Timothy B. Erickson
Michael E. Nelson
• Ethanol overdose in children may result in hypoglycemia.
• Methanol ingestion is associated with visual disturbance, metabolic acidosis, and possibly multi-organ system failure.
• Ethylene glycol poisoning is associated with metabolic acidosis, renal failure, and possibly multi-organ system failure.
• Isopropanol may cause CNS depression but does not usually cause metabolic acidosis.
• All of the toxic alcohols can produce an osmol gap.
• Fomepizole is the only FDA-approved antidote for ethylene glycol and methanol toxicity.
• Hemodialysis is indicated in severe toxic alcohol ingestions not responsive to conventional medical therapy, or with evidence of end-organ damage or severe acidosis.
According to a 2-year prospective study in Norway, of poisonings in 8 to 15 year old children, 46% involved ethanol.1 In the Slovak Republic, ethanol accounted for 34% of all intoxications in children 9–18 years old and the proportion of children admitted for ethanol intoxication increased yearly over 10 years.2 In the United States, alcohol is the drug most commonly used by youth. “Binge drinking” tendencies (five or more consecutive drinks on one occasion) have been reported in 9.5–27.4% of 8th–12th graders respectively.3 Regardless of country of origin, ethanol is a common problem among children.
PHARMACOKINETICS AND PATHOPHYSIOLOGY
Ethanol undergoes hepatic metabolism via two metabolic pathways: alcohol dehydrogenase and the microsomal ethanol oxidizing system (MEOS). Alcohol dehydrogenase is the major metabolic pathway and the rate-limiting step in converting ethanol to acetaldehyde. In general, non-tolerant individuals metabolize ethanol at 10–25 mg/dL/h and those with tolerance metabolize it up to a rate of 30 mg/dL/h. Children may ingest large amounts of ethanol in relation to their body weight, resulting in rapid development of high blood concentrations. In children younger than 5 years, the ability to metabolize ethanol is diminished because of immature hepatic dehydrogenase activity.
Ethanol is a selective CNS depressant at low concentrations, and a general depressant at high concentrations. Initially, ethanol produces exhilaration and loss of inhibition, which progresses to lack of coordination, ataxia, slurred speech, gait disturbances, drowsiness, and, ultimately, stupor, and coma. The intoxicated child may demonstrate a flushed face, dilated pupils, excessive sweating, gastrointestinal distress, hypoventilation, hypothermia, and hypotension. Death from respiratory depression may occur at serum ethanol concentrations >500 mg/dL. Convulsions and death have been reported in children with acute ethanol intoxication owing to alcohol-induced hypoglycemia. Hypoglycemia results from inhibition of hepatic gluconeogenesis and is most common in children younger than 5 years. It does not appear to be directly related to the quantity of ethanol ingested.4
In symptomatic children who have suspected ethanol intoxication, the most critical laboratory tests are the serum ethanol and glucose concentrations.5 Although blood ethanol concentrations roughly correlate with clinical signs, the physician must treat patients based on their clinical status, not the absolute level.5 If the ethanol level does not correlate with the clinical picture, co-ingestants or other causes of altered mental status should be considered. If children have experienced fluid losses, serum electrolytes should be measured.
The majority of children with accidental acute ingestions of ethanol respond to supportive care. Attention is directed toward management of the patient’s airway, circulation, and glucose status. A bedside glucose is obtained; younger hypoglycemic patients should receive 2–4 mL/kg of D25 W; older children and adolescents receive 1 amp of D50 W. Serial glucose levels are followed to detect recurrent hypoglycemia. In obtunded patients, naloxone 0.01 mg/kg IV push can be given for suspected opiate co-intoxication.
Gastric decontamination is not indicated in ethanol-poisoned patients chiefly because it is absorbed so quickly from the stomach. Hemodialysis does increase ethanol clearance by three to four times and may be considered in massive ethanol ingestions in patients who do not respond to conventional therapy.8
Any infant with significantly altered mental status following acute ethanol ingestion should be admitted for observation of respiratory status, fluid resuscitation, and glucose monitoring. Asymptomatic patients may be discharged home with reliable caretakers. Adolescent patients should be referred for counseling in an alcohol addiction program if a recurrent pattern of ethanol abuse is suspected.
Methanol is present in a variety of substances found around the home and workplace, including paint solvents, gasoline additives, air or brake line antifreeze, canned-heat products, windshield washer fluid, and duplicating chemicals.
