|TOXICOLOGY SYMPOSIA – REVIEW ARTICLE
|Year : 2015 | Volume
| Issue : 1 | Page : 38-45
Meera Ekka, Praveen Aggarwal
Department of Emergency Medicine, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||19-Feb-2015|
Dr. Praveen Aggarwal
Department of Emergency Medicine, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Ethanol ingestion with alcoholic intoxication is one of the commonest emergencies followed by "alcohol withdrawal syndrome" in chronic alcoholics presenting to the emergency department with medical conditions. Isolated toxic alcohol (other than ethanol) ingestion cases may report to the emergency department when inadvertently methanol or ethylene glycol is ingested. In areas with prohibition occasionally outbreaks of toxic alcohol ingestion are observed. As an emergency physician, it is important to identify toxic alcohol ingestion as timely treatment will prevent morbidity and mortality.
Keywords: Alcohol ingestion, ethylene glycol, methanol, toxic alcohol
|How to cite this article:|
Ekka M, Aggarwal P. Toxic alcohols. J Mahatma Gandhi Inst Med Sci 2015;20:38-45
| Introduction|| |
The term toxic alcohol has generally referred to isopropanol, methanol, and ethylene glycol (EG).  However, any alcohol can be toxic if ingested in large quantities. Early recognition and treatment of patients intoxicated with these substances in the emergency department (ED) can reduce the morbidity and mortality associated with these alcohols.
| Ethyl Alcohol (Ethanol)|| |
Ethanol is a low molecular weight hydrocarbon. It is widely available both as a beverage and as an ingredient in food extracts, cough and cold medications, and mouthwashes. Ethanol intoxication is common in modern society, largely because of its widespread availability. It is a common co-ingestant in suicide attempts. The morbidity is often from co-ingestants or coexisting injuries and illnesses as ethanol greatly increases the risk of trauma, especially trauma due to motor vehicle collisions or violent crimes. 
Ethanol is rapidly absorbed across both the gastric mucosa and the small intestines, reaching a peak concentration 20-60 min after ingestion. Once absorbed, it is converted to acetaldehyde by the enzyme alcohol dehydrogenase (ADH). Acetaldehyde is then converted to acetate, which is converted to acetyl CoA, and ultimately carbon dioxide and water. 
Genetic polymorphisms coding for ADH, the amount of alcohol consumed, and the frequency at which ethanol is consumed all affect the speed of metabolism. Chronic alcoholics and those with severe liver disease have increased rates of metabolism. However, drinkers who do not chronically abuse the ethanol eliminate it at a rate of 15 mg/dL/h, whereas chronic abusers eliminate it around 20-25 mg/dL.
Acute alcohol intoxication is defined as the pathological state produced by the ingestion of alcohol. Binge drinking, which is generally defined as consuming ≥5 alcoholic drinks on a single occasion, generally results in acute intoxication.  The character of symptoms associated with intoxication varies with severity and symptoms depend on both the serum concentration as well as the pattern of drinking. Levels <25 mg/dL are associated with a sense of warmth and well-being. Euphoria and decreased judgment occur at levels between 25 and 50 mg/dL. At levels of 50-100 mg/dL, incoordination, decreased reaction time/reflexes, and ataxia occur. Cerebellar dysfunction (i.e., ataxia, slurred speech, nystagmus) are common at levels of 100-250 mg/dL. Coma can occur at levels of >250 mg/dL, whereas respiratory depression, loss of protective reflexes, and death occurs at levels >400 mg/dL. Hypotension and tachycardia may occur as a result of ethanol-induced peripheral vasodilation, or secondary to volume loss.  Acute alcohol intoxication can also induce multiple metabolic derangements, including hypoglycemia, lactic acidosis, hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia.  Children are at higher risks of developing hypoglycemia following a single ingestion than are adults.
The single most important laboratory test in a patient who appears intoxicated with ethanol is a blood glucose level by bedside finger prick test. Serum ethanol concentration and basic electrolytes, blood gas analysis is also required though measurement of serum ethanol concentrations is controversial and is not readily available in many centers. Anion gap (AG) and osmolal gap (OG) should be calculated to rule poisoning with other toxic alcohols. Urine drug testing should be done to rule out other coingestants.
