Toxic Alcohols

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Chapter 155

Toxic Alcohols

Suzanne R. White

Methanol

Perspective

Methanol is a colorless, volatile, slightly sweet-tasting alcohol. It is a product of natural fermentation and originally was manufactured from the distillation of wood, but currently, methanol is almost all synthetically produced. Certain products found in the home may contain high concentrations of methanol; these include antifreeze, windshield washer fluid, carburetor fluid, duplicator fluid, hobby engine fuel, gasohol, dry gas, Sterno, glass cleaners, cleaning agents, and thinners for shellacs, lacquers, adhesives, and inks. Methanol is a precursor in the manufacture of plastics, films, and dyes. Methanol is also found in formalin and embalming fluid. Illicit alcohol production remains a global source of methanol poisoning from products such as chang’aa (Kenya), raki (Turkey), and tuica (Romania).

Although epidemic poisonings from methanol are reported occasionally, most exposures are sporadic. In 2009, of the 2162 cases of methanol poisoning reported to American poison centers, 77% were unintentional, 6% had moderate to major complications, and 10 were fatalities. Treatment delay is associated with increased morbidity, making early recognition of clinical and laboratory clues crucial.

Methanol is absorbed rapidly from the gastrointestinal tract, and blood levels peak 30 to 60 minutes after ingestion.¹ Transdermal and respiratory tract absorption also has resulted in toxicity, especially in infants. Certain occupations, including painting, glazing, varnishing, lithography, and printing, are high risk for inhalational exposure to methanol. Inhalational abuse of methanol is a recent trend that can result in toxic serum levels.²

At low serum concentrations, the elimination of methanol follows first-order kinetics; but at concentrations after overdose, zero-order kinetics predominate. This produces a prolonged half-life of 24 to 30 hours, which may be extended even further by the concurrent ingestion of ethanol. First-order elimination prevails at high levels (>300 mg/dL), possibly as a result of enhanced pulmonary elimination. Small amounts of ingested methanol may be exceptionally toxic. In adults, the smallest lethal dose reported is 15 mL of 40% methanol, and 4 mL of pure methanol has led to blindness. With appropriate and timely treatment, however, survival without loss of eyesight has been reported despite extremely high levels. From a pediatric perspective, the ingestion of only 1.5 mL of 100% methanol in a toddler (0.15 mL/kg) is sufficient to produce a toxic blood level of 20 mg/dL. Any suspected pediatric methanol ingestion warrants aggressive evaluation and treatment.

Methanol itself has little toxicity, producing less central nervous system (CNS) depression and inebriation than ethanol. Metabolites of the parent alcohol are extremely toxic, however. Although small amounts of methanol are eliminated by renal and pulmonary routes, 90% is metabolized in the liver. Methanol is oxidized by alcohol dehydrogenase (ADH) to formaldehyde, which is rapidly converted by aldehyde dehydrogenase to formic acid (Fig. 155-1). Formic acid is the primary toxicant and accounts for much of the anion gap metabolic acidosis and ocular toxicity peculiar to methanol ingestion.³ Through a folate-dependent pathway, formic acid is degraded to carbon dioxide and water.

Figure 155-1 Metabolism of methanol. NAD, nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.

Pathophysiology

Optic neuropathy and putaminal necrosis are the two main complications of severe methanol poisoning. Long-term morbidity takes the form of visual impairment, including blindness, and parkinsonian motor dysfunction, characterized by hypokinesis and rigidity. Formic acid has a high affinity for iron and inhibits mitochondrial cytochrome oxidase, halting cellular respiration.⁴ Methanol metabolism in the cytosol and mitochondria may account for a second mechanism of adenosine triphosphate depletion.⁵ Lactate accumulation resulting from hypotension or seizures further compounds the metabolic acidosis predominantly caused by formate. Other mechanisms of toxicity involve increased lipid peroxidation, free radical formation, and impaired protective antioxidant reactions.^4,6 Severe dysfunction of subcellular metabolism from methanol also has been linked to significant disturbance in proteolytic-antiproteolytic balance.⁷

The primary sites of ocular injury are the retrolaminar optic nerve and retina. Selective myelin damage to the retrolaminar optic nerve has been seen at autopsy after methanol toxicity. Müller cells, the principal glial cells of retinal neurons and photoreceptors, have been proposed as the initial target in methanol-induced visual toxicity. It seems that they alone harbor the enzymes necessary to metabolize methanol to formate. Histopathologic correlates suggest that retinal cells develop intra-axonal swelling, calcium influx, mitochondrial destruction, and microtubular disruption. Ultimately, this interferes with transport of essential proteins from the retinal neuron cell body to the nerve fiber axoplasm. Oligodendrocyte involvement causes myelin degeneration and leads to visual decrements. Acidosis may accelerate this process by enhancing nonionic diffusion of formic acid into neurons and further increasing lactate production.⁴ This self-perpetuating cycle of acidosis, termed circulus hypoxicus,⁸ underscores the need for aggressive correction of pH to accomplish ion trapping of formate outside the CNS.

Methanol adversely affects other areas of the CNS, specifically the basal ganglia. Bilateral, symmetrical putaminal hypodensities, hemorrhages, or cystic lesions are characteristic, occurring in 13.5% of patients. Necrosis is described in the subcortical white matter, spinal cord anterior horn cells, and cerebellum.⁹ Acute signs and symptoms may be lacking or may take several days to develop despite the presence of these radiographic findings. The cellular mechanisms of injury may be similar to the mechanisms of the ophthalmologic injury, but the reason for localization of neurologic damage to the basal ganglia is unknown. Quantitative neuropathologic studies conflict as to whether concentrations of formic acid within the putamen are higher than levels in the blood or other tissues. Massive edema adjacent to the putamen shown by magnetic resonance imaging (MRI) suggests a possible localized disruption of the blood-brain barrier. Other proposed mechanisms for the vulnerability of this region include the unique pattern of arterial blood supply and venous drainage and greater metabolic activity.