PHARMACOKINETICS AND PATHOPHYSIOLOGY
Methanol is rapidly absorbed following ingestion. Peak serum concentration can be reached as early as 30–90 minutes after ingestion. As with ethanol, methanol is primarily metabolized by hepatic alcohol dehydrogenase. The half-life of methanol may be as long as 24 hours, but in the presence of ethanol or fomepizole, it is longer. In one report of methanol poisoning in an infant, methanol metabolism demonstrated first-order elimination kinetics.6 Methanol itself is harmless; however, its main metabolite, formic acid, is extremely toxic. Fatalities have been reported after ingestion of as little as 15 mL of a 40% methanol solution, although 30 mL is generally considered a minimal lethal dose. Ingestion of only 10 mL can lead to blindness. Adults have survived ingestions of 500 mL.
The onset of symptoms following methanol ingestion varies from 1 to 72 hours. Patients may have the classic triad consisting of visual complaints, abdominal pain, and metabolic acidosis. Eye signs and symptoms are generally delayed and include blurring of vision, photophobia, constricted visual fields, snowfield vision, and hyperemia of the optic disk. Although the blindness is usually permanent, recovery has been reported.7
Patients typically complain of nausea and vomiting and can experience gastrointestinal bleeding and acute pancreatitis. Unlike other alcohols, these patients often lack the odor of ethanol on their breath and typically have a clear sensorium. Methanol toxicity should be suspected in patients with altered mental status and metabolic acidosis of unclear etiology, especially if they have complaints involving vision.8
Measurement of the serum methanol concentration is the key laboratory test. Other recommended studies include a complete blood cell count, serum electrolytes and blood glucose, lipase, blood urea nitrogen (BUN) and serum creatinine, a urinalysis, and an arterial blood gas. Classically, methanol-intoxicated patients develop an elevated anion gap metabolic acidosis, although this may not be present if the patient presents before a significant quantity of formic acid has been generated.9 The anion gap is calculated using the equation:
(Na) - (Cl + HCO3). The normal anion gap is 8–12 mEq/L.
Another equation that assists in establishing the diagnosis is the presence of an elevated osmol gap, which is the difference between the measured and calculated serum osmolarities. An elevated osmol gap indicates the presence of an unmeasured osmotically active substance in the serum.
The formula for calculating serum osmolarity is: 2(NA) + glucose/18 + BUN/2.8.
Normally, the difference between the measured and calculated serum osmolalities is less than 10 mOsm (other toxicological causes of an elevated osmol gap include ethylene glycol, ethanol, and isopropanol poisoning, all of which are highly osmotically active compounds). Although the osmol gap is a useful indicator, cases of significant methanol and ethylene glycol overdoses have been reported with normal osmol gaps.
Generally, levels <20 mg/dL result in no effects. It is generally stated, but undocumented, that methanol levels <20 mg/dL are non-toxic and peak levels >50 mg/dL indicate serious toxicity. Ocular effects occur at levels >100 mg/dL, and fatalities have been reported in untreated victims with levels >150 mg/dL.10 One problem in interpreting levels is the time of ingestion versus the time of patient presentation and serum level assessment. Patients with low serum methanol concentrations may still be significantly poisoned and acidotic if they present late in their clinical course.
As for ethanol poisoning, gastric decontamination is not indicated in methanol poisoning chiefly because it is absorbed so quickly from the stomach. If a significant ingestion of methanol is likely, empiric treatment with the intravenous alcohol dehydrogenase inhibitor fomepizole is recommended11,12 even if laboratory tests are unavailable. Fomepizole binds hepatic alcohol dehydrogenase and prevents the metabolism of methanol to the toxic metabolite formic acid. Other indications for fomepizole therapy include serum methanol levels >20 mg/dL or acidemia (pH < 7.20). A fomepizole loading dose of 15 mg/kg should be administered, followed by doses 10 mg/kg every 12 hours for four doses until methanol levels are less than 20 mg/dL. Fomepizole is the only FDA-approved antidote for methanol poisoning.13 A recent investigation demonstrated that oral administration of fomepizole produced similar blood levels as an identical intravenous dose.14
If fomepizole is unavailable, ethanol may be administered to block alcohol dehydrogenase.15 To inhibit toxic metabolite formation, ethanol levels are maintained between 100 and 120 mg/dL. An intravenous solution of 10% ethanol in D5 W is optimal, with a loading dose of 0.6 g/kg. A simplified approximation of the loading dose is 1 mL/kg of 10% diluted absolute ethanol. Close monitoring of the ethanol level every 1–2 hours is necessary in order to adjust the maintenance infusion rate for each individual patient. If IV ethanol preparations are unavailable, oral ethanol therapy can be instituted. Since hypoglycemia is a complication of toxic ethanol levels in young children, serum glucose concentrations must be closely monitored.
