She died despite supportive care (Bologa et al, 2014).

H) NEUROPATHY

1) WITH POISONING/EXPOSURE

a) Paresthesias and tingling of the extremities may occasionally develop during the first few days of recovery from acute methanol poisoning (Bennett, 1953).
b) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, 4 patients had bilateral putaminal necrosis with delayed onset neuropathy and axonopathy. Bilateral 7th and 8th cranial nerve palsies were observed in 2 patients (Jarwani et al, 2013).

I) OPTIC ATROPHY

1) WITH POISONING/EXPOSURE

a) Toxic effects to the optic nerve and necrosis of the basal ganglia, resulting in blindness and acute encephalopathy, may occur following significant methanol exposures. Totally cupped optic nerves, with optic disc atrophy, may be due to methanol-induced progressive demyelination. Central axonal necrosis of the orbital sector of the optic nerve may occur (Airas et al, 2008; Yang et al, 2005; Adanir et al, 2005; Sharma et al, 1999; Hantson et al, 1999). Early electrophysiologic data and the occurrence of optic neuropathy are correlated.
b) CASE REPORT: Intravenous injection of 250 mL of industrial alcohol (95% ethanol, 100 ppm methanol or 25 mg) in an adult resulted in retinal injury without anion gap metabolic acidosis. Hyperemia of the optic disc with peripapillary hemorrhage and cotton-wool spots were noted on ophthalmologic examination 1 week after the injection. Local production of formaldehyde and formic acid (0.8 mmol) in the retina is thought to be responsible for the optic papillitis and retinal edema with subsequent blindness (Wang et al, 1999).

1) Other authors have disputed the claim that injection of an estimated 25 mg of methanol, a less than toxic amount, could result in blindness. They suggest the patient may have had a second subsequent exposure to methanol not reported to health care providers (Sivilotti et al, 2000).

J) OPISTHOTONUS

1) WITH POISONING/EXPOSURE

a) In terminal cases, opisthotonos suddenly develops, followed by a deep gasp. The chest then "locks" in the full inspiratory position and respirations cease, although the heart may continue to beat for several minutes (Bennett, 1953).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting with severe abdominal pain have been reported (Iscan et al, 2013; Singh et al, 2013; Osterloh et al, 1986; Williams et al, 1997).
b) INCIDENCE

1) CASE SERIES: In a chart review of methanol poisonings (n=113) reported to a poison center, gastrointestinal symptoms (not specified) were reported in 12 cases (10.6%) (Kalkan et al, 2003).
2) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, nausea and vomiting developed in 80 and 64 patients, respectively (Jarwani et al, 2013).

B) LOSS OF APPETITE

1) WITH POISONING/EXPOSURE

a) Anorexia has been noted.

C) ABDOMINAL PAIN

1) WITH POISONING/EXPOSURE

a) Abdominal pain may occur (Osterloh et al, 1986; Bennett, 1953; Williams et al, 1997). Absence of abdominal pain does not rule out a significant ingestion.
b) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, abdominal pain developed in 12 patients (Jarwani et al, 2013).

D) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea is not a prominent sign of acute methanol intoxication, occurring in 10% of patients in a series of 323 cases (Bennett, 1953).

E) CONSTIPATION

1) WITH POISONING/EXPOSURE

a) Severe constipation and obstipation (ie, intestinal blockage or obstruction) may accompany recovery from methanol poisoning (Bennett, 1953).

F) PANCREATITIS

1) WITH POISONING/EXPOSURE

a) Acute necrotizing pancreatitis may result from severe methanol poisoning (Hantson & Mahieu, 2000; Bennett, 1953; Dethlefs & Naraqi, 1978).
b) INCIDENCE: A case series of 22 methanol poisoning victims reported evidence of pancreatic damage in 11 patients. Seven of the 11 patients had pancreatic abnormalities prior to ethanol therapy, and 4 developed abnormalities after ethanol therapy. None of the patients had a prior history of pancreatitis. Three patients had moderate to severe pancreatitis requiring aggressive supportive therapy, and 1 patient died as a direct consequence of acute necrotizing pancreatitis. Ethanol therapy may be a contributing factor. The authors recommend use of fomepizole as antidotal therapy to avoid pancreatitis (Hantson & Mahieu, 2000).

Hepatic

3.9.2)

A) HEPATIC FAILURE

1) WITH POISONING/EXPOSURE

a) In fatal cases of methanol intoxications, multiple organ failure, including hepatic failure, may occur prior to death (Foster & Schoenhals, 1995; Deniz et al, 2000).

B) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) HISTOLOGICAL LIVER CHANGES: In one study, 44 cases (mean age 37.36 +/- 14.95 years; range: 10 to 66 years) of fatal methanol poisoning with liver toxicity were identified. Histological liver changes included micro-vesicular steatosis (72.7%), macro-vesicular steatosis (34.1%), focal hepatocyte necrosis/drop out necrosis (13.64%), mild intrahepatocyte bile stasis (13.64%), feathery (vacuolar) degeneration (13.64%) and hydropic degeneration (9.1%). Eighteen cases (40.9%) had only one histopathology change. The mean blood and vitreous humor methanol concentrations in cases with more than one pathologic features was 127 +/- 38.9 mg/dL, which was higher than the cases with one pathologic finding (p=0.0021) (Akhgari et al, 2013).

Genitourinary

3.10.2)

A) RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis and myoglobinuric, anuric renal failure have been described in a patient with a peak blood methanol level of 410 mg/dL (Grufferman et al, 1985) and in 2 fatalities (Williams et al, 1997).
b) CASE REPORT: A 24-year-old man presented unconscious (Glasgow Coma score 10) about 2 hours after ingesting about 100 mL of methanol and 50 g of sodium ferrocyanide. His vital signs included a blood pressure of 78/34 mmHg, heart rate of 56 beats/min, irregular respiratory rate, and pulse oxygen saturation of 65%. Laboratory results revealed increased leukocytes, respiratory failure, acute kidney injury, and metabolic acidosis. Serum concentrations of sodium ferrocyanide, methanol, and its product formic acid at 2 hours postingestion were 361.2 mg/L, 1244.1 mg/L, and 728.6 mg/L, respectively. Following supportive care, including endotracheal intubation and mechanical ventilation, gastric lavage, sodium bicarbonate, ethanol, plasmapheresis (plasma exchange), and continuous renal replacement therapy (CRRT), his condition gradually improved and he was discharged on day 6 without further sequelae (Liu et al, 2015).
c) PREVALENCE OF RENAL INJURY

1) CASE SERIES: In a retrospective chart review of 25 consecutive patients with severe intentional methanol poisoning, the prevalence of acute renal injury (defined as a serum creatinine of 177 mcmol/L or higher, or a urinary output below 0.5 mL/kg/hour for the first 24 hours) and possible risk factors associated with acute exposure were studied. Fifteen patients (60%) developed evidence of renal impairment within 48 hours of methanol poisoning, while 10 patients did not. Of those 15 patients, 8 had significant myoglobinuria, and 11 had evidence of hemolysis. In the renal impairment group, patients were more likely to have a lower blood pH (6.97 +/- 0.20 as compared with 7.30 +/- 0.16 in the control group), a higher serum osmolality, and a higher peak formate concentration (16.7 +/- 10.8 as compared with 8 +/- 4.6). Although the maximum blood methanol concentration was higher in the acute renal injury group, the difference was not statistically significant.

a) Of the 15 patients with renal impairment, 6 died with the primary cause of death being brain edema (n=5) or acute necrotizing pancreatitis (n=1). Based on this study, proximal tubular dysfunction was prominent in the renal impairment groups. The authors concluded that the mechanism responsible for nephrotoxicity is likely multifactorial (hypotension, hemolysis, myoglobinuria, hyperosmolality) (Verhelst et al, 2004).

B) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) Hematuria has been reported and appears to be related to the degree of acidosis (Harchelroad, 1993a)

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis is classic. Severe methanol intoxication usually leads to metabolic acidosis, which may cause cerebral edema and brain death. Acidosis may be delayed for 18 to 24 hours, or longer with concurrent ethanol ingestion (Cao et al, 2016; Liu et al, 2015; Askar & Al-Suwaida, 2007; Barbera et al, 2014; Vara-Castrodeza et al, 2007; Airas et al, 2008; Sebe et al, 2006; Bitar et al, 2004; Hantson et al, 2002; Cursiefen & Bergua, 2002; Radam et al, 2002; Polak et al, 2002; Girault et al, 1999; Jacobsen et al, 1982).
b) One of the most significant clinical effects of methanol poisoning is the presence of a severe anion gap metabolic acidosis. The severity of symptoms secondary to methanol poisoning appear to correlate with the degree of metabolic acidosis (Jacobsen et al, 1982). Liu et al (1998), in a retrospective analysis, determined that patients with residual visual sequelae had more prolonged acidosis than patients with complete recovery (Liu et al, 1998).

1) A pH of less than 7.0 and bicarbonate less than 10 mEq/L are not uncommon following severe intoxication (Adanir et al, 2005; Yang et al, 2005) .
2) The onset of acidosis may be delayed up to 18 to 48 hours, especially if ethanol has also been ingested. Therefore, the absence of acidosis does not rule out a significant methanol ingestion.
3) A severe metabolic acidosis with normokalemia and coma has resulted in death following methanol poisoning (serum level 1.9 g/L) (Girault et al, 1999).

c) CASE REPORT: A 49-year-old man presented unconscious 2.5 hours after ingesting 152 g of ethanol and 20 mL of methomyl pesticide containing methanol (exact amount unknown) as a solvent in a suicide attempt. On presentation, he became semicomatose and developed respiratory failure and was treated with supportive care. At this time, he didn't have any cholinergic symptoms and his cholinesterase concentrations were within normal range; however, laboratory results revealed rhabdomyolysis, high anion gap metabolic acidosis, blood ethanol concentration of 74.8 mg/dL, urine methanol concentration of 55.6 mg/dL, and urine ethanol concentration of 22 mg/dL. He underwent 4 hours of hemodialysis and his condition improved gradually. He was extubated the next day and was discharged on day 7 (Gil et al, 2012).
d) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, 32% of patients presented with dyspnea. Mean pH values was 7.17 +/- 0.22 and mean bicarbonate was 12.3 +/- 7.3 mmol/L. Both values significantly correlated with the serum methanol concentration (p less than 0.05) and mortality (p less than 0.01). Fatal cases had much lower mean pH (6.94 +/- 0.33 versus 7.23 +/- 0.15, p less than 0.01) and bicarbonate concentrations (7.5 +/- 4.1 mmol/L versus 13.3 +/- 6.7 mmol/L, p less than 0.01) than those who survived. Serum methanol concentrations ranged from 12 mg/dL to 376 mg/dL (mean, 87.1 mg/dL). Significantly higher serum methanol concentrations were observed in patients who expired (53.1 +/- 41 mg/dL versus 121 +/- 92 mg/dL, p less than 0.05) (Jarwani et al, 2013).
e) Metabolic acidosis and osmolar gap was reported in a 49-year-old man with methanol poisoning (methanol plasma levels 0.8 g/L) (Figueras Coll et al, 2008).
f) A normal anion gap metabolic acidosis has been reported following concomitant ingestion of ethanol and methanol (Haviv et al, 1998). Normal anion and osmolal gaps do NOT rule out methanol poisoning.
g) A mixture of organic acids, which contains a high proportion of formic and lactic acids, accumulates in the blood and contributes to the acidosis (McMartin et al, 1980; Cytryn & Futeral, 1983).
h) The degree of acidosis may be most closely related to the serum formate level (Sejersted et al, 1983). The plasma bicarbonate level is markedly reduced and may even fall to zero in cases of terminal poisoning (Bennett, 1953). Urinary pH concomitantly may drop to 5.
i) PROGNOSIS

1) CASE SERIES: In a retrospective study of 45 methanol ingestions, death was more common in patients who had a higher mean methanol concentration, those who remained acidotic longer (mean 7.6 hours), and those with an initial pH less than 7.1 (Liu & Daya, 1997).
2) Meyer et al (2000) found the strongest predictor of death or a poor outcome was a blood pH less than 7.0 in a case series (n=24) of methanol poisoning (Meyer et al, 2000).
3) Patient prognosis is dependent on the severity of metabolic acidosis on admission. Severe metabolic acidosis (pH less than 6.9, base deficit greater than 28 mmol/L) on admission, as well as a lack of ability to compensate via hyperventilation, were strong prognostic indicators of poor outcome in a series of 51 methanol-poisoned patients(Hovda et al, 2005).

j) ANION AND OSMOLAL GAPS

1) In a clinical observational study during an outbreak of methanol poisoning (n=28), anion and osmolal gaps measurements were evaluated as a diagnostic tool. The findings indicated a linear (y = 1.03x + 12.71, R(2) = 0.94) correlation between osmolal gaps and serum methanol concentrations at admission. Anion gaps also correlated with the serum formate concentrations (y = 1.12x+13.82, R(2) = 0.86) (Hovda et al, 2004).
2) The authors make the following suggestions to use these measures as a diagnostic aid. Since there are few conditions in which both AG and OG are increased at the same time (a few exceptions include diabetic coma, acidosis in alcoholics, chronic renal failure, and shock following major trauma), these measures can aid in the diagnosis and appropriate treatment of metabolic acidosis of unknown origin. It's proposed that an OG of 25 mOsm/kgH2O be considered the therapeutic intervention level for antidotes. Overall, this approach would reduce sensitivity but increase specificity. Confounders can include low serum methanol and concomitant ethanol ingestion. The authors concluded that the use of AG and OG in patients who present with metabolic acidosis of unknown origin helps in diagnosing methanol (or ethylene glycol) poisoning at an early stage where treatment can effectively reduce morbidity and mortality (Hovda et al, 2004).

k) INCIDENCE

1) CASE SERIES: In a chart review of methanol poisonings (n=113) reported to a poison center, metabolic acidosis was reported in 26 cases (23%) (Kalkan et al, 2003).
2) CASE REPORTS: Of 10 patients presenting with methanol intoxication due to moonshine ingestion, 2 had Glasgow Coma Score 3, pH less than 6.7, and HCO3 3. These patients died 2 days postadmission, despite aggressive supportive care, including ethanol therapy and hemodialysis (Smyth et al, 1997).
3) INHALATIONAL EXPOSURE: In a retrospective study of 22 patients with inhalational exposure to methanol-containing carburetor cleaners (mean serum methanol concentration of 28 mg/dL obtained at a mean of 3.5 hours postexposure; range 0 to 34), 6 (27.2%) presented with metabolic acidosis (serum bicarbonate 22 mmol/L or less or pH 7.35 or less). Throughout the course of therapy, 17 of the 22 patients (77%) also developed acidosis (an average bicarbonate level of 16 mmol/L and pH of 7.15). Overall, significant toxicity was rare with symptoms improving without aggressive care (dialysis, alcohol dehydrogenase blockade). Neither visual disturbances nor neurological sequelae developed in any patient (LoVecchio et al, 2004).
4) CASE REPORT: Anion gap metabolic acidosis with a high osmolar gap was reported in a 21-year-old man following methanol intoxication. A severe high anion gap metabolic acidosis (pH 7.15; calculated anion gap 39 mmol/L) and high osmolar gap (77.2 mOsm/kg H2O) were present in this comatose patient 2 days after the ingestion (Yu et al, 1995).
5) CASE REPORT: A 14-month-old child presented to the emergency department (ED) with lethargy, tachycardia (HR 112 beats per minute), tachypnea (46 breaths per minute), hypotension (81/50 mmHg), and metabolic acidosis with elevated anion and osmolar gaps (pH 7.2, CO2 13 mmHg, O2 134 mmHg, and serum osmolarity of 306). Toxicology results revealed a serum methanol level of 90 mg/dL. The patient recovered following 10% ethanol infusion and dialysis. It is believed that the source of intoxication may have been windshield washer fluid (Carpentieri et al, 2003).
6) CASE REPORT: A 51-year-old woman developed severe methanol toxicity (coma, high-anion-gap metabolic acidosis, hypotension, methanol level of 3.3 mg/dL) after repeated transdermal application of methanol ("spirit") to her head. The patient's relatives denied oral ingestion of methanol-containing substances. Despite supportive treatment and hemodialysis, she died after 4 days of hospitalization (Soysal et al, 2007).