Alcohol intoxication as a cause of altered mental status is a diagnosis of exclusion and should be considered only after ruling out more serious conditions such as head trauma, hypoxia, hypoglycemia, hypothermia, hepatic encephalopathy, and other metabolic and physiologic derangements. However, intoxication can be diagnosed more typically by history of ethanol intake, clinical presentation and by using the measurement of serum ethanol concentrations. However, routine use of a serum blood alcohol level is controversial, largely because it is unlikely to affect management in a patient who is awake and alert.
Management in the emergency department
Initial treatment should be focused on the airway, breathing, and circulation. Gastric decontamination is rarely necessary for any of the alcohols. The treatment for isolated acute ethanol intoxication is primarily supportive. Hypoglycemia and respiratory depression are two important issues to address promptly. Hypoglycemia should be promptly detected by rapid bedside glucose determination in all intoxicated patients and should receive dextrose infusion. Patients presenting with coma should receive at least 100 mg of parenteral thiamine to prevent or treat Wernicke's encephalopathy, along with dextrose. Intravenous (IV) crystalloids and vasopressures are used to treat hypotension, if present. Patient with altered sensorium can be agitated, violent, and uncooperative. Chemical sedation like benzodiazepines may be needed to prevent the patient from harming themselves or others. However, caution must be taken as these drugs can worsen the respiratory depression caused by alcohol. Metadoxine, is a new, specific drug useful in the treatment of acute alcohol intoxication, which accelerate ethanol excretion. 
Hypoglycemia is common. Holiday heart syndrome may occur in patients with acute intoxication, in which dysrrhythmias, especially atrial fibrillation, occur. Other complications in heavy intoxications include acute pancreatitis, severe myocardial depression, Hypotension, lactic acidosis, pulmonary edema, cardiovascular collapse, and sudden death.
Isopropanol is a clear, colorless liquid with a fruity odor and a mild bitter taste. Most commonly found domestically as rubbing alcohol, isopropanol is also found in numerous household and commercial products including cleaners, disinfectants, antifreezes, cosmetics, solvents, inks, and pharmaceuticals. The majority of isopropanol exposures are suicidal, but, unintentional in children <6 years of age can occur. Although isopropanol poisoning appears to be a reasonably common occurrence, deaths are rare, but can result from injury due to inebriant effects, untreated airway compromise due to coma, or rarely, cardiovascular depression and shock following massive ingestion. Supportive care can avert most morbidity and mortality.
Isopropanol is rapidly and completely absorbed following ingestion with peak plasma concentrations occurring within 30 min. Significant absorption can occur following inhalation or dermal exposure, especially in infant.  Isopropanol is metabolized by ADH to acetone. The elimination of isopropanol is predominantly renal though some pulmonary excretion of isopropanol and acetone occur. In the absence of ethanol or fomepizole, the elimination half-life of isopropanol is between 2.5 and 8.0 h, whereas elimination of acetone is slower with a half-life following the isopropanol ingestion of between 7.7 and 27 h.  Both isopropyl alcohol and acetone are rapidly cleared by hemodialysis, with clearance rates in excess of 200 mL/min. 
Mechanisms of toxicity
Isopropanol is a central nervous system (CNS) inebriant and depressant; brain stem depression is thought to be the predominant mechanism. In addition, it is irritating to the GI tract causing hemorrhagic gastritis. Acetone itself is a mild CNS depressant and may exacerbate the CNS depression caused by isopropyl alcohol. The most common metabolic effects are an increased OG, ketonemia and ketonuria without any AG metabolic acidosis unlike the toxic alcohols (methanol and EG). The absence of a high AG metabolic acidosis 4-6 h postingestion is useful to distinguish isopropyl alcohol from methanol or EG intoxication in most cases. The lethal dose is 250 mL in humans estimated from various sources.