Continued therapy with fomepizole or ethanol is recommended until methanol level falls below 20 mg/dL. Although there are no clinical outcome data confirming the superiority of either of these antidotes, there are significant disadvantages with ethanol therapy. These include difficulty in maintaining therapeutic concentrations, induced hypoglycemia, and CNS depression that may require endotracheal intubation, particularly in children. Unlike ethanol, fomepizole does not cause CNS depression and hypoglycemia. Particularly in children, minimal side effects make fomepizole the antidote of choice.
Additional therapies for methanol poisonings may include bicarbonate if the serum pH falls below 7.20. Folate, the active form of folic acid, is a coenzyme in the metabolic step converting the toxic metabolite formate to CO2 and H2O and can be administered to the methanol-poisoned patient. Up to 50 mg of folate can be given intravenously every 4 hours until the acidosis is corrected and methanol levels fall below 20 mg/dL.
Hemodialysis effectively removes methanol and formic acid. Indications for dialysis include visual impairment, metabolic acidosis not corrected with bicarbonate administration, renal failure, and methanol levels >50 mg/dL (with or without clinical signs or symptoms). It is important to note that fomepizole and ethanol are readily dialyzed, so the rate of IV administration may have to be increased during dialysis. For fomepizole, the recommendation is increasing the frequency of dosing to every 4 hours during hemodialysis.16
Any patient who is comatose and has abnormal vital signs, visual complaints, metabolic acidosis, or high methanol levels require admission to a pediatric intensive care unit. Asymptomatic patients without evidence of acidosis and with a methanol level <20 mg/dL may be discharged after observation in the emergency department.4
Ethylene glycol is an odorless, sweet-tasting compound that is found in antifreeze products, coolants, preservatives, and glycerin substitutes.
PHARMACOKINETICS AND PATHOPHYSIOLOGY
Ethylene glycol undergoes rapid absorption from the gastrointestinal tract, and initial signs of intoxication may occur as early as 30 minutes after ingestion. It undergoes hepatic metabolism via alcohol dehydrogenase to form the toxic metabolites glycolaldehyde, glycolic acid, and ultimately oxalic acid, which is excreted in the urine. The hallmarks of ethylene glycol toxicity are an anion gap metabolic acidosis, hypocalcemia, and renal failure, which results from the precipitation of calcium oxalate crystals in the kidney.17
The clinical effects of ethylene glycol toxicity can be divided into three stages:
• Stage I occurs within the first 12 hours of ingestion with CNS symptoms similar to that experienced with ethanol including slurred speech, nystagmus, ataxia, vomiting, lethargy, and coma. Convulsions, myoclonic jerks, and tetanic contractions may occur because of hypocalcemia. As in methanol poisoning, patients can have an anion gap acidosis with an elevated osmol gap. In approximately one-third of cases, calcium oxalate crystals will be found in the urine (Fig. 124-1).
FIGURE 124-1. Calcium oxalate crystals found with ethylene glycol poisoning.
• Stage II occurs within 12–36 hours after ingestion and is characterized by rapidly progressive tachypnea, cyanosis, pulmonary edema, adult respiratory distress syndrome, and cardiomegaly.
• Death is most common during this stage.
• Stage III occurs 2–3 days after ingestion and is heralded by flank pain, oliguria, proteinuria, anuria, and renal failure.
Ethylene glycol poisoning is possible in any inebriated patient lacking an odor of ethanol who has severe acidosis, oxalate crystalluria, hematuria, or renal failure. This diagnosis should be considered in a child with a metabolic acidosis of an unclear etiology.18
Measurement of the serum ethylene glycol concentration is the key laboratory test. Other recommended studies include complete blood cell count, serum electrolytes, blood glucose, calcium, creatine kinase, an arterial blood gas, BUN serum creatinine, serum osmolarity, and urinalysis for crystals, protein, and blood. Both anion and osmolal gaps are calculated. Because of the potential for severe cardiopulmonary toxicity, a chest radiograph and an electrocardiogram are recommended.
Like other alcohols, gastric decontamination is not indicated because ethylene glycol is rapidly absorbed from the GI tract. Patients with seizures are treated with standard doses of benzodiazepines and barbiturates.
The alcohol dehydrogenase inhibitor fomepizole has been approved by FDA for the treatment of ethylene glycol poisoning.13,19 A recent review in children suggests using the same dosing regimen of fomepizole as in adults.20Indications include a metabolic acidosis (pH less than 7.20 of unknown cause) or an ethylene glycol level >20 mg/dL. In cases where a significant ingestion is suspected, therapy should not be delayed pending an ethylene glycol level.