Hematologic

3.13.2)

A) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) Increased leukocytes has been reported (Liu et al, 2015).
b) Leukocytosis (19,900/microliter) developed 2 days following a toxic ingestion of methanol (Yu et al, 1995). In another case, leukocytosis (21,390/mcL) was reported 2 days after a toxic ingestion in a 16-year-old (Foster & Schoenhals, 1995).

B) BLOOD COAGULATION PATHWAY FINDING

1) WITH POISONING/EXPOSURE

a) Persistent coagulopathy, with increased prothrombin and partial thromboplastin times, has been reported after severe methanol intoxications (Foster & Schoenhals, 1995).

Dermatologic

3.14.2)

A) SKIN ABSORPTION

1) WITH POISONING/EXPOSURE

a) A 52-year-old woman developed coma, hypotension (90/60), and severe metabolic acidosis (pH 6.94, pCO2 13.3 mmHg, pO2 189.9 mmHg, anion gap 32, osmolarity 316 mOsm/kg) after repeated dermal application of methanol-containing cologne and spirits for chronic musculoskeletal pain(Adanir et al, 2005). She was treated with ethanol, folate, bicarbonate, and hemodialysis, and improved.
b) CASE REPORT: A 51-year-old woman developed severe methanol toxicity (coma, high-anion-gap metabolic acidosis, hypotension, methanol level of 3.3 mg/dL) after repeated dermal application of methanol ("spirit") to her head. The patient's relatives denied oral ingestion of methanol-containing substances. Despite supportive treatment and hemodialysis, she died after 4 days of hospitalization (Soysal et al, 2007).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Severe poisonings may result in the complication of rhabdomyolysis and possibly compartment syndrome. Williams et al (1997) describe methanol ingestion in an adult resulting in status epilepticus, respiratory arrest, and eventual gross rhabdomyolysis with bilateral compartment syndrome in his legs. An increased CPK of 4280 units/L was reported. The patient died on day 4.
b) Hantson et al (2000) described a patient who developed rapid onset of rhabdomyolysis and acute renal failure with prolonged coma following a fatal intentional methanol ingestion (Hantson & Mahieu, 2000).
c) CASE REPORT: A 49-year-old man presented unconscious 2.5 hours after ingesting 152 g of ethanol and 20 mL of methomyl pesticide containing methanol (exact amount unknown) as a solvent in a suicide attempt. On presentation, he became semicomatose and developed respiratory failure and was treated with supportive care. At this time, he didn't have any cholinergic symptoms and his cholinesterase concentrations were within normal range; however, laboratory results revealed rhabdomyolysis, high anion gap metabolic acidosis, blood ethanol concentration of 74.8 mg/dL, urine methanol concentration of 55.6 mg/dL, and urine ethanol concentration of 22 mg/dL. He underwent 4 hours of hemodialysis and his condition improved gradually. He was extubated the next day and was discharged on day 7 (Gil et al, 2012).

B) COMPARTMENT SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 49-year-old man with methanol poisoning (methanol plasma levels 0.8 g/L) and who was obtunded for 1 day developed compartment syndrome of all compartments of both legs, and the anterior compartments of both thighs, secondary to prolonged immobility and compression. Complications included rhabdomyolysis (creatine kinase 66,000 units/L), and acute renal insufficiency (creatinine 2.7 mg/dL). He was able to walk autonomously after 4 weeks of hemodialysis for acute renal insufficiency and covering of the fasciotomies with cutaneous autograft, as well as 6 months of rehabilitation treatment (Figueras Coll et al, 2008).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Elevated blood sugar levels, requiring insulin infusions, have been reported following severe methanol intoxications (Williams et al, 1997).

Reproductive

3.20.1)

A) Methanol, together with other solvents, has been linked with birth defects of the central nervous system in humans (Holmberg, 1979), but methanol cannot be considered a human reproductive hazard, because of mixed or poorly documented exposures.

3.20.2)

A) CONGENITAL ANOMALY

1) ANIMAL STUDIES

a) Pregnant rats exposed to 20,000 parts per million (ppm) methanol in air during gestation experienced a significant increase in skeletal, urinary, and cardiovascular defects in the fetuses when compared with unexposed controls (Nelson et al, 1985).
b) Exencephaly (no brain covering) and cleft palate were increased in fetal mice exposed to methanol at 5000 ppm or higher for 7 hours per day on days 6 to 15 of gestation. Embryo- and fetotoxicity were seen at 7500 ppm and above, and reduced fetal weight at 10,000 ppm or above. The NOAEL was 1000 ppm. Effects similar to those seen in the 10,000 ppm dosage group were also seen in offspring of mice given 4 g/kg orally (Rogers et al, 1993). Further studies found vertebral and rib anomalies and defined specific sensitive periods for the various malformations (Rogers & Mole, 1997). The effects of methanol in the system are aggravated by maternal folate deficiency (Sakanashi et al, 1996).
c) Central nervous system, facial, and ocular defects, including exencephaly, were produced by exposures to the high concentration of 15,000 ppm for 6 hours per day during days 7 to 9 of gestation in mice (Bolon et al, 1994).
d) Single dose oral administration of methanol to rats on day 10 of gestation at dosages of 0 to 5.1 mL/kg produced a dose-dependent increase in visceral malformations with specific increases in undescended testes anophthalmia and exophthalmia (Youssef et al, 1997).
e) Exencephaly and cleft palate were increased in fetal mice exposed to methanol at an airborne concentration of 5000 ppm or higher for 7 hours per day on days 6 to 15 of gestation. Embryotoxicity and fetotoxicity were seen with maternal exposure to airborne concentrations of 7500 ppm and above, and reduced fetal weights with concentrations of 10,000 ppm or greater. The NOAEL was 1000 ppm. Effects similar to those seen in the 10,000 ppm dosage group were also seen in offspring of mice given a dose of 4 g/kg orally (Rogers et al, 1993).
f) Marginal folate nutritional status produced 13% of litters with cleft palate in mice, and with additional methanol at 2.5 g/kg, twice per day on days 6 through 10 of gestation, there were 72% affected litters (Fu et al, 1996).
g) In mice, central nervous system, facial, and ocular defects, including exencephaly, were produced by maternal exposure to an airborne concentration of 15,000 ppm for 6 hours per day during days 7 to 9 of gestation (Bolon et al, 1994).
h) Pregnant mice were given 2 intraperitoneal injections of methanol totaling 3.4 or 4.9 g/kg or distilled water 4 hours apart on gestational day (GD) 7. Litters were examined on GD 17. Fetal weight was lower in the high-dose group; the number of live fetuses per litter was reduced at both methanol doses. In the high-dose group, 91% of the fetuses per litter exhibited at least 1 craniofacial malformation; 84.2% of the fetuses per litter exhibited anophthalmia or microphthalmia. At the low dose, 55.8% per litter exhibited craniofacial defects; 44% exhibited micro- or anophthalmia.

1) Effects on skeletal development were limited to the cervical vertebrae, craniofacial skeleton, and supernumerary lumbar ribs. At the high dose, malformations of the facial bones were observed in 51.2% of the fetuses and exoccipital fusions were observed in 73.7% of the fetuses in these litters. The forebrains of embryos were clearly dysmorphic, with missing or small optic vessels and small telencephalons (Rogers et al, 2004).

i) Methanol has been successfully used for freezing mouse embryos and returning them to viability (Rall, 1984), the latter indicating that 1 or more methanol metabolites may actually be responsible for the teratogenic effects.
j) Intrauterine exposure to maternally ingested methanol is reported to produce behavioral changes in newborn rats (Infurna & Weiss, 1986; Stern et al, 1997).

3.20.3)

A) PRENATAL EXPOSURE

1) CASE REPORT: A 28-year-old woman, gravida 3, para 2 with a history of HIV infection, asthma, and prior cocaine abuse, was admitted with lethargy and respiratory distress. Despite attempts to stabilize the mother, the fetus developed bradycardia, and an emergent C-section was performed. Initial labs revealed metabolic acidosis in the mother. At birth, Apgar scores were 1 and 3 at 1 and 5 minutes, respectively, and the newborn was treated for bradycardia (HR 70-90 bpm). Other clinical manifestations included respiratory depression and metabolic acidosis. By hospital days 2 and 3, methanol toxicity (54 mg/dL {mother} and 61.6 mg/dL {newborn}) was confirmed in both the mother and newborn. Fomepizole therapy was considered for the newborn; however, his status deteriorated with a grade 4 intraventricular hemorrhage diagnosed. The family withdrew all care, and the newborn died a short time later. By hospital day 10, the mother also died, despite hemodialysis, ethanol, and leucovorin therapies (Belson & Morgan, 2004).
2) CASE REPORT: A 31-year-old pregnant woman (gravida 4 para 3) who was frequently inhaling lacquer thinner containing methanol, presented with abdominal pain and dyspnea on 4 different occasions during her third trimester. Laboratory results revealed metabolic acidosis with elevated anion gap, and her methanol concentrations ranged from 8.5 to 11.9 mmol/L (27.2 to 38.1 mg/dL). She received IV fomepizole (Pregnancy category C) during each presentation, but also underwent hemodialysis during the first admission. During her last visit (37 weeks 5 days gestational age), she delivered a term infant (Apgar scores were 8 [1 min] and 9 [5 min]). Both mother and infant were discharged without adverse outcomes(Piggott et al, 2015).

B) ANIMAL STUDIES

1) DECREASED UTERINE BLOOD FLOW

a) High-dose intravenous methanol reduces uterine blood flow in rats (Ward & Pollack, 1996).

2) HYPERPROLACTINEMIA

a) Methanol exposure via inhalation in rats resulted in increased prolactin concentrations (Cooper, 1992).

3) PLACENTAL BARRIER

a) Intrauterine microdialysis was used to determine that methanol is transferred to the uterus of 20-day-pregnant rats by apparent first-order kinetics, and equilibrium concentrations in the uterus were 25% higher than those in the dam. Methanol reduced the rate of bicarbonate uptake into fetal rats and mice, and may possibly produce fetal hypoxia (Ward & Pollack, 1996).

4) ROUTE OF EXPOSURE

a) Methanol given to rats by gavage at doses up to 3.2 g/kg/day on days 1 through 8 of gestation had no effect on survival or development of the offspring (Cummings, 1993). Rats exposed prenatally to 15,000 ppm methanol for 7 hours per day on days 7 to 19 of gestation did not show measurable changes in neurodevelopmental tests (Stanton et al, 1995). Methanol has caused birth defects in rats exposed by the oral (Infurna, 1981) and inhalation routes (Nelson, 1984; Nelson et al, 1985).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS67-56-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor mental status, vital signs, and ECG.
B) In patients with significant CNS depression or metabolic acidosis, obtain arterial or venous blood gases.
C) Obtain a serum methanol and ethanol concentration and serial serum electrolytes; calculate anion gap.
D) If serum methanol cannot be obtained in a timely fashion, measure serum osmolality and calculate osmolal gap. The osmolal gap is equal to the measured serum osmolality minus (2 x serum sodium + BUN/2.8) + glucose/18 + ethanol/4.6). An elevated osmolal gap (greater than 10) suggests the presence of toxic alcohols, but a normal osmolal gap does NOT rule this out.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) ELECTROLYTES

a) Measure serum electrolytes in all patients with suspected methanol poisoning, and determine the anion gap.
b) In a retrospective study of 46 patients with methanol poisoning, the calculated anion gap correlated well (R(2) = 0.086) with the serum formate concentration (Hovda et al, 2004).

2) METHANOL CONCENTRATION

a) Blood methanol levels greater than 25 mg/dL (8 millimole [mmol]/L) are generally considered toxic (Goldfrank et al, 1994).
b) Detectable methanol serum levels may result from excessive alcoholic beverage consumption in the absence of methanol ingestion, due to the inhibition of endogenous methanol metabolism by ethanol (Tintinalli, 1995).
c) Of 373 patients with a positive blood ethanol (range 6 to 570 mg% ) who presented to an emergency department, 18 (4.8% ) also had measurable blood methanol levels (range 2.3 to 4 mg/dL% ) thought to be due to endogenous production and not from poisoning (Wargotz & Werner, 1987).

3) MEASURED SERUM OSMOLALITY

a) INCREASED OSMOLAL GAP: The presence of an increased osmolal gap suggests the possibility of a toxic alcohol (including methanol) ingestion.
b) DETERMINATION OF OSMOLAL GAP: Measure the serum osmolality (using the freezing point depression method).

1) Determine the calculated serum osmolality (Osm-Cal):

             TRADITIONAL UNITS
Osm-Cal = 1.86 Na + Glucose + BUN
                    -------   ---
                       18     2.8
          -----------------------
                     0.93
where:
   1.86 = osmotic coefficient of Na
     Na = mEq/L MEASURED sodium
Glucose = mg/dL MEASURED glucose
    BUN = mg/dL MEASURED blood urea 
nitrogen
     18 = molecular wt glucose/
deciliter conversion
    2.8 = molecular wt BUN/deciliter
 conversion
   0.93 = correct for serum water
                    SI UNITS
Osm-Cal = 1.86 Na + Glucose + BUN
          -----------------------
                    0.93
where:
   1.86 = osmotic coefficient of Na
     Na = mmol/L MEASURED sodium
Glucose = mmol/L MEASURED glucose
    BUN = mmol/L MEASURED blood urea
 nitrogen
   0.93 = correct for serum water

2) Correct for coingested ethanol by dividing the measured blood ethanol concentration (in mg/dL) by 4.6 and adding the result to the calculated osmolality before determining the osmolal gap.
3) Subtract the calculated serum osmolality from the measured serum osmolality to determine the osmolal gap. This difference can be accounted for by the presence of osmotically active substances (including methanol).
4) For each increase of serum osmolality of 1 milliosmole (mOsm)/kg H2O caused by methanol, the methanol concentration causing it will be approximately 2.6 mg/dL. Conversely, for each increase of 1 mg/dL of methanol, the serum osmolality will increase by 0.34 mOsm/kg H2O (Kulig et al, 1984).
5) HYPERTONIC HYPONATREMIA: In patients with hyperglycemia, free water moves into the extracellular space, and measured serum sodium concentrations are lower. This must be corrected for in the calculation of the serum osmolality, or the osmolal gap will be falsely elevated. The serum sodium concentration must be corrected by about 1.6 mEq/L for every increase of 100 mg/dL in serum glucose above 100 mg/dL(Sztajnkrycer & Scaglione, 2005).

c) While the above guidelines are the standard procedure, some authors believe that this method consistently overestimates osmolal gap. It is suggested to use head-space instead of injection gas chromatography to measure blood methanol (Demedts et al, 1994).
d) OTHER LIMITATIONS: Isopropyl alcohol, ethylene glycol, ethanol, and acetone can cause an osmolal gap (Cadnapaphornchai et al, 1981). The sensitivity and accuracy of this method of estimating blood methanol levels diminish when levels fall below 50 to 100 mg/dL.
e) PRECAUTIONS IN INTERPRETATION OF OSMOLAL GAP: The absence of an osmolal gap (difference between measured and calculated osmolality) cannot be reliably used to exclude significant methanol (or other osmotically active toxicant) ingestion. An increased osmolal gap suggests the possibility of toxic alcohol ingestion (eg, methanol, ethylene glycol, isopropanol, ethanol). Marcus et al suggest that the osmolar gap calculation is only a fair surrogate marker for the presence of a toxic alcohol (Marcus et al, 2001).