Clinical manifestations include varying degrees of CNS depression, ranging from inebriation with disinhibition, sedation, stupor and coma.  These effects, due primarily to the parent alcohol, develop shortly after exposure, and peak within the 1 st h after ingestion, however, it's metabolite acetone, causes less sedation. Steady improvement in the patient's level of consciousness is the expected clinical course in mild to moderate poisoning. Severe poisoning due to massive ingestion present as coma, respiratory depression, hematemesis, pulmonary edema, hemorrhagic tracheobronchitis, shock, and circulatory collapse. Isopropanol concentrations of 50-100 mg/dL typically result in intoxication, which can progress to dysarthria and ataxia. Lethargy and coma can be seen with levels above 150 mg/dL. Cardiovascular collapse can occur with levels exceeding 450 mg/dL. 
The following tests and calculations should also be performed in patients suspected of ingesting isopropyl alcohol: Serum isopropyl alcohol and acetone levels (or serum osmolality if direct serum drug levels are unavailable). Basic electrolytes, with calculation of AG and OG, blood urea nitrogen, and creatinine, serum and urine ketones and Arterial or venous blood gas analysis should be done.
Poisoning can be diagnosed using the measurement of isopropanol serum concentrations though these may not be readily available and also of limited value. Diagnosis is, therefore, more typically made on the basis of the patient's history and clinical presentation. An osmol gap, ketonemia, and/or ketonuria without metabolic acidosis, along with a fruity or sweet odor on the breath and CNS depression support the diagnosis. Ketone usually present in the serum as early as 30 min after ingestion. If there is no coexisting ethanol ingestion, the absence of ketones effectively rules out the isopropanol ingestion.  However, starvation, alcoholic and diabetic forms of ketoacidosis presenting with depressed mental status and ketosis should be ruled out in these patients. 
Supportive care is the mainstay of management with primary emphasis on assessment and stabilization of the airway, breathing, and circulation.
There is no role for gastrointestinal (GI) decontamination in most cases of isolated isopropyl alcohol intoxication. Activated charcoal may be useful for coingestants.
The primary metabolite acetone is less toxic than isopropyl alcohol. Hence, there is no indication for ADH inhibition with fomepizole or ethanol following isopropyl alcohol exposure.  Because of the hemorrhagic gastritis that can follow the isopropanol ingestion, H2 blockade or proton-pump inhibitors may be helpful.
Rare patients with massive intentional ingestions may be hemodynamically unstable despite IV fluids and vasopressors. These patients with hemodynamic instability despite aggressive fluid resuscitation may require hemodialysis. 
Severe isopropanol poisoning results in coma, respiratory depression, hematemesis due to hemorrhagic gastritis, pulmonary edema hemorrhagic tracheobronchitis, shock, and circulatory collapse. 
| Methyl Alcohol|| |
Methyl alcohol is widely used as a solvent in many household products, such as antifreeze, cleaning solutions, dyes and paint remover. It is also used in photocopying fluid, shellacs, and windshield-washing fluids. Consumption of illegally produced or homemade alcoholic beverages containing relatively high levels of methanol poses risk and had caused several outbreaks in the past.  Poisoning may occur through accidental ingestion, attempted inebriation or suicide attempt. It can also occur from prolonged inhalation or skin absorption. Methyl alcohol poisoning is associated with significant morbidity and mortality.
Methanol is rapidly absorbed from the gastric mucosa, and achieves a maximal concentration 30-90 min after ingestion. Methanol is primarily metabolized in the liver via ADH into formaldehyde. Formaldehyde is subsequently metabolized via aldehyde dehydrogenase into formic acid, which ultimately is metabolized to folic acid, folinic acid, carbon dioxide, and water. A small portion is excreted unchanged by the lungs. Methanol undergoes zero-order metabolism, and is excreted at a rate of 8.5 mg/dL/h to 20 mg/dL/h in the absence of competitive inhibition. In the presence of competitive inhibitors like ethanol or fomepizole, the metabolism changes to first order. In this later scenario, the excretion half-life ranges from 22 to 87 h.