Ethanol competitively binds alcohol dehydrogenase with an affinity 100 times greater than ethylene glycol and slows the accumulation of toxic metabolites; it is an alternative to therapy if fomepizole is not available.15 If an intravenous preparation of ethanol is unavailable, it can be given orally in doses calculated to achieve an ethanol level of 100–120 mg/dL. Refer to the methanol management section for ethanol dosing instructions. Since high ethanol levels can produce hypoglycemia in small children, serial glucose measurements are indicated.
Bicarbonate administration is recommended for patients with pH < 7.20. Serum calcium levels are monitored, and if the patient has clinical signs of hypocalcaemia, treat with 10% calcium gluconate. Calcium replacement is not indicated for hypocalcaemia alone, since this will encourage the formation of calcium oxalate crystals. In addition, thiamine and pyridoxine (vitamin B6) are recommended in ethylene glycol poisonings to shunt or reroute the metabolism of ethylene glycol toward less toxic metabolites.
Hemodialysis effectively removes ethylene glycol, as well as its major circulating toxic metabolites, glycolic and oxalic acid. It is indicated in the setting of metabolic acidosis, pulmonary edema, or renal failure. Serum ethylene glycol level >50 mg/dL, regardless of clinical signs, is an indication for hemodialysis in patients who are being treated with ethanol.21 Recent data have suggested that hemodialysis may not be necessary for cases of ethylene glycol poisoning that can be treated with fomepizole as blocking therapy before acidosis or renal dysfunction develops.20,22
Any patient with altered mental status, metabolic acidosis, high ethylene glycol serum concentration or evidence of renal dysfunction should be admitted to a pediatric intensive care unit. Asymptomatic patients without acidosis and an ethylene glycol serum concentration <20 mg/mL can be discharged from the emergency department.
Isopropyl alcohol (also called isopropanol) is a common solvent and disinfectant with CNS-depressant properties similar to ethanol. The majority of pediatric exposures (up to 90%) occur in children younger than 6 years. Exposure from isopropyl alcohol occurs more frequently in these children than methanol, or ethylene glycol ingestions. Toxicity results from both accidental and intentional ingestions, as well as inhalation and dermal exposures in young children given “rubbing alcohol” sponge baths for fever.
PHARMACOKINETICS AND PATHOPHYSIOLOGY
Isopropanol is rapidly absorbed across the gastric mucosa, with acute intoxication occurring within 30 minutes of ingestion. It is metabolized by alcohol dehydrogenase, but, unlike methanol and ethylene glycol, it is not metabolized to an acidosis producing metabolite. Rather, isopropanol is converted to the CNS depressant acetone. Respiratory elimination of the acetone causes a fruity odor on the patient’s breath similar to diabetic ketoacidosis. Since isopropanol is a potent inebriant that is about twice as intoxicating as ethanol, a level of 50 mg/dL is comparable to an ethanol level of 100 mg/dL.
Isopropanol-intoxicated patients are classically lethargic or comatose, hypotensive and have tachycardia, with the characteristic breath odor of rubbing alcohol or acetone. Coma develops at levels >100 mg/dL. Hypotension results from peripheral vasodilation and cardiac depression. Gastrointestinal irritation with acute abdominal pain and hematemesis can also occur. However, like ethanol, methanol, and ethylene glycol, isopropanol can produce a significant osmol gap.9 (Table 124-1).
Comparisons of Toxic Alcohols
Blood and urine are tested for the presence of acetone. Unlike diabetic ketoacidosis, the acetone is typically found in the absence of glucosuria, hyperglycemia, or acidemia. Indicated laboratory studies include a complete blood cell count, serum electrolytes, an arterial blood gas, blood glucose, serum ethanol and isopropanol levels, serum osmolarity, and BUN and creatinine. Isopropanol levels >400 mg/dL correspond to severe, life-threatening toxicity.
Patients are managed with particular attention paid to the integrity of the airway. Hypotension is treated with intravenous crystalloid. Since isopropanol is so rapidly absorbed from the gastrointestinal tract, gastric decontamination is not indicated. No alcohol dehydrogenase inhibition is indicated since the metabolite acetone is relatively nontoxic and excreted through the lungs. Hemodialysis is effective in removing isopropanol and should be considered for prolonged coma, hypotension, and isopropanol levels >400–500 mg/dL. Typically, patients do well with supportive care alone.23
Isopropanol-intoxicated patients who are lethargic should be admitted, while asymptomatic children may be observed in the emergency department. Ingestion of more than three swallows (15 mL) of 70% isopropanol by a 10-kg child (1.5 mL/kg) is an indication for several hours of observation.8
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