1) NORMAL OSMOLAL GAP: There are wide variations in "normal" osmolal gaps depending on the formula used. An individual's osmolal gap may fall within the "normal" range and still be distinctly elevated for that individual. Thus, a "normal" osmolal gap cannot be used reliably to exclude the possibility of methanol ingestion (Hoffman et al, 1993; Aabakken et al, 1994; Glaser, 1996; Marcus et al, 2001). The metabolites of methanol are not as osmotically active; thus, a normal osmolal gap in the face of a severe metabolic acidosis also does not rule out methanol as an ingested substance. Significant methanol ingestion is unlikely if neither an anion gap metabolic acidosis nor an osmolal gap is present (Hovda et al, 2004). Marcus et al suggest a "normal" osmolar gap of 12 mOsm (as opposed to the accepted to less than 8 mOsm) would increase specificity dramatically without a drastic drop in sensitivity (Marcus et al, 2001).

4) FORMIC ACID

a) A detectable serum formate level may be consistent with methanol poisoning, as methanol is metabolized to formic acid (Hovda et al, 2005a; Young & McCormick, 1995).

B) ACID/BASE

1) Arterial blood gases and electrolytes should be monitored in symptomatic patients.

C) HEMATOLOGIC

1) Complete blood count should be monitored in symptomatic patients.

D) OTHER

1) An alcohol oxidase test (Alcohol Screen dipstick) is a rapid, 2 minute, qualitative method for detecting the presence of methanol in serum or other bodily fluids into which methanol distributes . In the absence of ethanol, this test may be relatively specific for the presence of methanol (Chiang et al, 1997; Hack et al, 2000) and may facilitate an early diagnosis. The alcohol oxidase test is not able to separate the alcohols when ethanol and methanol are coingested. Confirmation by a quantitative assay (gas chromatography) is recommended.
2) BREATH TEST: A portable Fourier transform infrared (FT-IR) point-of-care analyzer is described for the diagnosis of methanol poisonings. The breath analyzer appeared to be sensitive and accurate in detecting and quantitating clinically significant amounts of ethanol and methanol in 5 out of 6 seriously ill patients. Monitoring of exhaled methanol during hemodialysis was also reported. Good correlations with blood samples were reported. This method is not intended to replace serum methanol levels to guide therapy (Laakso et al, 2001).
3) LAB INTERFERENCE/JAFFE METHOD: Nitromethane, a component of radio-controlled vehicle fuels (R/C; also containing methanol), can cause a false elevation of serum creatinine concentration using the Jaffe colorimetric method. In a study of 7 patients with known serum creatinine concentrations after ingestion of nitromethane-containing R/C vehicle fuels, 6 patients had elevated serum creatinine (range, 1.9 to 11.5 mg/dL). The higher the serum creatinine concentration, the higher the serum methanol concentration (Cook & Clark, 2007).

4.1.4)

A) OTHER

1) OPTICAL COHERENCE TOMOGRAPHY

a) Optical coherence tomography (OCT) was found to be very useful for evaluating the severity of retinal edema and detecting swelling of nerve fibers in a patient with methanol poisoning. The authors suggested that OCT was beneficial in detecting the severity of methanol toxicity in both the acute and chronic phases (Fujihara et al, 2006).

Radiographic Studies

A)

1) The following neuroradiological findings have been reported following methanol intoxication: bilateral putamen hemorrhagic necrosis, cerebral and intraventricular hemorrhage, diffuse cerebral edema, and cerebellar necrosis with involvement of the subcortical region, sparing the subcortical association fibers (Srivastava & Kadam, 2013; Vara-Castrodeza et al, 2007; Bhatia et al, 2008; Harchelroad & Wilson, 1993c; Roberge et al, 1998; Kuteifan et al, 1998; Faris et al, 2000). Some authors recommend repeated CT or MRI scanning of methanol-intoxicated patients to track damage (Pelletier et al, 1992; Quartarone et al, 2000). Scans should be done within a few days of admission, throughout the clinical course, and may provide information on postnecrotic areas years after the toxic episode (Glazer & Dross, 1993; Chen et al, 1991). It has been proposed that diffusion-weighted MRI (DWI) can help in differentiating between intracellular and extracellular edema, with lesions with restricted diffusion probably representing cytotoxic edema, similar to that found in acute ischemic injury (Vara-Castrodeza et al, 2007).

a) UNILATERAL INTRAPARENCHYMATOUS INSULAR HEMATOMA : A 34-year-old woman presented with high anion gap metabolic acidosis and confusion after inadvertently ingesting an unknown amount of methanol. Lesions in putamen and cerebral deep white matter were observed in a CT scan. She developed coma and cardiorespiratory arrest about 16 days after methanol exposure. A massive unilateral intraparenchymatous insular hematoma was observed in a second CT scan. She died despite supportive care (Bologa et al, 2014).
b) Seven days after a man ingested an unknown amount of methanol, a T2-weighted brain MRI revealed subacute hemorrhagic necrosis in bilateral basal ganglia and abnormal high signal intensity in occipital areas (Razmjoo et al, 2010).
c) Brain MRI of a man with methanol-induced metabolic acidosis, retinal edema with hyperemia of the optic disc, revealed necrosis of bilateral putamina, cerebral white matter, and involvement of left side of the splenium of corpus callosum (Keles et al, 2007).
d) In a case of a 40-year-old woman with methanol intoxication, the MRI and diffusion-weighted MRI (DWI) performed several days postingestion revealed an extensive symmetrical bilateral lesion of the supratentorial white matter, sparing the subcortical association fibers, with hypointensity in T1-weighted sequences, and hyperintensity in T2-weighted and fluid attenuated-inversion recovery (FLAIR) sequences, with restricted diffusion. The lateral and posterior regions of both putamina had increased necrosis-related diffusion (Vara-Castrodeza et al, 2007).
e) Brain MRI of a man with methanol-induced optic atrophy with blindness and extrapyramidal syndrome revealed putaminal injury and hyperintensity in the subcortical white matter. PET scanning with 6-[18F]fluoro-L-dopa performed 3.5 months after methanol poisoning showed symmetrical impaired presynaptic dopaminergic activity in the striatum, indicative of functional impairment of dopaminergic nigrostriatal neurons (Airas et al, 2008).
f) In 1 case, MRI was useful for detecting and evaluating toxic optic neuropathy (Bernstein et al, 1993).
g) Necrosis of the putamen and subcortical white matter has been seen on neuroimaging in methanol toxicity cases (Anderson et al, 1997; Faris et al, 2000; Yang et al, 2005; Blanco et al, 2006).
h) In 1 patient with methanol poisoning, MRI scan performed 24 hours after ingestion revealed bilateral putaminal lesions, appearing hyperintense on T2 weighted (T2W) images and hypointense on T1 weighted (T1W) images, suggestive of nonhemorrhagic necrosis. At this time, there was no abnormal signal in the optic nerves. In another patient, a cranial MRI on the sixth day after ingestion revealed bilateral, symmetrical hyperintensities with central hypointensities on T2W images in the putaminal region, appearing hypointense and hyperintense on T1W images. In addition, high signal intensity on T2W images in the external and internal capsules suggested edema. Peripheral white matter lesions were also noted in both temporal and frontal lobes, with sparing of a thin rim of subcortical white matter (Arora et al, 2007).
i) Brain imaging, using diffusion-weighted MRI (DWI), was performed in a 32-year-old man in coma with focal neurological signs. On fast spin echo T2-weighted sequences, bilateral putaminal hyperintensity was seen. It was also seen on Fluid Attenuated Inversion Recovery (FLAIR) images and on diffusion-weighted images. Additionally, diffuse hypersignal in the subarachnoid space was reported on FLAIR images (Deniz et al, 2000). In another case, a 42-year-old man with methanol poisoning (admitted several days following ingestion) and respiratory arrest within 30 minutes of admission was treated with conventional therapy. An MRI obtained 3 days after admission showed extensive, symmetrical, bilateral increased signal in FLAIR and T2-weighted images in the lentiform nuclei, extending to the coronal radiata, centrum semiovale, and subcortical white matter. DWI imaging was consistent with cytotoxic edema. Despite therapy, the patient had permanent brain damage and reduced vision (Server et al, 2003).
j) Conventional brain MRI with 1.5-T Gyroscan Interna scanner in 5 patients and nonenhanced CT in 3 patients with methanol poisoning (aged 19 to 42 years ; mean methanol level 24.3 mg/dL; range, 13 mg/dL to 49.5 mg/dL), showed bilateral hemorrhagic or nonhemorrhagic necrosis of the putamina, diffuse white matter necrosis, and subarachnoid hemorrhage. In addition, various patterns of enhancement of basal ganglial lesions, including no enhancement, strong enhancement, and rim enhancement, were observed (Sefidbakht et al, 2007).
k) CT scan of 1 patient with methanol poisoning and extensive cerebral changes showed bilateral putaminal and cerebral deep white matter low attenuation. A predominant frontal and occipital distribution to the white matter involvement was noted. Bilateral foci of cerebellar white matter low attenuation were also observed. In this patient, the MRI was slightly degraded by movement artefact; however, it mirrored the CT results. In another patient with methanol poisoning and extensive cerebral changes, a more striking generalized cerebral deep white matter low attenuation was observed on the CT. The cerebellum was unaffected. The brain MRI revealed multiple scattered foci of hemorrhage at the grey-white interface of the cerebral hemispheres. The largest focus (approximately 2 cm in diameter) was located in the left frontal lobe. Putaminal necrosis and extensive deep white matter signal alteration consistent with edema/necrosis, extending to involve the subcortical U fibres were observed (Bessell-Browne & Bynevelt, 2007).

B)

1) Cranial CT demonstrated an early onset of cerebral lesions in a fatal methanol poisoning case (Girault et al, 1999).
2) A cranial CT, performed on a 35-year-old man 5 days post-hospital admission for methanol intoxication showed putaminal hemorrhagic necrosis with superficial white matter lesions (Blanco et al, 2006).
3) CT scan of 1 patient with methanol poisoning and extensive cerebral changes showed bilateral putaminal and cerebral deep white matter low attenuation. A predominant frontal and occipital distribution to the white matter involvement was noted. Bilateral foci of cerebellar white matter low attenuation were also observed (Bessell-Browne & Bynevelt, 2007).
4) A brain CT scan 2 hours after hemodialysis of a woman with chronic alcohol abuse admitted with alcohol-induced metabolic acidosis, severely altered CNS, and minimally responsive revealed a large hematoma in the left basal ganglia that extended into the left frontal and parietal white matter accompanied by intraventricular extension, midline shift, and loss of grey-white differentiation throughout, suggesting tonsillar herniation. Forty-eight hours later, imaging revealed no intracranial blood flow (Babu et al, 2008).

C)

1) Electrophysiologic investigations of the visual toxicity observed in early stages of methanol poisoning have been studied. Retinal dysfunction and optic neuropathy were detected. The authors found that the development of optic neuropathy and early electrophysiologic data are correlated (Hantson et al, 1999).

Methods

A)

1) BLOOD ALCOHOL LEVELS: Obtain blood alcohol levels to include ethanol, methanol, and ethylene glycol. If blood level analysis for methanol is unavailable, evaluate severity of intoxication by clinical findings including vital signs and visual acuity.
2) METHANOL LEVELS: Enzymatic ethanol methods used by many clinical laboratories do not reliably detect methanol. Gas chromatographic technique is the method of choice (Anzimlt, 1986).

a) Headspace gas chromatography is currently used for quantitative analysis of serum methanol and formic acid (Kinoshita et al, 1998).

3) An HPLC method was developed to simultaneously analyze postmortem biological samples for methanol, ethanol, and isopropyl alcohol. The detection limit was 5 mg/dL, with linearity up to 500 mg/dL; reproducibility was greater than 90% (Sharma et al, 1991).
4) FORMATE: A modified headspace gas chromatographic technique for analysis of formate in biologic fluids has been described (Fraser & MacNeil, 1989).

B)

1) A technique employing a proton nuclear magnetic resonance (1H NMR) spectroscopy method for quantitative determination of serum and urine methanol and ethylene glycol and their metabolites, formate and glycolate, respectively, and of lactate and ethanol used as antidotes, has been reported. This method offers the advantages of rapid diagnosis and small sample size (Carpentieri et al, 2003; Wahl et al, 1998).

C)

1) A simple and rapid screening test for methanol and ethylene glycol, based on the Toxi-Lab alcohol screen, is available (Jarvie & Simpson, 1990). The procedure involves converting the alcohol to formaldehyde, which is then measured by standard techniques. While this test will exclude ethanol, it cannot distinguish between methanol and ethylene glycol.
2) Breath alcohol analyzers, including semiconductor sensors, electrochemical fuel cells, and infrared methods, cannot distinguish between methanol and ethanol (Jones, 1989).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who are acidotic, have visual symptoms, or have serum methanol concentrations above 25 mg/dL should be admitted.
B) Based on a world review of literature, the guidelines to treat an asymptomatic patient with a methanol level of greater than 20 mg/dL is not well supported. The authors suggest that further prospective studies are required to determine if treatment is required for asymptomatic patients without acidosis who arrive soon after exposure with a peak methanol level between 20 and 30 mg/dL (Kostic & Dart, 2003).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist in cases of severe poisonings, in cases where a methanol level is not readily available, or in cases where the ingestion is uncertain. Consult a nephrologist for any patient who may require hemodialysis.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Intentional ingestions should be evaluated in a health care facility. Potential serum levels can be calculated using methanol percentage, amount ingested, and patient weight. All levels potentially greater than 25 mg/dL should be evaluated in a health care facility.

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) There is no role for prehospital decontamination.

6.5.2)

A) SUMMARY: In general, gastrointestinal decontamination is not very useful, because methanol is rapidly absorbed and binds poorly to activated charcoal. Insertion of a nasogastric tube to aspirate gastric contents may be useful in rare patients who present shortly after large ingestions.
B) ACTIVATED CHARCOAL

1) EFFICACY

a) Activated charcoal may be used to prevent absorption of coingested substances.

1) In an in vitro stomach model, 5 g activated charcoal adsorbed 59% of 1 mL, 48% of 10 mL, 35% of 50 mL, and 26% of 100 mL of methanol (Decker et al, 1981).

b) ETHANOL: Activated charcoal does not appear to impair absorption of ethanol. In several crossover human studies, administration of from 20 g activated charcoal to 60 g superactivated charcoal given 5 to 30 minutes before or after an ethanol load (resulting in blood ethanol levels of 100 to 130 mg%), had no effect on ethanol absorption (Neuvonen et al, 1984; Hulten et al, 1985; Minocha et al, 1985; Olkkola, 1985).

2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) NASOGASTRIC SUCTION

1) Large volumes of methanol ingestion may produce delayed gastric emptying; thus, there may be significant recovery of methanol by gastric aspiration even hours after ingestion. Consideration for gastric aspiration must be based on the clinician's judgment that a significant amount of methanol will be returned.
2) If gastric emptying is deemed necessary, insert a small NG tube and aspirate stomach contents. Follow with instillation of activated charcoal. Control seizures first. Protect airway by endotracheal intubation if necessary.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor mental status, vital signs, and ECG.
2) Obtain a serum methanol and ethanol concentration and serial serum electrolytes; calculate anion gap.
3) In patients with significant CNS depression or metabolic acidosis, obtain arterial or venous blood gases.
4) If serum methanol cannot be obtained in a timely fashion, measure serum osmolality and calculate osmolal gap. The osmolal gap is equal to the measured serum osmolality minus (2 x serum sodium + BUN/2.8) + glucose/18 + ethanol/4.6). An elevated osmolal gap (greater than 10) suggests the presence of toxic alcohols, but a normal osmolal gap does not rule this out.

B) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

C) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

D) ACIDOSIS

1) Significant acidosis may not develop until 18 to 48 hours following ingestion and should be treated with sodium bicarbonate with close monitoring of arterial blood gases. Severe acidosis may initially be treated with 1 to 2 mEq/kg bicarbonate. Bicarbonate should be titrated to normalize arterial pH.
2) Monitor arterial blood gas as a guide to severity of intoxication. Severe anion gap metabolic acidosis is common. A pH of less than 7.0 and bicarbonate less than 10 mEq/L are not uncommon following severe intoxication. The onset of acidosis may be delayed for 18 to 48 hours, especially if ethanol has also been ingested. Therefore, THE ABSENCE OF ACIDOSIS DOES NOT RULE OUT A SIGNIFICANT METHANOL INGESTION.
3) Acidosis may be refractory to treatment, especially if the absorption of methanol is ongoing or if ethanol, fomepizole, or both has not been administered.
4) Sodium bicarbonate should be administered to correct acidosis (ADULT: 1 to 2 mEq/kg; CHILDREN: 1 to 2 mEq/kg) titrated to correct arterial pH.
5) In a retrospective series of 32 patients who survived severe methanol intoxication, Liu et al (1998) reported no difference in initial pH and time to dialysis between patients with permanent visual sequelae and those with complete recovery. However, the time to correction of acidosis (initially with intravenous sodium bicarbonate boluses) tended to be longer (mean 5.4 hours) in patients with visual loss than in patients with complete recovery (mean 3.0 hours, p=0.06). When corrected for initial pH, the statistical significance of this finding was reduced (p=0.08). The authors suggest that early correction of pH with intravenous bicarbonate may improve visual outcome, but further studies are needed.

E) ALCOHOL DEHYDROGENASE INHIBITOR

1) The decision as to which antidote to use depends on a number of factors. Fomepizole is easier to use clinically, requires less monitoring, does not cause CNS depression or hypoglycemia, and may obviate the need for dialysis in some patients. Ethanol requires continuous administration and frequent monitoring of serum ethanol and glucose levels, and may cause CNS depression and hypoglycemia (especially in children). The drug cost associated with ethanol use is generally much lower than with fomepizole; however, other costs associated with ethanol use (eg, continuous intravenous infusion, hourly blood draws and ethanol levels, possibly greater use of hemodialysis) may make the costs more comparable.

a) One study recommended that the critically ill patients with severe metabolic acidosis (base deficit greater than 15 mmol/L) or visual disturbances should receive sodium bicarbonate, fomepizole, and hemodialysis as soon as possible. Stable patients, with little to moderate metabolic acidosis (base deficit less than 15 mmol/L) and no visual disturbances should receive sodium bicarbonate and fomepizole. In these patients, the use of hemodialysis should be discussed with an experienced nephrologist or clinical toxicologist (Hovda & Jacobsen, 2008).

F) FOMEPIZOLE

1) Fomepizole, a specific antagonist of alcohol dehydrogenase, is approved for the treatment of methanol and ethylene glycol poisoning. It had previously been used in experimental animals and in humans and showed an apparent low level of toxicity and ability to replace ethanol as treatment for methanol poisoning (Brent et al, 2001; Prod Info ANTIZOL(R) IV injection, 2006; Megarbane et al, 2001; Burns et al, 1997; Brent et al, 1997; Blomstrand et al, 1980).
2) AVAILABILITY

a) Fomepizole (Antizole(R); 4-MP) is currently approved and available in the United States for the treatment of methanol poisoning (Prod Info ANTIZOL(R) IV injection, 2006).

3) ADVERSE EFFECTS

a) Studies in healthy human volunteers show fewer adverse effects and slower elimination rate compared with ethanol (McMartin et al, 1987).
b) The manufacturer reported the most frequent adverse effects in 78 patients and 63 normal volunteers receiving fomepizole to be headache (14%), nausea (11%), and dizziness, increased drowsiness, and dysgeusia (6% each) (Prod Info ANTIZOL(R) IV injection, 2006).
c) Megarbane et al (2001) reported transient adverse effects of nausea, headache, eosinophilia, lymphangitis, and fever following therapeutic doses of fomepizole in acute methanol intoxication (Megarbane et al, 2001). Brent et al (2001) also reported only minor transient adverse effects in 6 methanol-intoxicated patients treated with fomepizole (Brent et al, 2001).
d) A placebo-controlled, double-blind study among HEALTHY volunteers showed mild, transient increase in liver function tests and slower elimination rate of fomepizole (4-methylpyrazole). The mild, sporadic, and transient elevations in blood pressure were not dose-related (Jacobsen et al, 1990).

4) DOSE

a) Dosing should be started immediately on suspicion of methanol ingestion based on patient history or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, OR a documented methanol serum concentration of greater than 20 mg/dL (Prod Info ANTIZOL(R) IV injection, 2006).

1) Give fomepizole loading dose of 15 mg/kg, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until methanol concentrations are undetectable or have been reduced below 20 mg/dL and the patient is asymptomatic with normal pH. Administer all doses as a slow intravenous infusion over 30 minutes (Prod Info ANTIZOL(R) IV injection, 2006).
2) Plasma level of fomepizole necessary to inhibit alcohol dehydrogenase is approximately 0.8 mcg/mL (Brent et al, 2001). Under fomepizole treatment, the decay of methanol follows first-order kinetics, with a plasma elimination half-life of methanol reported as 48 to 54 hours (Bekka et al, 2001; Brent et al, 2001).

b) DOSING WITH HEMODIALYSIS

1) Consider hemodialysis in addition to fomepizole therapy in cases of renal failure, severe metabolic acidosis, or a measured methanol concentration of greater than 50 mg/dL. Fomepizole is dialyzable; the frequency of dosing should be increased to every 4 hours during hemodialysis (Prod Info ANTIZOL(R) IV injection, 2006).

a) DOSE AT THE BEGINNING OF HEMODIALYSIS: If less than 6 hours have elapsed since last dose, do not give a dose; if 6 hours or more have elapsed since the last fomepizole dose, give the next scheduled dose (Prod Info ANTIZOL(R) IV injection, 2006).
b) DURING HEMODIALYSIS: 15 mg/kg IV loading dose, followed by 10 mg/kg IV every 4 hours for 4 doses, then 15 mg/kg IV every 4 hours until ethylene glycol or methanol concentrations are below 20 mg/dL (Prod Info ANTIZOL(R) IV injection, 2006).
c) DOSING AT THE TIME HEMODIALYSIS IS COMPLETED: If the time between the last dose and the end of hemodialysis is less than 1 hour, do not give a dose; if the time between the last dose and the end of hemodialysis is 1 to 3 hours, give 50% of the next scheduled dose; if the time between the last dose and the end of hemodialysis is greater than 3 hours, give the next scheduled dose (Prod Info ANTIZOL(R) IV injection, 2006).

c) One study recommended that the critically ill patients with severe metabolic acidosis (base deficit greater than 15 mmol/L), visual disturbances, or both should receive sodium bicarbonate, fomepizole, and hemodialysis as soon as possible. Stable patients, with little to moderate metabolic acidosis (base deficit less than 15 mmol/L) and no visual disturbances should receive sodium bicarbonate and fomepizole. In these patients, the use of hemodialysis should be discussed with an experienced nephrologist or clinical toxicologist (Hovda & Jacobsen, 2008; Hovda et al, 2005b).

5) ADMINISTRATION

a) Fomepizole solidifies at temperatures below 25 degrees C (77 degrees F); thus, the vial should be liquefied by running warm water over it or holding it in the hand. Solidification does NOT affect efficacy, safety, or stability. Draw appropriate fomepizole dose from vial and inject into at least 100 mL of sterile 0.9% sodium chloride injection or dextrose 5% injection. Infuse over 30 minutes (Prod Info ANTIZOL(R) IV injection, 2006).

6) CONCURRENT FOMEPIZOLE AND ETHANOL

a) A combination of fomepizole and ethanol does not appear to reliably decrease ethanol clearance antidotally during the treatment of methanol toxicity. Wax et al (1998) measured mean ethanol t1/2 and elimination rate after fomepizole (4-MP) dosing in 6 patients who had serum ethanol levels prior and during fomepizole (4-MP). Ethanol half-life and elimination rate were 4.3 hr (+/-2.6) and 25.1 mg/dL/hr (+/-32.6) before fomepizole (4-MP) and 2.6 hr (+/-0.8) and 14.6 mg/dL/hr (+/-7.4) after fomepizole (4-MP) (Wax et al, 1998).

7) ETHANOL VERSUS FOMEPIZOLE

a) In a cohort study of 172 cases of suspected methanol and ethylene glycol poisoning, fomepizole was associated with a lower adverse drug events rate than ethanol. At least 1 adverse drug event was identified in 74 of 130 (57%) ethanol-treated and 5 of 42 (12%) fomepizole-treated cases. The most frequent adverse effect was CNS depression (48% ethanol, 2% fomepizole). Severe adverse drug events occurred in 26 of 130 (20%) ethanol-treated patients (coma, extreme agitation, cardiovascular) and 2 of 42 (5%) fomepizole-treated patients (coma, cardiovascular). Serious (life-threatening) adverse events occurred in 11 of 130 (8%) ethanol-treated patients (respiratory depression, hypotension), and 1 of 42 (2%) fomepizole-treated patients (hypotension, bradycardia) (Lepik et al, 2009).

8) CASE REPORTS/FOMEPIZOLE AND BICARBONATE: Four patients with methanol poisoning (the mean serum methanol level was 14.4 mmol/L {45 mg/dL} range 9.4 to 18.8) with moderate metabolic acidosis (mean pH was 7.23 {range 7.12 and 7.33}) and no visual disturbances were successfully treated with fomepizole and bicarbonate; hemodialysis was not required. Frequent acid/base monitoring was found to be normal throughout therapy, indicating that formic acid did not accumulate in any patient. The mean plasma half-life of methanol was 25 hours during treatment. The authors concluded that patients with serum methanol levels up to 19 mmol/L (60 mg/L), moderate metabolic acidosis, and no visual disturbances can be safely treated with fomepizole and bicarbonate without dialysis (Spillum et al, 2003). Because of the prolonged half-life of methanol in patients receiving fomepizole (25 hours or more), patients treated with fomepizole alone may require prolonged hospitalization.
9) CASE REPORT (MIXED INGESTION): A 35-year-old man ingested a glass cleaner solution containing approximately 100 g methanol and 36 g isopropanol over a 24-hour period. Fomepizole was started about 5 hours after his most recent ingestion, with a starting dose of 10 mg/kg. This was given twice daily for 8 days, in a tapering dose schedule until methanol and isopropanol levels were undetectable. No adverse effects due to fomepizole were noted. The patient was discharged with no toxic-related sequelae (Bekka et al, 2001).
10) PREGNANCY

a) CASE REPORT: A 21-year-old woman with a long history of inhalant abuse and in the first trimester of pregnancy developed methanol poisoning (serum level, 24 mg/dL) after inhaling a carburetor cleaner. She received 1 dose of fomepizole (15 mg/kg) and vitamins. Her methanol level was then undetectable. The patient was discharged and returned again (now at gestational age of 16 to 17 weeks) when she was found inhaling the methanol product. She recovered following 1 dose of fomepizole and hemodialysis. No gross fetal anomalies were seen on ultrasound. The outcome of the pregnancy is unknown since the patient did not return for follow-up (Kulstad et al, 2001).
b) CASE REPORT: A 31-year-old pregnant woman (gravida 4 para 3) who was frequently inhaling lacquer thinner containing methanol, presented with abdominal pain and dyspnea on 4 different occasions during her third trimester. Laboratory results revealed metabolic acidosis with elevated anion gap, and her methanol concentrations ranged from 8.5 to 11.9 mmol/L (27.2 to 38.1 mg/dL). She received IV fomepizole (a single dose of 15 mg/kg IV or 15 mg/kg loading dose followed by 10 mg/kg every 12 hours for 7 doses) during each presentation, but also underwent hemodialysis during the first admission. During her last visit (37 weeks 5 days gestational age), she delivered a term infant (Apgar scores were 8 [1 min] and 9 [5 min]). Both mother and infant were discharged without adverse outcomes(Piggott et al, 2015).

11) ETHANOL INTERFERENCE

a) A study in RATS demonstrated that the rate of fomepizole (4-methylpyrazole) elimination was decreased about 50% by concomitant administration of ethanol. In this study, fomepizole (4-MP) was dosed orally at 5, 10, or 20 mg/kg and ethanol was dosed orally at 1 g/kg/hr for 3 hours (McMartin & Collins, 1988).

G) ETHANOL

1) EFFICACY

a) Dosing the patient with ethanol effectively inhibits oxidation of methanol into its far more toxic products. Ethanol has about 20 times the affinity for alcohol dehydrogenase compared with methanol. This competitive effect of ethanol gains more time for excretion of unchanged methanol from the body, and it also inhibits the formation of methanol metabolites that produce severe acidosis. Formic acid is metabolized to carbon dioxide and water via a folate-dependent system.
b) A rebound in blood formate levels was observed in 4 methanol-intoxicated patients after ethanol infusion was discontinued. In 2 well-documented cases, the formate levels rose from 2.4 to 2.5 mg/L during ethanol therapy to 43 and 100 mg/L after discontinuation. Methanol blood levels were 22 and 32 mg/dL, respectively (Mahieu et al, 1989).

2) INDICATIONS

a) Ethanol therapy must be considered in any of the following situations (Barceloux et al, 2002):

1) Documented plasma methanol concentration greater than 20 mg/dL (greater than 200 mg/L);
2) Documented recent history of ingesting toxic amounts of methanol and osmolal gap greater than 10 mOsm/L;
3) History or strong clinical suspicion of methanol poisoning and at least 2 of the following criterion: arterial pH less than 7.3; serum bicarbonate less than 20 mEq/L; osmolol gap greater than 10 mOsm/L.

3) PREPARATION

a) CONCENTRATIONS AVAILABLE (V/V)

1) In the United States, 5% or 10% (V/V) ethanol in 5% dextrose for intravenous infusion is no longer available commercially (Howland, 2011a). Ethanol 10% (V/V) contains approximately 0.08 gram ethanol/mL.
2) ABSOLUTE ETHANOL or dehydrated ethanol, USP contains no less than 99.5% volume/volume or 99.2% weight/weight of ethanol with a specific gravity of not more than 0.7964 at 15.56 degrees C. Absolute ethanol is hygroscopic (absorbs water from the atmosphere) and when exposed to air may be less than 99.5% ethanol by volume (S Sweetman , 2002).

b) PREPARATION OF 10% V/V ETHANOL IN A 5% DEXTROSE SOLUTION

1) A 10% (V/V) solution can be prepared by the following method (Howland, 2011a):

a) If available, use sterile ethanol USP (absolute ethanol). Add 55 mL of the absolute ethanol to 500 mL of 5% dextrose in water for infusion. This yields a total volume of 555 mL. This produces an approximate solution of 10% ethanol in 5% dextrose for intravenous infusion (Howland, 2011a).

c) Instead of using a micron filter when preparing the ethanol infusion, possibly a better alternative would be to use the filter between the solution and the patient.

4) PRECAUTIONS

a) HYPOGLYCEMIA

1) Hypoglycemia may occur, especially in children. Monitor blood glucose frequently (Howland, 2011a; Barceloux et al, 2002).

b) CONCURRENT ETHANOL

1) If the patient concurrently has ingested ethanol, then the ethanol loading dose must be modified so that the blood ethanol level does not exceed 100 to 150 mg/dL (Barceloux et al, 2002).

c) DISULFIRAM

1) Fomepizole is preferred as an alcohol dehydrogenase inhibitor in patients taking disulfiram. If fomepizole is not available, ethanol therapy should be initiated in those patients with signs or symptoms of severe poisoning (acidemia, toxic blood level) despite a history of recent disulfiram (Antabuse(R)) ingestion.
2) The risk of not treating these patients is excessive, especially if hemodialysis is not immediately available.
3) Administer the ethanol cautiously with special attention to the severity of the "Antabuse reaction" (flushing, sweating, severe hypotension, and cardiac dysrhythmias).
4) Be prepared to treat hypotension with fluids and pressor agents (norepinephrine or dopamine). Monitor ECG and vital signs carefully. Hemodialysis should be performed as soon as adequate vital signs are established, and every effort should be made to obtain fomepizole.