Mechanism of toxicity
Formic acid, the major toxic metabolite of methanol is responsible for the majority of the toxicity. This toxic metabolite is primarily responsible for the retinal and optic nerve damage as well as metabolic acidosis may be caused by disruption of mitochondrial electron transport. Specific changes can occur in the basal ganglia in the later stages. There are reports of pancreatitis with this poisoning. The lethal dose of pure methanol is estimated to be 1-2 mL/kg bodyweight.  However, there are reports of permanent blindness and deaths with 0.1 mL/kg bodyweight. 
Onset of symptoms ranges from 40 min to 72 h with an average of 24 h depending on the co-ingestion of ethanol as ethanol ingestion delayed the manifestation. Unlike ethanol or isopropanol, it does not cause as much of an inebriated state.  Early stage are mild and transient, manifesting as mild euphoria or inebriation, followed by a latent phase lasting from 6 to 30 h and during this stage toxic metabolites are formed.  The main systems involved in methanol toxicity are the neurologic, gastroenterologic, and ophthalmologic systems. Eye involvement is seen approximately in (50%) of patients and is associated with high methanol intake manifesting at 6 h or more postingestion may be delayed up to 24 h. Eye symptoms include blurred vision, photophobia, visual hallucination (often described as a snow field), partial to complete visual loss which are reversible in many patients in the early stage.  Ocular examination may reveal dilated pupils minimally or unreactive to light with hyperemia of the optic disc, nystagmus, papilledema, retinal edema and hemorrhages; but, over several days, the red disc becomes pale, and the patient become blind. Permanent visual sequelae have been described in severe intoxication.  Regarding CNS symptoms, patient often alert on presentation. However, altered sensorium, confusion, severe headache, lethargy and ataxia are not uncommon. In severe cases, coma and seizures may occur. Parkinson-like extrapyramidal (magnetic resonance imaging and/or computed tomography of the brain may reveal basal ganglia infarct) symptoms have also been reported.  Gastroenterological manifestations include nausea, vomiting, flank pain, abdominal pain, GI hemorrhage, diarrhea, liver function abnormalities, and pancreatiti.  Patient may also complain of breathlessness related to hyperventilation as a consequence of severe metabolic acidosis.
| Ethylene Glycol|| |
Ethylene glycol is a colorless, odorless, sweet tasting liquid, which is used in many manufacturing processes and is a common component of antifreeze and de-icing solutions around the house. It's a low molecular weight toxic alcohol that can result in serious morbidity and mortality.
Ethylene glycol itself is nontoxic; but, its metabolic byproducts are toxic. EG is oxidized via ADH into glycoaldehyde. Glycoaldehyde subsequently undergoes metabolism via aldehyde dehydrogenase into glycolic acid.  The glycolic acid is converted to glyoxylic acid. This is slower process and the rate-limiting step in the metabolism of EG. Glyoxylic acid is subsequently metabolized into oxalic acid. The excretion half-life of EG is approximately 3 h in patients with normal renal function in absence of ethanol or fomepizole. However, in the presence of these two antidotes, ADH undergoes competitive inhibition, and the resulting excretion half-life increases to approximately 17-20 h. 
Mechanism of toxicity
The main toxicity of EG is related to the production of oxalic acid and glycolic acid. The toxicity occurs from both the ensuing metabolic acidosis as well as the oxalate itself. The oxalic acid combines with calcium to form insoluble calcium oxalate crystals, occasionally leading to hypocalcemia. Hypocalcemia can cause coma, seizure and dysrhythmias. These calcium oxalate crystals deposit in various organs causing acute renal failure and myocardial, neurological and pulmonary dysfunction. , Lethal dose vary depending on the individual susceptibility to the adverse effects of EG. In human, it is reported to be 1.5 mL/kg body weight. 