5) LOADING DOSE

a) INTRAVENOUS LOADING DOSE

1) Ethanol is given to maintain a patient’s serum ethanol concentration at 100 to 150 mg/dL. This can be accomplished by using a 5% or 10% ethanol solution administered intravenously through a central line (10% ethanol is generally preferred due to the large volumes required for 5%). Intravenous therapy dosing, which is preferred, is 0.8 g/kg as a loading dose (8 mL/kg of 10% ethanol) administered over 20 to 60 minutes as tolerated. Begin the maintenance infusion as soon as the loading dose is infused (Howland, 2011a).

b) ORAL LOADING DOSE

1) Oral ethanol may be used as a temporizing measure until intravenous ethanol or fomepizole can be obtained, but it is more difficult to achieve the desired stable ethanol concentrations. The loading dose is 0.8 g/kg (4 mL/kg) of 20% (40 proof) ethanol diluted in juice administered orally or via a nasogastric tube(Howland, 2011a).

6) MAINTENANCE DOSE

a) MAINTENANCE DOSE

1) Maintain a serum ethanol concentration of 100 to 150 mg/dL. Intravenous administration is preferred, but oral ethanol may be used if intravenous is unavailable(Howland, 2011a; Barceloux et al, 2002).

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.8 to 1.3 mL/kg/hr)
Chronic drinker	150 mg/kg/hr (1.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL*
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.4 to 0.7 mL/kg/hr) orally or via nasogastric tube
Chronic drinker	150 mg/kg/hr (0.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

b) MAINTENANCE DOSE/ETHANOL DIALYSATE

1) During hemodialysis maintenance doses of ethanol should be increased in accordance with the recommendation given below, or ethanol should be added to the dialysate to achieve a concentration of 100 milligrams/deciliter (Pappas & Silverman, 1982a).

c) MAINTENANCE DOSE/ETHANOL-FREE DIALYSATE

1) Maintain a serum ethanol concentration of 100 to 150 mg/dL(Howland, 2011a; Barceloux et al, 2002):

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL - 250 to 350 mg/kg/hr (2.5 to 3.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL* - 250 to 350 mg/kg/hr (1.3 to 1.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

2) Variations in blood flow rate and the ethanol extraction efficiency of the dialyzer will affect the dialysance(McCoy et al, 1979).
3) If the ethanol dialysance ((CL)D) is calculated, the infusion rate during dialysis (Kod) can be individually adjusted using the following expression (McCoy et al, 1979):

Kod = Vmax x   Cp   + (CL)D x Cp
             -------
             Km + Cp
where Cp = desired blood ethanol level
*  Vmax = 175 mg/kg/hr in chronic ethanol drinkers 
*  Vmax = 75 mg/kg/hr in non-chronic drinkers
*  Km = 13.8 mg/dL

7) PEDIATRIC DOSE

a) There is very little information on ethanol dosing in the pediatric patient (Barceloux et al, 2002). The loading dose and maintenance infusion should be the same as for an adult non-drinker. Loading dose is 0.8 g/kg (8 mL/kg) of 10% ethanol infused over 1 hour, maintenance dose is 80 mg/kg/hr (0.8 mL/kg/hr) of 10% ethanol (Howland, 2011a).
b) Blood ethanol concentration should be initially monitored hourly and the infusion rate should be adjusted to obtain an ethanol concentration of 100 to 150 mg/dL (Howland, 2011a; Barceloux et al, 2002).

1) Monitor blood glucose and mental status frequently during therapy (Howland, 2011a). Ethanol-induced hypoglycemia is more common in children (Barceloux et al, 2002) and children may develop more significant CNS depression.

c) PEDIATRIC ADVERSE EFFECTS: In a retrospective review of 60 pediatric patients receiving oral or IV ethanol, the rate of clinically important adverse effects due to ethanol was low. Mild glycemia, drowsiness, 3% of patients with hypotension, and 1 patient with erosive gastritis were reported. Good prognosis was reported in children treated with ethanol in spite of a wide variation in ethanol levels (Roy et al, 2001; Roy et al, 2001a).

8) MONITORING PARAMETERS

a) ETHANOL CONCENTRATION

1) Blood ethanol concentrations should be determined every 1 to 2 hours until concentrations are maintained within the therapeutic range (100 - 150 mg/dL). Thereafter concentrations should be monitored every 2 to 4 hours. Any change in infusion rate will require monitoring every 1 to 2 hours until the therapeutic range is reached and maintained (Barceloux et al, 2002).

b) ADDITIONAL MONITORING

1) Monitor serum electrolytes and blood glucose, monitor for CNS depression (Howland, 2011a).

9) DURATION OF THERAPY

a) SERUM CONCENTRATIONS AVAILABLE: Ethanol therapy should be continued until the following criteria are met:

1) Methanol blood concentration, measured by a reliable technique, is less than 10 mg/dL.
2) Formate blood concentration is less than 1.2 mg/dL (Abolin et al, 1980; Baumann & Angerer, 1979; Martin-Amat et al, 1978; Sejersted et al, 1983).
3) Methanol-induced acidosis (pH, blood gases), clinical findings (CNS), electrolyte abnormalities (bicarbonate), serum amylase, and osmolal gap have resolved.

b) NO SERUM CONCENTRATIONS AVAILABLE: When unable to obtain methanol blood levels, ethanol therapy should be initiated and the patient transported as soon as possible to a facility capable of measuring serum methanol concentrations and performing hemodialysis.

1) Ethanol therapy should be continued for a minimum of 9 days in the absence of dialysis, 1 day when dialysis has been performed, or until clinical findings resolve, whichever is longer. It is extremely difficult to maintain therapeutic ethanol levels for long periods of time. Hemodialysis is strongly recommended in patients with acidosis or serum methanol levels of greater than 25 to 50 mg/dL.
2) If the clinical findings have not resolved, it may indicate the continued presence of methanol, metabolites, both, or some other etiology.

c) Based on pharmacokinetic theory, 93.75% of methanol is eliminated over a period of 4 elimination half-lives (Winter, 1988). Assuming a prolonged methanol elimination half-life of up to 52 hours during ethanol therapy (Palatnick et al, 1995), pharmacokinetic theory would predict elimination of 93.75% of the absorbed dose of methanol over 208 hours (9 days). Therefore, ethanol therapy (in the absence of hemodialysis) should be continued for at least 9 days.
d) It is possible that 5-day treatment may be inadequate in some cases. Jacobsen et al (1988) reported zero-order elimination of methanol with a rate of 8.5 mg/dL/hr prior to institution of ethanol therapy or dialysis.
e) Palatnick et al (1995) found that methanol elimination in the presence of treatment levels of ethanol follows first-order kinetics. However, since hepatic metabolism is inhibited by the ethanol, the primary pathways for elimination become renal and pulmonary clearance. These 2 mechanisms are very inefficient, and thus the methanol half-life is considerably prolonged, up to 52 hours.
f) In a series of 3 methanol-poisoned patients treated with only ethanol and 3 cases retrieved from a literature review, methanol half-life while on IV ethanol was 43 hours (range 30 to 52 hours) (Palatnick et al, 1995). Because of the prolonged need for ethanol therapy and the difficulty in consistently maintaining therapeutic ethanol levels, these authors suggested that dialysis be considered in all patients requiring ethanol infusion.

10) METHANOL INGESTION

a) Patients who concurrently ingested ethanol and methanol may have a normal acid-base profile despite a dangerously elevated blood methanol level. Consider implementing the ethanol treatment regimen in these patients until a methanol level can be determined. Determine blood ETHANOL level before beginning ETHANOL therapy and modify the loading dose accordingly. Ingestion of Sterno fuel products (which contain greater than 60% ethanol and less than 4% methanol) may result in delayed toxicity due to the high ethanol concentration in these products.
b) In a series of 84 chronic alcoholics who ingested a cleaning solution containing 90% ethanol and 5% methanol, no acidosis was reported despite mean methanol levels of 64 mg/dL and absence of specific therapy (ethanol or hemodialysis). Insufficient data are presented to determine the safety of this conservative treatment. Individual or pooled blood gas data are not given, although 13 patients were stated to have a decrease in base excess. No outcome data are given, and methanol levels were measured only until less than 48 mg/dL (Martensson et al, 1988).
c) To modify the loading dose for the patients who have concurrently ingested ethanol, use the following equation to calculate the loading dose:

      LD=(100 mg/dL-existing) apparent
      ETOH plasma concentration) x vol of
           (in mg/dL) distribution

d) Note the loading dose obtained by this method is the amount of pure ethanol in mg/kg. It must be converted for intravenous and oral use to mL/kg. This can be accomplished by using the following relationship:

             LD(mg/kg)
LD(mL/kg)=----------------------------------
          (spec gravity    (concentration
            of ETOH)        as a fraction)

e) Ten percent (V/V) ethanol for intravenous infusion:

               LD(mg/kg)
LD(mL/kg)=---------------------------
             (790 mg/mL) (10/100)

f) 95 percent (V/V) ethanol for oral use:

               LD(mg/kg)
LD(mL/kg)=-------------------------- 
             (754 mg/mL)  (95/100)

g) Calculation of loading dose assumes instantaneous absorption.

11) ADVERSE EFFECTS

a) In a retrospective study, the hospital records of 49 adults treated with ethanol for methanol (n=15) or ethylene glycol (n=32) ingestion were evaluated. Two patients ingested both methanol and ethylene glycol. Adverse effects developed in 45 (92%) patients, including tachycardia (heart rate greater than 100 beats/min; n=16; 33%), hypotension (n=9; 18%), decreased level of consciousness (necessitating intubation; n=10; 20%), agitation (necessitating chemical or physical restraints; n=35; 71%), seizures (n=3; 6%), vomiting (n=11; 22%), and phlebitis (n=5; 10%). It is unclear if the adverse effects were related to the ethanol, underlying poisoning or other therapies. Hypoglycemia (blood glucose less than 4 mmol/L) did not develop in any patients. Four patients died; 38% were admitted to an ICU unit and 92% of patients (n=45) were treated with hemodialysis. Serum ethanol concentrations were obtained a median of 6 times per case (range, 0 to 24). Patients were treated with ethanol for 0.5 to 119 hours (median, 21 hours). Serum ethanol concentration was within target range (22 to 30 mmol/L) in only 27% of measurements; 47% were below the target range and 25% were above the target range. Inappropriate change in ethanol dosing was reported in 59% of the cases when a serum ethanol concentration was outside the target. Inappropriate dosing changes were also reported during 69% of the hemodialysis sessions. Overall, 92% of patients survived and were discharged home (Wedge et al, 2012).

H) FOLIC ACID

1) Leucovorin and folic acid enhance the metabolism of formic acid (formate) to carbon dioxide and water (Noker et al, 1980; Anon, 1979; Makar & Tephly, 1976).
2) Either folic acid or leucovorin (folinic acid) may be used in patients with methanol toxicity (Howland, 2011). Leucovorin (folinic acid) is the active form of folic acid and does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions using folate as a source of one-carbon moieties. It may be used for the initial dose in symptomatic patients, but it is more expensive than folic acid and there is no data that it improves outcome compared with folic acid. In symptomatic patients (anion gap acidosis, visual disturbances) and asymptomatic patients with known or suspected methanol intoxication, administer intravenous folic acid.

a) DOSE: 1 to 2 mg/kg every 4 to 6 hours for the first 24 hours. It should be continued until methanol is cleared and acidosis resolved. Folate is removed by hemodialysis so in patients undergoing hemodialysis, administer one dose prior to and another at the completion of hemodialysis. In studies, the use of folic acid 50 to 70 mg IV every 4 hours for the first 24 hours did not produce any complications (Howland, 2011).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) Methanol is an eye irritant.
B) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

A)

1) The EXTRIP (Extracorporeal Treatments in Poisoning) workgroup conducted a systemic review of the literature to develop evidence-based consensus recommendations for extracorporeal treatment in methanol poisoning. The recommendation to initiate extracorporeal treatment (ECTR) are as follows (Roberts et al, 2015):

a) Severe methanol poisoning, including any of the following conditions:

1) Coma;
2) Seizures;
3) New vision deficits;
4) Persistent metabolic acidosis from methanol poisoning (blood pH 7.15 or less; persistent metabolic acidosis despite adequate supportive measures and antidotes); and serum anion gap greater than 24 mmol/L.

b) Serum methanol concentrations:

1) Greater than 700 mg/L or 21.8 mmol/L in the context of fomepizole therapy;
2) Greater than 600 mg/L or 18.7 mmol/L in the context of ethanol treatment;
3) Greater than 500 mg/L or 15.6 mmol/L in the absence of an alcohol dehydrogenase inhibitor;
4) If no methanol concentration is available, the osmolal/osmolar gap may be informative.

c) In context of impaired kidney function.
d) Other recommendations to optimize ECTR outcomes:

1) The modality of choice is intermittent hemodialysis. If unavailable, consider continuous modalities.
2) Continue using alcohol dehydrogenase inhibitors during ECTR in addition to folic acid.
3) Discontinue ECTR when the methanol concentration is less than 200 mg/L or 6.2 mmol/L and clinical improvement is noted.

B)

1) INDICATIONS: Peak blood methanol concentration greater than 50 mg/dL (15 mmol/L), severe acidosis regardless of the blood methanol level, severe acid-base and or fluid-electrolyte disturbances despite conventional therapy, renal failure, and visual symptoms are indications for dialysis (Prod Info Antizol(R), fomepizole injection, 2000; Vogt et al, 1993).

a) Because chronic alcoholics who have ingested methanol may be at higher risk for severe sequelae or death despite ethanol infusion, some authors have advocated hemodialysis for these patients regardless of peak methanol levels (Roeggla et al, 1993).
b) In a series of 3 methanol-poisoned patients treated with ethanol only and 3 cases retrieved from a literature review, methanol half-life on ethanol was 43 hours (range 30 to 52 hours) (Palatnick et al, 1995). Because of the prolonged need for ethanol therapy and the difficulty in consistently maintaining therapeutic ethanol levels, these authors suggested that dialysis be considered in all patients requiring ethanol infusion.

2) EFFICACY: Hemodialysis is highly effective at removing methanol (McCoy et al, 1979; Girault et al, 1999) but ETHANOL or FOMEPIZOLE therapy should be continued during dialysis.

a) A methanol half-life of 2.5 hours during concurrent ethanol therapy and hemodialysis has been reported (McCoy et al, 1979).
b) A mean dialysance of 149 mL/min and 176 mL/min was reported by Jacobsen et al (1982) in 2 patients during hemodialysis with a blood flow rate of 200 mL/min and 215 mL/min, respectively (Jacobsen et al, 1982a).
c) Hay et al (1983) reported a mean clearance of 160 mL/min and a mean methanol extraction from plasma of 64% (Hay et al, 1983).
d) Methanol extraction (arterial-venous/arterial) and clearance values during hemolysis (Swartz et al, 1984)

Dialyzer Surface Area (m2)	Blood Flow (mL/min)	Methanol Extraction (A-V/A)	Methanol Clearance (mL/min)
2.5	250	60%	150
2.5	270	63%	170
2.5	300	73%	215
1.0	215	58%	125

3) FORMATE may be cleared even more rapidly by hemodialysis than is methanol. This may enhance the effectiveness of hemodialysis in therapy (Jacobsen et al, 1983).
4) LENGTH OF TREATMENT: Dialysis, once begun, should continue until the patient's clinical picture improves and the methanol level decreases below 20 mg/dL. Some patients, including those with renal insufficiency, may need to be dialyzed for as long as 20 hours (Burgess, 1992).
5) REBOUND/CASE REPORT: A 38-year-old man with a history of schizophrenia ingested "3 gulps" of windshield washing fluid and 64 ounces of beer, and had initial methanol and ethanol levels of 57 mg/dL and 148 mg/dL, respectively. Since the patient was asymptomatic, fomepizole 500 mg every 12 hours was begun. However, about 5 hours after admission, the methanol level rose to 75 mg/dL and peaked approximately 8 hours after ingestion at 108 mg/dL. The patient continued to be asymptomatic, but hemodialysis was begun secondary to the methanol concentration; the patient was dialyzed for 4.5 hours using a high-efficiency hemophan dialyzer. During this period, the methanol level dropped from 90 mg/dL to 39 mg/dL but rebounded 2 hours postdialysis to 56 mg/dL. A second course of dialysis was performed and the level dropped and remained below detection over the next 10 hours. Although rebound was not expected with methanol due to the relatively low volume of distribution (Vd = 0.7 L/kg) , the authors suggested that the use of a high-efficiency dialyzer capable of rapid solute clearance could have contributed to the effects observed. Ongoing monitoring postdialysis was recommended (Elwell et al, 2004).
6) REQUIRED DIALYSIS TIME: Hirsch et al (2001) described a simple method to estimate required dialysis time following methanol poisoning, using an assumption that toxic alcohols have a dialysis clearance similar to urea. To reach the therapeutic toxin concentration of 5 mmol/L-or-less, the proposed dialysis time is: [-V ln(5/A)]/0.06k, where V (liters) is the Watson estimate of total body water, A is the initial toxin concentration (mmol/L), and k is 80% of the manufacturer-specified dialyzer urea clearance (mL/min) at the initial observed blood flow rate. This method would limit the need for toxin concentration measurements to predialysis and postdialysis samples (Hirsch et al, 2001). Another study evaluated the accuracy of this formula and found that it provides a useful tool for predicting required dialysis time in patients with methanol or ethylene glycol poisoning. No clinically or statistically significant differences between mean predicted (8.7 +/- 3.4 [SD] hours) and required (8.4 +/- 3.2 hours) dialysis time were observed in a group of patients with methanol (n=3) and ethylene glycol (n=10) poisoning (Youssef & Hirsch, 2005).
7) ETHANOL-ENRICHED DIALYSATE: Chow et al (1997) report treating an acute methanol poisoning with an ethanol-enriched, bicarbonate-based dialysate. An intradialytic plasma ethanol level of 80 to 102 mg/dL was maintained. The dialysis solution ethanol concentration was 100 mg/dL, which was prepared by the addition of 95% ethanol into the dialysate inlet tubing of the dialyzer with a side-tube at a rate of 40 mL/hr (Chow et al, 1997).
8) CASE REPORT: Greiner et al (1989) reported visual recovery following an acute ingestion of sterno (71% ethanol, 3.6% methanol) approximately 24 hours prior to admission. Acidosis was corrected with sodium bicarbonate, intravenous ethanol (8 g/hr X 5 doses) was administered, and hemodialysis (200 to 250 mL/min for 3 hours 40 minutes) was initiated 6 hours after admission. Methanol level was reported to be 75 mmolL prior to treatment (Greiner et al, 1989).

a) The history of ingestion in this case is not consistent with the observed methanol concentration. Also, the visual effects noted (blurred vision, photophobia, reduced visual acuity) have been reported to be transient.

9) PHOSPHORUS-ENRICHED HEMODIALYSIS

a) CASE SERIES: Three patients with severe methanol poisoning were treated with phosphorus-enriched hemodialysis, in order to prevent hypophosphatemia that may occur with intensive and prolonged hemodialysis therapy. Two of the 3 patients were intravenously given a loading dose of 10% ethanol (0.6 g/kg) followed by a constant ethanol infusion of 166 mg/kg/hr. Hemodialysis was performed on all 3 patients using a phosphorus-enriched dialysis solution. The average dialyzer blood flow rate was 350 mL/min and the average dialysate flow rate was 500 mL/min. The plasma methanol levels were undetectable at the end of the hemodialysis sessions and there were no dialysis-related complications reported (Chebrolu et al, 2005).

10) CONTINUOUS HEMODIALYSIS (CHD)

a) CASE REPORT: A 65-year-old man with a history of ethanol abuse was admitted to ICU drowsy and in severe metabolic acidosis (pH 6.62, base excess - 26.2 mmol/L and lactate 8.3 mmol/L). Because of worsening CNS depression, the patient was intubated and mechanically ventilated and sodium bicarbonate begun. The initial diagnosis was presumed methanol or ethylene glycol intoxication, and treatment consisted of ethanol administration via a NG tube and continuous hemodialysis for 11 hours. Within 3 hours of CHD, the patient began to clear mentally, and acidosis normalized. Following extubation, the patient admitted to drinking 40 mL of methanol (admission methanol level was 883 mg/L and 134 mg/L following CHD) and complained of visual loss with papilledema observed. During the sixth hospital day, a decrease in level of consciousness was observed with hemiplegia. A repeat CT scan showed bilateral putaminal necrosis and neurological status did not improve by hospital day 12 (Fujita et al, 2004).
b) CASE REPORT: A 31-year-old man presented with coma and a pH of 6.9 after ingestion of an unknown amount of methanol. The initial serum methanol level was 189 mmol/L (about 605 mg/dL). Hemodialysis was begun approximately 7 hours after admission and continued for 12 hours. Neurological improvement was noted, with return of corneal, doll's eye, and ocular vestibular reflexes. Because methanol levels remained high, another course of dialysis was commenced for 9 hours until the methanol level was below the toxic range. Residual signs included a dilated, fixed left pupil and bilateral sensorimotor hip and leg neuropathy. Methanol clearance during dialysis was essentially equivalent to blood flow, while the corresponding renal clearance was negligible (Burgess, 1992).

11) CONTINUOUS VS INTERMITTENT HEMODIALYSIS

a) A prospective observational study of 24 patients with methanol poisoning evaluated methanol and formate elimination using either intermittent hemodialysis (IHD; n=11) or continuous veno-venous hemodialysis/hemodiafiltration (CVVHD/HDF; n=13) during an outbreak of methanol poisonings in the Czech Republic in 2012. Overall, patients in the CVVHD/HDF were more acidotic (mean pH 6.9 vs 7.1 IHD). The mean elimination half-life of methanol and formate were 3.7 hours and 1.6 hours for IHD and 8.1 hours and 3.6 hours for CVVHD/HDF, respectively. The higher blood and dialysate flow rates during IHD produced 54% greater reduction in methanol and 56% reduction in formate elimination half-life. During CVVHD/HDF, increased blood and dialysate flow rate also increased elimination significantly. It was concluded that IHD is superior to CVVHD/HDF for more rapid methanol and formate elimination. Of note, if only CVVHD/HDF is available, elimination can be greater with increased blood flow and dialysate flow rates (Zakharov et al, 2014).

C)

1) Peritoneal dialysis and continuous venovenous hemofiltration are less effective than hemodialysis but may be of some use (Keyvan-Larijarni & Tannenberg, 1974). These methods have been used when hemodynamic complications (systolic blood pressure too low, even following catecholamine infusion) have limited the use of hemodialysis (Hantson et al, 2000a).
2) Is technically easier in infants and has been successfully used (Wenzl et al, 1968).

D)

1) In a study of 3 severely intoxicated patients who ingested a 54% methanol (MeOH) solution, 2 received continuous veno-venous hemodiafiltration (CVVHDF) (the only treatment available) and the third received hemodialysis (HD) at another hospital. In comparing the 2 methods, clearance was approximately 5-fold greater with hemodialysis and duration of therapy was approximately half (12 hours as compared with 24 hours). In addition, toxicokinetic analyses confirmed the superiority of HD over CVVHDF in reaching target serum MEOH concentrations and correcting metabolic derangement (note: formic acid toxicokinetics was not examined in this study). The authors concluded that although CVVHDF can be effective, it is NOT as effective as hemodialysis; it may have some limited application in less severely poisoned patients or if HD is not available (Kan et al, 2003).

E)

1) CASE REPORT: A 24-year-old man presented unconscious (Glasgow Coma score 10) about 2 hours after ingesting about 100 mL of methanol and 50 g of sodium ferrocyanide. His vital signs included a blood pressure of 78/34 mmHg, heart rate of 56 beats/min, irregular respiratory rate, and pulse oxygen saturation of 65%. Laboratory results revealed increased leukocytes, respiratory failure, acute kidney injury, and metabolic acidosis. Serum concentrations of sodium ferrocyanide, methanol, and its product formic acid at 2 hours postingestion were 361.2 mg/L, 1244.1 mg/L, and 728.6 mg/L, respectively. Following supportive care, including endotracheal intubation and mechanical ventilation, gastric lavage, sodium bicarbonate, ethanol, plasmapheresis (plasma exchange), and continuous renal replacement therapy (CRRT), his condition gradually improved and he was discharged on day 6 without further sequelae (Liu et al, 2015).

Abstracts

Case Reports

A)

1) INHALATION

a) A 17-year-old intoxicated boy was brought to the emergency department with a blood methanol level of 23 mg/dL after inhaling fumes of a carburetor cleaner containing 22.5% methanol. Initial arterial blood gas results included a pH of 7.39, pCO2 33 mmHg, and plasma bicarbonate of 19 mEq/L. The patient denied any ingestion of substances and recovered completely after treatment with 100% oxygen and an intravenous ethanol (McCormick et al, 1990).
b) Frenia & Schauben (1993) described a series of 7 cases (4 patients) involving inhalation exposure to methanol through intentional abuse of carburetor cleaner (approximately 23% methanol). Absorption was significant, with measured blood methanol levels ranging from 50.4 to 128.6 mg/dL. One patient was unable to be resuscitated at the scene. The remaining patients required IV ethanol and folate, and 2 required hemodialysis. All recovered fully within 1 week (Frenia & Schauben, 1993).

2) DERMAL

a) An 8-month-old boy died after being treated at home with methanol-soaked chest poultices for a cold . The poultices were applied for 12 hours each on 2 consecutive nights. On admission, the child was cyanotic and comatose, with a blood pH of 6.5 and bicarbonate less than 3 mEq/L. Treatment consisted of intravenous ethanol, supportive treatment, and peritoneal dialysis. No other sources of toxicants were identified (Kahn & Blum, 1979).
b) One case of industrial methanol intoxication with visual symptoms is reported (Downie et al, 1992). In this case, inhalation exposure was unlikely due to use of a positive pressure supplied air respirator.
c) Percutaneous absorption of methanol occurred in a 27-week gestation infant who developed severe skin necrosis after treatment of an umbilical catheterization site using denatured alcohol. Eighteen hours later, blood methanol was 26 mg/dL, with ethanol at 259 mg/dL (Harpin & Rutter, 1982).
d) A 51-year-old woman developed severe methanol toxicity (coma, high-anion-gap metabolic acidosis, hypotension, methanol level of 3.3 mg/dL obtained 3 days after exposure and after 1 hemodialysis session) after repeated dermal application of methanol ("spirit") to her head. The patient's relatives denied oral ingestion of methanol-containing substances. Despite supportive treatment and hemodialysis, she died after 4 days of hospitalization (Soysal et al, 2007).

3) ORAL

a) Four inmates at a prison ingested an unknown amount of a mixture of fruit juice and copy fluid (predominantly methanol) and were admitted to the hospital 40 hours later.

1) On admission, blood methanol levels ranged from 24 to 222 mg/dL; vital signs were all normal; HCO3 ranged from 11 to 26 mEq; serum pH values were 7.35 to 7.41; and potassium levels decreased to between 3.1 and 3.6 mEq/L. Blood formate levels corresponded to methanol levels in the 4 patients as follows (formate: methanol reported in mg/dL): less than 0.5 to 33:72; 55:24; and 75:222.
2) Clinical signs included abdominal cramps and nausea. All patients were treated with intravenous ethanol and the patients with blood methanol levels of 72 and 222 mg/dL were also hemodialyzed. All recovered uneventfully (Osterloh et al, 1986).

b) A 50-year-old woman with a history of chronic alcoholism became comatose following accidental ingestion of embalming fluid (pure methanol) (Kuteifan et al, 1998). On admission, blood pH was 6.71, PCO2 41 mmHg, HCO3 5 mmol/L, osmolal gap 84 mosm/L, and blood methanol 39.7 mmol/L (approximately 124 mg/dL). Despite treatment with hemodialysis, IV ethanol, and folate, the patient remained comatose. At the time of publication, the patient had been in a vegetative state for 1 year.

Range Of Toxicity

Summary

A)

Minimum Lethal Exposure

A)

B)

C)

D)

E)

F)

G)

Maximum Tolerated Exposure

A)

1) Most exposures to methanol result from ingestion; however, symptoms may also occur from inhalation, skin absorption, or intravenous injection. Patients develop nausea, abdominal pain, headache, abnormally slow, deep breathing, and visual symptoms ranging from blurred or double vision and changes in color perception to constricted visual fields and complete blindness within 18 to 48 hours of ingestion. Chronic exposures to airborne concentrations of 1200 to 8300 parts per million (ppm) can lead to impaired vision. Exposure to airborne vapor concentrations ranging from 365 to 3080 ppm may result in blurred vision, headache, dizziness, and nausea (Grant & Schuman, 1993; Hathaway et al, 1996).
2) On a scale of 1 to 6 (1 is practically nontoxic; 6 is super toxic), methanol is rated as 3 (moderately toxic) (Gosselin et al, 1984).

a) Note: The metabolism of methanol in rats is different than in humans. This might lead to a discrepancy between the experimental animal findings and the actual toxicity of methanol in humans. In particular, rats can assimilate higher levels of methanol than humans without serious physical effects (Kinney & Kavet, 1988). Methanol toxicity in humans should probably be upgraded to level 4, highly toxic.

3) The range of toxicity of methanol is extremely variable. Blindness has followed ingestion of about 4 mL of absolute methanol (Bennett, 1953).
4) Extremely high exposures (greater than 25,000 ppm) are necessary to produce sensory irritation (Bingham et al, 2001).

B)

1) INHALATIONAL EXPOSURE: In a retrospective study of 22 patients with inhalational exposure to methanol-containing carburetor cleaners (mean serum methanol concentration of 28 mg/dL obtained at a mean of 3.5 hours postexposure; range 0 to 34), all patients presented with neurotoxicity. Vomiting and metabolic acidosis developed in 14 (63.6%) and 17 (77%) patients, respectively. Overall, significant toxicity was rare, with symptoms improving without aggressive care (dialysis, alcohol dehydrogenase blockade). Visual disturbances or neurological sequelae did not develop in any patients (LoVecchio et al, 2004).
2) A 24-year-old man presented unconscious (Glasgow Coma score 10) about 2 hours after ingesting about 100 mL of methanol and 50 g of sodium ferrocyanide. His vital signs included a blood pressure of 78/34 mmHg, heart rate of 56 beats/min, irregular respiratory rate, and pulse oxygen saturation of 65%. Laboratory results revealed increased leukocytes, respiratory failure, acute kidney injury, and metabolic acidosis. Serum concentrations of sodium ferrocyanide, methanol, and its product formic acid at 2 hours postingestion were 361.2 mg/L, 1244.1 mg/L, and 728.6 mg/L, respectively. Following supportive care, including endotracheal intubation and mechanical ventilation, gastric lavage, sodium bicarbonate, ethanol, plasmapheresis (plasma exchange), and continuous renal replacement therapy (CRRT), his condition gradually improved and he was discharged on day 6 without further sequelae (Liu et al, 2015).
3) One patient survived after drinking 500 mL of 40% methanol (Martens et al, 1982).
4) The occurrence of severe methanol poisoning with fatal outcome or ocular sequelae appeared to be related to the time between ingestion and initiation of treatment. All of 4 patients admitted before 10 hours postingestion had a favorable outcome. Of 6 patients admitted 20 hours or more after ingestion, 4 had ocular sequelae and 1 died (Mahieu et al, 1989).
5) In a letter to the editor, 1 case of intravenous injection of approximately 250 mg of methanol was reported to result in optic papillitis and retinal edema with subsequent blindness in a 20-year-old man (Wang et al, 1999). Sivilotti et al (2000) question whether this small dose of methanol could cause serious methanol toxicity and suggest that the patient may have had an additional source of methanol (Sivilotti et al, 2000).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) FATAL: A plasma methanol concentration of about 40 mg/100 mL (12 mmol/L) of blood (= 40 mg% = 40 mg/dL) has been fatal in humans, but there is a wide variation in individual sensitivity (Kahn & Blum, 1979).