Acute EG toxicity can occur through three distinct stages.  The first stage (neurologic phase: CNS depression), can occur within 30 min up to 12 h. During this stage, the patient appears inebriated, mild confusion or stupor may be present. The patient may not have any other significant findings during this stage. Occasionally, hypocalcemia can occur at this point and induce muscle spasms and abnormal reflexes. As the intoxication progresses, neurological symptoms can become more profound. EG may cause severe neurological deficits, and even mimic a clinical state of brain death.  The second stage (cardiopulmonary stage), occurs between 12 and 24 h after ingestion. During this stage, the patient commonly develops mild tachycardia and hypertension. Acute respiratory distress syndrome can also occur. Significant hypocalcemia can occur leading to hyperreflexia and arrhythmias.  Metabolic acidosis arises and patient compensate by hyperventilation at this stage. The third stage (renal stage), typically starts after 24-72 h. During this stage, acute renal failure and flank pain manifest. In severe intoxication, renal failure appears early and progress to anuria and in severe cases multiorgan failure and death can occur. 
Laboratory studies in ethylene glycol and methanol poisoning
Serum methanol concentration should be obtained, usually determined by gas chromatography, but this technique is not widely available on 24 h basis in the ED. The measurement of OG and AG can be useful in the diagnosis. In the early phase of intoxication, serum osmolality can be increased due to increase in methanol level. An unexplained, large OG is presumptive evidence of recent methanol exposure.  The higher OG, especially if ≥20 mOsm/L, is specific for the presence of alcohol.  As the metabolism of methanol progress, the OG decreases, and AG increases due to accumulation of toxic metabolites. In the last stage, only AG remains high and OG normalized.  If the AG is unexplained and other possible causes have been excluded, methanol poisoning should be suspected and considered for empiric treatment of toxic alcohol poisoning.  In EG poisoning, needle shaped and envelop shaped oxalate crystal may be present in urine. 
Treatment of methanol and ethylene glycol poisoning
Methanol or EG poisoning is a lethal condition needs immediate resuscitation in the ED. Moderate poisoning required management in ward. However, severe and life threatening poisoning required intensive care in the Intensive Care Unit (ICU). Prompt consultation with a poison control center is strongly recommended. Treatment is divided into four categories. It includes gastric decontamination, general supportive care, use of antidotes, and hemodialysis.
Gastric decontamination: gastric lavage or activated charcoal is not recommended as absorption rate is very rapid.
General supportive care
It includes IV fluids, mechanical ventilation, sodium bicarbonate therapy, calcium gluconate (in EG) and vasopressor indicated in severe poisoning. The administration of sodium bicarbonate is recommended in case of severe acidosis (pH ≤7.3) liberally.  Severe hypocalcemia, due to formation of oxalate crystal, causing symptoms such as muscle spasms or seizures required calcium gluconate therapy. 
Therapy with antidotes
Antidotes are most effective when given in the early phase of the intoxication, before significant levels of toxic metabolites are formed. Antidotes therapy increases the half-life of EG and methanol and prevent formation of toxic metabolites. Currently, only two antidotes are approved and used to block ADH-mediated metabolism of EG and methanol: Ethanol, a competitive ADH substrate, and fomepizole, an ADH inhibitor.
Criteria for initiating antidotes therapy in EG and methanol poisoning include: ,, (1) Documented plasma concentration ≥20 mg/dL, or (2) documented recent history of ingesting toxic amounts of EG/menthol and OG ≥10 mOsm/L, or (3) suspected EG/methanol ingestion and at least 3 (for EG) or 2 (for methanol) of the following criteria: A. Arterial pH <7.3, B. Serum bicarbonate <20 mmol/l, C. OG >10 mOsm/L and d. oxalate crystalluria (for EG only).
Fomepizole: Dosing scheme ,
For patients not on hemodialysis
Loading dose 15 mg/kg, followed by 10 mg/kg 12 hourly for 4 doses. After 48 h, dose should be increased to 15 mg/kg every 12 hourly. All doses are administered intravenously over 30 min. ,
For patient undergoing hemodialysis: Two proposed protocols ,
- A reduction in time interval between fomepizole doses: Loading dose 15 mg/kg followed by 10 mg/kg every 6 hourly for 4 doses and then 4 hourly. ,
- A continuous IV infusion of 1-1.5 mg/kg/h following the initial loading dose of 15 mg/kg. ,
Adverse effect of fomepizole
Fomepizole is generally well tolerated. However, injection site irritation, dizziness, tachycardia, headache, transaminitis, agitation and seizure are reported. ,
It is indicated for patients with a known fomepizole allergy, or during nonavailability of fomepizole. IV administration is preferred.
Target ethanol concentration is 100-150 mg/dL (1-1.5%).
7.5-12.5 mL ethanol 10% solution in glucose/kg intravenously (0.6-1.0 g/kg) or 2.5 mL/kg orally 40% ethanol solution.
Maintenance dose (intravenously)
1.4 mL ethanol 10% solution in glucose/kg/h. During hemodialysis (an additional dose of 1.9 mL ethanol 10% solution in glucose/kg/h should be administered intravenously). In adult, 3.3 mL ethanol 10% solution in glucose/kg/h.
It is considered the key element for the treatment in severe EG and methanol poisoning and aimed at removing both the parent compound and its toxic metabolites, to correct metabolic acidosis, and electrolyte disturbances, thus reducing the duration of hospitalization and antidotal treatment.  Current indications for HD based on clinical experience only includes:
- Arterial pH <7.3,
- A decline of arterial pH >0.05 despite bicarbonate therapy,
- pH <7.3 despite bicarbonate therapy,
- Initial plasma EG or Methanol concentration ≥50 mg/dL,
- Renal failure,
- Electrolyte imbalances unresponsive to conventional therapy,
- Deterioration of vital signs despite intensive supportive care, and
- Visual disturbances (in methanol poisoning). ,,
Adjunctive (co-factor) therapies
In methanol poisoning, folinic acid or folic acid (if folinic acid is not available) should be administered at a dose of 1 mg/kg, with a maximum does of 50 mg every 4 hourly. Folinic acid augment the conversion of formic acid to carbon dioxide and water by the tetrahydrofolate synthetase, an enzyme dependent on folinic acid. In EG poisoning, Thiamine 100 mg intravenously every 6 hourly and pyridoxine 50 mg every 6 hourly should be given to shunt metabolism of glyoxilic acid away from oxalate and favor the formation of less toxic metabolites. ,
Preferred antidote: Ethanol versus fomepizole
Fomepizole has higher potency to inhibit ADH with longer duration of action, administration is easy, dosing schedule is simple, may obviate the need for hemodialysis in specific cases, and most important there is no need for fomepizole blood concentration and blood glucose monitoring as required in ethanol. Therefore, has low overall cost and better safety consideration. These are the reasons to prefer for fomepizole as an antidote instead of ethanol according to clinician preference.  However, in one systemic review on use of ethanol or fomepizole, the conclusion was inconclusive. 
Ethanol therapy is labor intensive, require intensive ICU monitoring. The overall cost of therapy is higher than fomepizole when the cost of frequent glucose monitoring and measurement of blood ethanol concentrations are accounted. Again in chronic alcoholics and during hemodialysis, maintenance dose should be increased. During therapy with this antidote, significant mental status changes, hypoglycemia, liver toxicity or pancreatitis can occur, therefore confuse the interpretation of the already complex clinical course of EG and methanol poisoning. However, despite these disadvantages, due to its low costs, physician experience and ready availability, ethanol is used as first line antidote in some centers. ,
Predictors of poor prognosis in methanol and ethylene glycol poisonings
Poor prognostic signs include severe metabolic acidosis (pH ≤7.0), cardiovascular shock, seizure and coma at presentation.  Outcome is best correlated with the severity of acidosis rather than methanol concentration. According to study by Coulter et al., a large OG, AG and low pH (<7.22) were associated with increased mortality; and pH has the highest predictive value.  Degree of acidosis at presentation determine visual outcome in methanol poisoning. 
It is associated with blindness, metabolic acidosis, coma, seizure, cardiovascular collapse, respiratory failure and death.
Ethylene glycol poisoning
It is associated with renal failure, metabolic acidosis, coma, seizure, hypocalcemia, myocarditis, cardiovascular collapse and death.
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