1) Thus, deaths have been reported with blood methanol levels of 19.4 (6 mmol/L), 27.7 (8.6 mmol/L) and 27.5 (8.6 mmol/L) mg/100 mL at 48, 50, and 50 hours, respectively, after ingestion. In most of these cases, the true peak methanol levels were not known.
2) CASE SERIES: In a single center, retrospective study of 178 cases of methanol toxicity (average amount ingested: 150 mL) in India, serum methanol concentrations ranged from 12 mg/dL to 376 mg/dL (mean, 87.1 mg/dL). Significantly higher serum methanol concentrations were observed in patients who died compared with those who survived (121 +/- 92 mg/dL versus 53.1 +/- 41 mg/dL, p less than 0.05) (Jarwani et al, 2013).
3) CASE REPORT: Serum methanol level of 170 mg/dL has been reported in a 26-year-old woman following ingestion of an unknown quantity. She died 3 weeks later, despite ongoing therapy (Feany et al, 2001).
4) CASE REPORT: A 51-year-old woman developed a serum methanol level of 89 mg/dL after consuming an unknown quantity of methanol. She died 7 days later, with necropsy revealing acute hemorrhage and necrosis of the putamen as subcortical white matter (Feany et al, 2001).
5) CASE REPORT: A 27-year-old man survived a blood methanol concentration of 12.9 g/L after possible ingestion of 1000 mL of a 60% methanol solution. The patient was treated with ethanol infusions, hemodialysis, and peritoneal dialysis. Permanent sequelae included visual deficits (optic neuropathy) and esophageal stenosis (Hantson et al, 2000a).
6) CASE REPORT: A blood methanol level of 811 mg/dL was reported in a 49-year-old man who developed severe metabolic acidosis and total blindness after ingesting an unknown amount of homemade herbal wine. Although his metabolic acidosis resolved following emergent hemodialysis, his visual defects persisted (Yang et al, 2005).
7) CASE REPORT: A 40-year-old woman presented with dysarthria, disorientation, and smelling of alcohol after ingesting an unknown amount of methanol-containing product. She developed severe agitation, tachypnea, tachycardia, generalized hypertonia, and a hypertensive crisis 5 hours postadmission. Laboratory analysis revealed severe metabolic acidosis with increased anion and osmol gaps. Laboratory analysis revealed a blood methanol level of 100 mg/dL. Despite supportive care, she died of gastrointestinal hemorrhage 33 days after presentation (Vara-Castrodeza et al, 2007).

b) PEDIATRIC

1) As a rough estimate, ingestion of 1.5 mL of 100% methanol by a child weighing 10 kg (assuming a volume of distribution of 0.6 L/kg) would produce a potential maximum peak plasma level of 20 mg/dL, a level at which institution of an ethanol drip would be considered. In the same child, an average swallow (2 to 8 mL) would produce a potential maximum peak level of 26 to 105 mg/dL.

a) CASE REPORT: A serum methanol level of 134 mg/dL was measured in a 1-year-old child who was found playing with an open container of 100% methanol. Three hours postexposure, trembling was noted, but the physical examination was unremarkable and there was no lethargy (Chiang et al, 1997).

2) CASE REPORT: A 14-month-old child presented to the emergency department (ED) with tachycardia (pulse 112 beats per minute), tachypnea (46 breaths per minute), hypotension (81/50 mmHg), and metabolic acidosis. Toxicology results revealed a serum methanol level of 90 mg/dL. The patient recovered following 10% ethanol infusion and dialysis. It is believed that the source of intoxication may have been windshield washer fluid (Carpentieri et al, 2003).

c) BASE EXCESS

1) pH levels and base excess may be better predictors of outcome than the absolute methanol level. In 33 cases, 12 of which were fatal, outcome was better related to the interval between the time of ingestion and initiation of therapy and the presence of severe metabolic acidosis than to the initial methanol level (Pappas & Silverman, 1982; Teo et al, 1996).
2) Mahieu et al (1989) found a correlation between blood formate concentrations and base deficit (r = 0.75) and the total CO2 (r = 0.79) in the blood based on 10 adult patients acutely intoxicated with methanol(Mahieu et al, 1989). No significant blood ethanol levels were present in 9 of 10 patients. All 4 patients with ocular sequelae had blood formate levels of greater than 0.5 g/L.

d) ETHANOL INTERACTION

1) Ethanol therapy is very effective at preventing toxicity of even extremely high methanol concentrations. A patient with an admission methanol level of 403 mg% and ethanol level of 158 mg% never developed acidosis despite having a serum methanol level greater than 50 mg% for over 18 hours (Palmisano et al, 1987).
2) Ingestion of 1000 to 1500 mL of red wine by human volunteers resulted in methanol levels of about 10 mg/dL at the time that ethanol levels approached zero, thereby leading to the postulate that methanol metabolism may be responsible for the symptoms of ethanol hangover (Jones, 1987).

e) POSTMORTEM

1) Tissue distributions of methanol in a man found dead after ingestion of an unknown amount of methanol included (in g/L) blood: 2.84; pericardial fluid: 3.29; vitreous humor: 3.96; gastric contents: 2.21; urine: 3.43; kidney: 5.13; liver: 4.18; and heart: 3.45 (Pla et al, 1991). Wu et al (1985) report postmortem tissue levels in a case with a blood methanol level of 142 mg/dL(Wu Chen et al, 1985). Tissue/fluid levels (mg/100 g) were bile: 175; vitreous: 173; brain: 159; kidney: 130; lung: 127; spleen: 125; muscle: 125; liver: 107; heart: 93.
2) Tissue distributions of FORMIC ACID in two 25-year-old men who died after ingestion of an unknown amount of methanol were (in mg/g except where noted): 0.11 and 1.17 in the brain; 0.54 and 0.51 in the liver; 0.13 and 1.19 in the kidneys; 0.32 and 0.23 mg/mL in the blood; 2.27 and 0.47 mg/mL in the urine; and 108 and 23.2 mg in the gastric contents (Tanaka et al, 1991).
3) Postmortem blood methanol levels were 240, 290, and 150 mg/dL measured at 10, 12, and 18 hours postingestion, respectively, in 3 fatal cases (Sharma et al, 1991) and 72 mg/dL in another case (Young & McCormick, 1995). In 17 fatal methanol poisoning victims, postmortem levels were 23 to 268 mg/dL(Hashemy-Tonkabony, 1975).

f) HIGHEST SURVIVAL LEVEL

1) A peak serum methanol level of 920 mg/dL (287.5 mmol/L) was reported in a patient who ingested 500 mL methanol in a suicide attempt and survived (Martens et al, 1982).

g) FORMIC ACID

1) Levels in normal individuals are 0 to 12 mcg/mL. Levels of 120 and 193 mcg/mL have been reported in toxic patients (Frenia & Schauben, 1992).
2) INHALATION: Inhalant abusers of methanol-containing products may be at a decreased risk of developing toxicity (visual dysfunction and refractory acidosis) despite significantly elevated methanol and formic acid concentrations (Bebarta et al, 2006).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Methanol

a) TLV:

1) TLV-TWA: 200 ppm
2) TLV-STEL: 250 ppm
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: BEI, Skin
3) Definitions:

a) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): Headache; eye dam
d) Molecular Weight: 32.04

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS67-56-1 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Methyl alcohol
2) REL:

a) TWA: 200 ppm (260 mg/m(3))
b) STEL: 250 ppm (325 mg/m(3))
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s):

3) IDLH:

a) IDLH: 6000 ppm
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS67-56-1 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Methanol
2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Methanol
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Methyl alcohol
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS67-56-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Methyl alcohol
2) Table Z-1 for Methyl alcohol:

a) 8-hour TWA:

1) ppm: 200

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 260

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) References: IPCS, 1997 ITI, 1995 Lewis, 2000 OHM/TADS, 2002 RTECS, 2002

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 10,765 mg/kg

2) LD50- (ORAL)MOUSE:

a) 0.420 g/kg (IPCS, 1997)
b) 7.3-10.0 g/kg (IPCS, 1997)
c) 7300 mg/kg

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 4100 mg/kg (ITI, 1995)
b) 9800 mg/kg

4) LD50- (INTRAPERITONEAL)RAT:

a) 7529 mg/kg

5) LD50- (ORAL)RAT:

a) 6.2 g/kg (IPCS, 1997)
b) 9.1 g/kg (IPCS, 1997)
c) 12.9 g/kg (IPCS, 1997)
d) 13.0 g/kg (IPCS, 1997)
e) 5628 mg/kg
f) Young, 5300 mg/kg (OHM/TADS, 2002)
g) 6200 mg/kg (OHM/TADS, 2002)
h) 12,880 mg/kg for 14D (OHM/TADS, 2002)

6) TCLo- (INHALATION)HUMAN:

a) 86,000 mg/m(3) -- lacrimation, cough, changes of the lung, thorax, or respiration
b) 300 ppm -- visual changes, headache; lung, thorax or respiration changes

7) TCLo- (INHALATION)MOUSE:

a) Female, 15,000 ppm at 7-9D of pregnancy -- postimplantation mortality; fetotoxicity (except death)
b) Female, 2000 ppm for 7H at 6-15D of pregnancy -- developmental abnormalities of musculoskeletal system
c) Female, 7500 ppm for 7H at 6-15D of pregnancy -- postimplantation mortality; fetal death
d) Female, 5000 ppm for 7H at 6-15D of pregnancy -- craniofacial and central nervous system effects
e) Female, 1500 ppm for 6H at 7-9D of pregnancy -- central nervous system effects

8) TCLo- (INHALATION)RAT:

a) Female, 10,000 ppm for 7H at 7-19D day of pregnancy -- fetotoxicity (except death)
b) 50 mg/m(3) for 12H/13W - intermittent -- degenerative changes of brain and coverings; muscle contraction or spasticity
c) 2610 ppm for 6H/4W - intermittent -- changes in spleen weight
d) Female, 20,000 ppm for 7H at 7-15D of pregnancy -- developmental abnormalities in musculoskeletal and endocrine systems
e) Female, 20,000 ppm for 7H at 1-22D of pregnancy -- developmental abnormalities in musculoskeletal, cardiovascular, and urogenital systems

Pharmacology Toxicology

Toxicologic Mechanism

A)

1) Methanol is converted relatively slowly (one-fifth the rate of ethanol oxidation) in the human liver to formaldehyde and then to formic acid by the catalytic action of alcohol dehydrogenase and acetaldehyde dehydrogenase. It is these 2 metabolites of methanol, rather than methanol per se, that are highly toxic and produce the severe metabolic acidosis, ocular symptoms, and other effects of acute methanol poisoning.

B)

1) It is suggested that formic acid inhibits cytochrome oxidase activity by binding to the ferric iron moiety; it is less potent in this regard than cyanide and carbon monoxide (Liesivuori & Savolainen, 1991a). The acidosis present in severe methanol poisoning increases the concentration of undissociated formic acid, thus potentiating inhibition of cellular respiration.
2) The result is tissue hypoxia and lactic acid formation, which further adds to the undissociated formic acid levels and perpetuates the circle of hypoxic damage. The anion gap observed clinically is due to both lactic acid and formic acid.
3) Secondary to anaerobic glycolysis and lactic acidosis, superoxide anions and hydroxyl radicals are generated, leading to cell membrane damage. There is an influx of calcium into the cell, resulting in mitochondrial dysfunction and cell death.
4) It has been found that methanol-induced retinal toxicity in experimental animals is due to formate accumulation(Garner et al, 1995). The data also suggested that intraretinal metabolism of methanol was responsible for toxic formate buildup.
5) Cytotoxic activity of formate within the retrolaminar optic nerve, retina, or both may be apparent within 24 hours of toxic exposures. The primary pathologic defect is hypothesized to be inhibition of axonal saltatory conduction. Direct inhibition of cytochrome oxidase by formic acid significantly alters neuronal mitochondrial respiration, which in turn results in a state of cytotoxic anoxia and stasis of axoplasmic flow causing neuronal conduction deficits (Sullivan-Mee & Solis, 1998).
6) It is speculated that formic acid may have an indirect effect on ammonia clearance, which may in turn contribute to the profound impairment of the central nervous system(Foster & Schoenhals, 1995).

C)

1) Administration of an alcohol dehydrogenase inhibitor (ethanol or fomepizole) effectively inhibits oxidation of methanol into its far more toxic products. Ethanol has about 20 times the affinity for alcohol dehydrogenase compared with methanol.

a) This competitive effect gains more time for excretion of unchanged methanol from the body, and it also inhibits the formation of methanol metabolites that produce severe acidosis. Formic acid is metabolized to carbon dioxide and water via a folate-dependent system.

2) Folic acid or leucovorin (active metabolite of folic acid) may enhance the elimination of formic acid following methanol overdose by stimulating formate oxidation or utilization (Noker et al, 1980).

D)

1) Patients may ingest products containing a variety of chemical agents, some of which may compete with methanol for conversion by liver dehydrogenases (much as ethanol does). Some authors postulate that the presence of these agents may ameliorate the clinical course of methanol-intoxicated patients.
2) PROPYLENE GLYCOL (PG): Shapiro et al (1993) state that the PG content of a methanol-containing antifreeze ingested by a patient may have inhibited the metabolism of methanol(Shapiro et al, 1993). The patient's methanol level was 200 mg/dL and the PG level was 47 mg/dL on admission; he was hemodialyzed for 7 hours and given intravenous ethanol treatment. Blood ethanol levels did not approach 100 mg/dL, but the patient--an alcoholic--experienced only moderate clinical effects. The authors suggest a protective effect from the blood PG.
3) METHYL ETHYL KETONE (MEK): Price et al (1994) report a case of an alcoholic patient's ingestion of a fluid containing MEK and methanol(Price et al, 1994). On admission, the methanol level was 214 mg/dL, serum formate was 6 mg/dL, and MEK was 124 mg/dL. The patient did not have an anion gap metabolic acidosis but did have an osmolar gap. The authors suggested that MEK could both competitively and noncompetitively inhibit liver dehydrogenases.

Physicochemical

Physical Characteristics

A)

Ph

1) No information found at the time of this review.

Molecular Weight

A)

Other

A)

1) 100 ppm (Bingham et al, 2001; Pohanish, 2002)
2) 2000-5900 ppm (Bingham et al, 2001)
3) Threshold for unadapted panelists: 2000 ppm (Verschueren, 2001)
4) After adaptation with pure odorant: 20,000 ppm (Verschueren, 2001)
5) Low: 13.1 mg/m(3) (HSDB , 2002)
6) Distinct odor: 8800 ppm; 11,700 mg/m(3) (Verschueren, 2001)
7) 13.1150 mg/m(3) (low) (HSDB , 2002)
8) 26840 mg/m(3) (high) (HSDB , 2002)
9) 22875 mg/m(3) (irritating concentration) (HSDB , 2002)
10) A range from 100 ppm to 1500 ppm has been reported (ACGIH, 1991)
11) Mild odor threshold of around 8-10 ppm (Baxter, 2000).

Animal Toxicology

Clinical Effects

11.1.2)

A) Cattle may exhibit ataxia, depression, then become recumbent, and attempt to vomit prior to death (Rousseaux et al, 1982).

11.1.3)

A) METABOLIC ACIDOSIS

1) Metabolic acidosis has been reproduced in only 10% to 15% of experimentally exposed dogs (Beasley et al, 1990).
2) Infusion of amounts lethal to 8 of 11 animals did not alter blood pH, PCO2, or PO2 until animals were close to death (DeFelice et al, 1976).

B) CARDIAC

1) Toxicity was predominantly manifested by hemodynamic disturbances (decreased stroke volume and cardiac output, hypotension, increased total peripheral resistance), leading to cardiac arrest at blood levels of about 400 mg/dL. These effects were attributed to methanol, and not to formaldehyde or formic acid (DeFelice et al, 1976).

C) OTHER SIGNS

1) Other signs that may be seen in dogs include seizures, coma, and respiratory arrest. Signs of toxicity appear within 15 minutes to 5 hours of ingestion (Beasley et al, 1990).
2) A 26 kg dog ingested a 98% methanol gas line antifreeze and was found weak and staggering. Upon examination, the dog was found to be depressed, febrile, and had evidence of abdominal pain. Acidosis was not reported, although ethanol and sodium bicarbonate were given initially. Ethanol was continued for 3 days (Hurd-Kuenzi, 1983).

11.1.10)

A) The pig has low levels of formate, and the ability to metabolize formate is limited and slow. Pigs are therefore easily methanol intoxicated (Makar et al, 1990).
B) MINI PIGS: Dorman et al (1993) experimentally exposed mini pigs to up to 5 mg/kg methanol by mouth. Dose-dependent signs observed included CNS depression, ataxia, and recumbency; signs appeared at 0.5 to 2 hours and had receded by 52 hours postdosing. None of the subjects developed optic nerve lesions, metabolic acidosis, or dangerous blood formate levels.

11.1.13)

A) OTHER

1) Clinical signs may include excitability, vocalizing, incontinence; depression; ataxia; unconsciousness, loss of reflexes, or coma; respiratory distress or arrest; cardiac arrest; and death (Valentine, 1990).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) If the animal is conscious, ambulatory, and showing only mild to moderate behavioral changes, only decontamination, symptomatic treatment, and observation are required. If profound CNS depression is present, the situation is an emergency and respiratory and cardiac support must be provided immediately (Valentine, 1990).
2) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

3) Treatment should always be done on the advice and with the consultation of a veterinarian.
4) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
5) ASPCA ANIMAL POISON CONTROL CENTER

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS/GASTRIC LAVAGE

1) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
2) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
3) DOGS AND CATS

a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

4) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.

a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ACTIVATED CHARCOAL/CATHARTIC

1) METHANOL: Activated charcoal does not adsorb significant amounts of methanol. Its use in the face of ingestion may be indicated to prevent absorption of coingested substances.
2) ACTIVATED CHARCOAL: Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
3) CATHARTIC: Administer a dose of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
4) ACTIVATED CHARCOAL/HORSES: Administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube. Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
5) ACTIVATED CHARCOAL/RUMINANTS: Administer 2 to 9 grams/ kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube. Sheep may be given 0.5 kilogram charcoal in slurry.
6) CATHARTICS/HORSES: Mineral oil is administered 30 minutes after activated charcoal. DOSE: 4 to 6 liters in adult horses and 1 to 4 liters in neonates or foals.

a) Magnesium sulfate: 0.2 to 0.9 grams/kilogram (500 grams for adults).
b) The sulfate laxatives are especially effective when given 30 to 45 minutes after mineral oil administration.
c) Carbachol (lentin): administer 1 milligram to an adult.

7) CATHARTICS/RUMINANTS & SWINE: Adult cattle: administer 500 grams sodium or magnesium sulfate. Other ruminants and swine: administer 1 to 2 grams/kilogram.

a) The sulfate laxatives are especially effective when given 30 to 45 minutes after cathartic administration.
b) Mineral oil: Do not administer within 30 minutes of activated charcoal. DOSE: small ruminants and swine, 60 to 200 milliliters; cattle, 0.5 to 1 gallon.
c) Magnesium oxide: (Milk of Magnesia) Small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os.
d) Give these solutions via stomach tube and monitor for aspiration.

c) DERMAL DECONTAMINATION

1) Wash exposed animals with soap and water. If possible, shave or clip long hair to facilitate thorough cleaning. All handlers should wear gloves and protect themselves from exposure.
2) Some chemicals can produce systemic toxicosis via absorption through the intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs and treat as necessary.

d) INHALATION DECONTAMINATION

1) Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.

e) OCULAR DECONTAMINATION

1) Rinse eyes with copious amounts of tepid water for 15 minutes. If irritation, pain, or photophobia persist, see your veterinarian.

11.2.5)

A) DOGS/CATS

1) Severe respiratory depression may lead to anoxia and death. Respiration must be supported with the necessary combination of oxygen, intubation or tracheostomy, and positive pressure ventilation.
2) CARDIAC SUPPORT

a) EPINEPHRINE: In case of cardiac arrest: DOGS: 0.5 to 1 mL of 1:10,000 (DILUTE) solution intravenously; CATS: 0.5 mL of 1:10,000 (DILUTE) solution intravenously. Be sure to dilute epinephrine from the bottle (1:1000), 1 part to 9 parts saline to obtain the correct concentration (1:10,000). If indicated, dose may be repeated.
b) Monitor EKG.
c) Bradycardias can be treated with atropine at 0.02 milligram/kilogram intravenously.
d) PREMATURE VENTRICULAR CONTRACTIONS IN DOGS: Can be treated with lidocaine (without epinephrine) at a dose of 1 to 2 milligrams/kilogram as an intravenous bolus followed by an intravenous drip of a 0.1 per cent solution at 30 to 50 micrograms/kilogram per minute.

1) Propranolol, a beta blocker, can be used in dogs refractory to lidocaine. It is dosed in dogs at 0.04 to 0.15 milligrams/kilogram intravenously over 1 to 2 minutes three times daily.

e) PREMATURE VENTRICULAR CONTRACTIONS IN CATS: DO NOT USE

1) LIDOCAINE IN CATS. Use propranolol instead of lidocaine; dose at 0.25 milligram diluted in 1 milliliter saline and give 0.2 milliliter boluses intravenously to effect. Monitor for hypotension and decrease in cardiac output.

3) SEIZURES/LARGE ANIMALS: May be controlled with diazepam.

a) HORSES/DIAZEPAM: Neonates: 0.05 to 0.4 milligrams/kilogram; Adults: 25 to 50 milligrams. Give slowly intravenously to effect; repeat in 30 minutes if necessary.
b) CATTLE, SHEEP AND SWINE/DIAZEPAM: 0.5 to 1.5 milligrams/kilogram intravenously to effect.

4) SEIZURES/DOGS & CATS:

a) DIAZEPAM: 0.5 to 2 milligrams/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes to effect.
b) PHENOBARBITAL: 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously to effect.
c) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

5) Begin electrolyte and fluid therapy with isotonic solutions as needed at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.
6) BICARBONATE: Add sodium bicarbonate to the intravenous fluids if metabolic acidosis is suspected. (If using lactated ringers solution and precipitate forms upon addition of bicarbonate, discard and substitute a different solution).

a) Formula for bicarbonate addition when blood gases are available: milliequivalents bicarbonate added = base deficit x 0.5 x body weight in kilograms. Give one half of the determined dose slowly over 3 to 4 hours intravenously; titrate as needed.
b) Continue to dose based on blood gas determinations. When blood gases are not available and patient is symptomatic, administer 1 to 4 milliequivalents/kilogram intravenously slowly over 4 to 8 hours.

7) HYPOGLYCEMIA: Intravenous dextrose may be needed to combat hypoglycemia.
8) HYPOKALEMIA: Monitor for low potassium level; hypokalemia in the presence of acidosis indicates a poor prognosis for recovery (Beasley et al, 1990).
9) ETHANOL THERAPY

a) Although alternative pathways to metabolize methanol, other than alcohol dehydrogenase, may be predominant in nonprimate animals, specific investigation of metabolism has not been reported. The absence of acid-base disturbance in an experimental overdose would question the value of ethanol therapy (DeFelice et al, 1976).
b) Nevertheless, ethanol is often recommended for therapy of methanol overdose and is used in dogs and cats (Hurd-Kuenzi, 1983). Ethanol will not be effective beyond 18 hours postingestion.
c) DOSE: 20% ethanol may be given at 1.1 mL/kg IV every 4 hours for 72 hours, or until methanol levels are undetectable (Hurd-Kuenzi, 1983).

1) Another protocol recommends that ethanol 10% solution be administered at an initial dose of 0.6 g/kg, followed by 66 to 154 mg/kg/hr.

a) Ethanol can be given orally or by nasogastric tube, but should be given intravenously in the compromised patient. This protocol has been recommended for primates (Valentine, 1990).

d) Ethanol treatment is continued until blood methanol levels decrease to 6 mmol/L, unless a high level of formate exists or clinical complications are present (Valentine, 1990).
e) Ethanol regimen should be coordinated with sodium bicarbonate administration.

10) FOLIC ACID: An optimal dose of folic acid was 2.5 mg/kg IV in methanol-poisoned dogs; this dose enhanced elimination of formic acid (Rietbrock et al, 1971). The role of this therapy in dogs is questionable, since the animals in this study were treated with a dihydrofolate reductase inhibitor.
11) 4-METHYLPYRAZOLE: This agent inhibits the activity of alcohol dehydrogenase. It is still considered experimental as a treatment for methanol toxicity. It may cause fewer adverse effects than ethanol in the dog but has not demonstrated this advantage in the cat.

a) A dosage protocol which has been recommended for the treatment of ethylene glycol poisoning may be applicable: Administer 4-MP intravenously at a dose of 20 mg/kg initially, then 15 mg/kg at 12 and 24 hours, and finally 5 mg/kg at 36 hours (El Bahri, 1991).
b) 4-MP must be diluted in polyethylene glycol.

12) MONITORING

a) Admit all symptomatic patients and begin treatment.
b) Symptomatic patients must be monitored continuously. Refer to an emergency hospital or critical care clinic for 24 hour monitoring.

13) FOLLOW-UP

a) Instruct the owner to return for a follow up appointment at which physical examination and appropriate laboratory tests will be repeated.

B) RUMINANTS/HORSES/SWINE

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
2) Severe respiratory depression may lead to anoxia and death. Respiration must be supported with the necessary combination of oxygen, intubation or tracheostomy, and positive pressure ventilation.
3) CARDIAC SUPPORT

a) NOREPINEPHRINE is the drug of choice to combat hypotension. Do NOT use epinephrine. Reported dosages are for small animals; modify as needed: Levarteranol bitartrate, in ampules of 2 mg/mL: Dilute 1 to 2 mL in 250 mL intravenous solution. Give as IV drip to effect (Kirk & Bistner, 1985).

4) SEIZURES/LARGE ANIMALS: May be controlled with diazepam.

a) HORSES/DIAZEPAM: Neonates: 0.05 to 0.4 milligrams/kilogram; Adults: 25 to 50 milligrams. Give slowly intravenously to effect; repeat in 30 minutes if necessary.
b) CATTLE, SHEEP AND SWINE/DIAZEPAM: 0.5 to 1.5 milligrams/kilogram intravenously to effect.

5) SEIZURES/DOGS & CATS:

a) DIAZEPAM: 0.5 to 2 milligrams/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes to effect.
b) PHENOBARBITAL: 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously to effect.
c) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

6) HORSE: Administer electrolyte and fluid therapy as needed. Maintenance dose of intravenous isotonic fluids: 10 to 20 milliliters/ kilogram per day. High dose for shock: 20 to 45 milliliters/kilogram/hour.

a) Monitor for packed cell volume, adequate urine output and pulmonary edema. Goal is to maintain a urinary flow of 0.1 milliliters/kilogram/minute (2.4 liters/hour for an 880 pound horse).

7) CATTLE: Administer electrolyte and fluid therapy, orally or parenterally as needed. Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day. Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.
8) FOLIC ACID: May be administered to speed the elimination of formic acid.
9) MONITORING

a) Admit all symptomatic patients and begin treatment.

Range Of Toxicity

11.3.2)

A) DOG

1) Blood levels of 130 to 200 mg/dL produced hemodynamic depression in dogs, with death due to cardiac arrest at levels of greater than 400 mg/dL (DeFelice et al, 1976).
2) Lethal oral dose: 4 to 8 g/kg (Valentine, 1990)

B) CAT

1) Lethal intravenous dose: 5.9 mL/kg. Intraperitoneal lethal dose: 10 g/kg (Valentine, 1990)

C) RODENT

1) RAT: LD50 (ORAL): 4.5 g/kg (Valentine, 1990)

D) CATTLE

1) Analysis of rumen contents from cattle that died of methanol toxicity showed a methanol concentration of 370 mg% (Rousseaux et al, 1982).

E) PRIMATE

1) RHESUS MONKEY: Minimal lethal dose is 3 g/kg (Beasley et al, 1990).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) If the animal is conscious, ambulatory, and showing only mild to moderate behavioral changes, only decontamination, symptomatic treatment, and observation are required. If profound CNS depression is present, the situation is an emergency and respiratory and cardiac support must be provided immediately (Valentine, 1990).
2) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

3) Treatment should always be done on the advice and with the consultation of a veterinarian.
4) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
5) ASPCA ANIMAL POISON CONTROL CENTER

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS/GASTRIC LAVAGE

1) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
2) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
3) DOGS AND CATS

a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

4) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.

a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ACTIVATED CHARCOAL/CATHARTIC

1) METHANOL: Activated charcoal does not adsorb significant amounts of methanol. Its use in the face of ingestion may be indicated to prevent absorption of coingested substances.
2) ACTIVATED CHARCOAL: Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
3) CATHARTIC: Administer a dose of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
4) ACTIVATED CHARCOAL/HORSES: Administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube. Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
5) ACTIVATED CHARCOAL/RUMINANTS: Administer 2 to 9 grams/ kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube. Sheep may be given 0.5 kilogram charcoal in slurry.
6) CATHARTICS/HORSES: Mineral oil is administered 30 minutes after activated charcoal. DOSE: 4 to 6 liters in adult horses and 1 to 4 liters in neonates or foals.

a) Magnesium sulfate: 0.2 to 0.9 grams/kilogram (500 grams for adults).
b) The sulfate laxatives are especially effective when given 30 to 45 minutes after mineral oil administration.
c) Carbachol (lentin): administer 1 milligram to an adult.

7) CATHARTICS/RUMINANTS & SWINE: Adult cattle: administer 500 grams sodium or magnesium sulfate. Other ruminants and swine: administer 1 to 2 grams/kilogram.

a) The sulfate laxatives are especially effective when given 30 to 45 minutes after cathartic administration.
b) Mineral oil: Do not administer within 30 minutes of activated charcoal. DOSE: small ruminants and swine, 60 to 200 milliliters; cattle, 0.5 to 1 gallon.
c) Magnesium oxide: (Milk of Magnesia) Small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os.
d) Give these solutions via stomach tube and monitor for aspiration.

c) DERMAL DECONTAMINATION

1) Wash exposed animals with soap and water. If possible, shave or clip long hair to facilitate thorough cleaning. All handlers should wear gloves and protect themselves from exposure.
2) Some chemicals can produce systemic toxicosis via absorption through the intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs and treat as necessary.

d) INHALATION DECONTAMINATION

1) Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.

e) OCULAR DECONTAMINATION

1) Rinse eyes with copious amounts of tepid water for 15 minutes. If irritation, pain, or photophobia persist, see your veterinarian.

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) GENERAL

a) LABORATORY/PREMORTEM

1) Electrolyte/acid-base abnormalities may include anion-gap metabolic acidosis; decreased plasma bicarbonate; low urine pH; and elevated pancreatic enzymes (Beasley et al, 1990). Blood methanol levels may be determined by toxicology laboratories or labs in human hospitals.

b) LABORATORY/POSTMORTEM

1) Postmortem lesions may include severe congestion and petechiation of the organs. The intestines may contain bloody fluid that is not clotted (Rousseaux et al, 1982).

Kinetics

11.5.1)

A) SPECIFIC TOXIN

1) Methanol is rapidly absorbed from the gastrointestinal tract.
2) MINIPIGS: Animals orally dosed with 1, 2.5, and 5 mg/kg methanol reached average peak plasma methanol concentrations of 3100 +/- 700, 6200 +/- 2300, and 15,200 +/- 900 mcg/mL, respectively. Peak levels were attained by 4 hours postdosing (Dorman et al, 1993).

11.5.4)

A) SPECIFIC TOXIN

1) The half-life of methanol is reported to be 43 hours in dogs (Von Neymark, 1936).
2) The half-life of formate generated during methanol metabolism was 77 minutes (Rietbrock et al, 1971).
3) MINI PIGS: Animals orally dosed with 1, 2.5, and 5 mg/kg methanol showed the mean elimination half-life for methanol to be 9 +/- 1.6, 22.4 +/- 6.1, and 18.9 +/- 4.3 hours, respectively (Dorman et al, 1993).

Sources

A)

1) Animals gain access to methanol by ingesting antifreeze/cleaner solutions for automobiles; fuels for picnic stoves and in soldering torches (Beasley et al, 1990); and through access to oil field solutions (Rousseaux et al, 1982).

References

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FeedBack

METHANOL

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Other

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Sources

General Bibliography