Clinical Features

With individual cases of methanol poisoning, the history may be unobtainable or unreliable. The diagnosis should be considered in patients with altered mental status, visual complaints, or metabolic acidosis and in patients with occupations that put them at high risk for exposure. Because methanol is a poor substrate for ADH, a latency period exists between the time of ingestion and metabolism to the formate that causes visual or metabolic disturbance. The typical 12- to 24-hour latency may be shorter when large amounts are consumed or longer when ethanol is coingested (range, 40 minutes to 72 hours).¹ Formic acid accumulation may be ongoing, with risk for significant toxicity, in patients who present early despite being initially asymptomatic. When symptoms are manifested, they are primarily neurologic, gastrointestinal, or ocular.

Although methanol is less inebriating than ethanol, early symptoms of methanol poisoning include depressed mental status, confusion, and ataxia. Nonspecific complaints of weakness, dizziness, anorexia, headache, and nausea develop; in severe cases, coma and seizures may be seen. Although vomiting and abdominal pain commonly result from mucosal irritation, the absence of gastrointestinal complaints does not rule out a serious ingestion.¹ Abdominal tenderness, however, may be so severe that it suggests an acute surgical abdomen.¹ This may result from pancreatitis, and elevation of serum amylase is relatively common, but increased salivary amylase isoenzyme can occur without pancreatic inflammation.

Visual disturbances are seen in 50% of patients, and their development may precede or parallel that of other symptoms.⁸ Patients may complain of cloudy, blurred, indistinct, or misty vision or may note yellow spots or, rarely, photophobia. The most common acute field defect is a dense central scotoma.¹⁰ Some patients compare their visual symptoms with “stepping out into a snowstorm,” a complaint unique to methanol ingestion. Patients can have a complete lack of light perception and total loss of vision. Visual acuity should be determined. On examination, optic disc hyperemia is seen at 18 to 48 hours after ingestion. Peripapillary retinal edema follows, is most striking in the nerve fiber layer along the vascular arcades, and only rarely involves the macula.^5,10 Sluggishly reactive or fixed and dilated pupils indicate a poor prognosis. Pallor and cupping, indicative of optic atrophy, are late findings suggesting a poor prognosis for visual recovery. On occasion, the fundus may appear normal, even in patients with visual symptoms.

Compensatory tachypnea heralds the onset of metabolic acidosis, which often may be severe, with reported serum bicarbonate concentrations of less than 5 mEq/L and an arterial pH less than 7.0. Early tachycardia has been noted, but in general, cardiovascular abnormalities are rare.¹ Hypotension and bradycardia, when present, are preterminal findings.¹¹ Historically, death is associated with a peculiar, abrupt cessation of respiration rather than with cardiovascular collapse.¹ Multiple organ failure is rare.¹¹

Prognosis after methanol ingestion seems to correlate with the degree of acidosis, time to presentation, and initiation of treatment within 8 hours of exposure.1,12 Poor prognosis is associated with coma, seizures, or arterial pH less than 7.0.¹¹ A large outbreak was associated with a fatality rate of 44%.¹³ Patients surviving the acute phase of toxicity may be left with permanent blindness or neurologic deficits, such as parkinsonism, toxic encephalopathy, polyneuropathy, cognitive dysfunction, transverse myelitis, primitive reflexes, or seizures.¹⁴

Ethylene Glycol

Perspective

Ethylene glycol is a viscous, colorless, odorless, slightly sweet-tasting liquid. Because it lowers the freezing point of water, its primary utility is as a commercial antifreeze or coolant. Other sources include airplane deicing solutions, hydraulic brake fluids, and industrial solvents and precursors; it also is a component of certain paints, lacquers, and cosmetics. Most ethylene glycol poisonings occur with the ingestion of antifreeze. Unusual poisoning scenarios are described, including an epidemic after the contamination of water supplies and the intentional poisoning of an infant, manifested as an inherited metabolic disorder. In 2009, the American Association of Poison Control Centers reported 5977 exposures to ethylene glycol. Of those exposures, 72% were unintentional, and 11% resulted in moderate or severe effects with 19 fatalities. If it is treated early and aggressively, ethylene glycol poisoning is unlikely to result in death. Conversely, failure to treat ethylene glycol ingestion may result in multiorgan failure and death within 24 to 36 hours.¹⁷

Principles of Disease

Pharmacology and Metabolism

Absorption of ethylene glycol is rapid after ingestion. It distributes evenly to tissues with a volume similar to that of body water. Peak blood levels are reached within 1 to 4 hours after ingestion. In contrast to methanol and isopropanol, ethylene glycol is nonvolatile at room temperature, so absorption by inhalation is unlikely. Reported half-lives range from 3 to 8.6 hours.¹⁸ When metabolism is blocked by fomepizole or ethanol, the half-life increases to 11 to 15 hours or 17 hours, respectively.¹⁹ The toxic and lethal doses of 100% ethylene glycol have been reported as 0.2 mL/kg and 1.4 mL/kg. At the other extreme, with modern treatment, patients who have ingested 3000 mL have survived. Twenty-seven percent of ethylene glycol is excreted unchanged by the kidneys. The remainder is oxidized through hepatic ADH and other oxidative enzymes to various toxic organic aldehydes and acids (Fig. 155-2).

Figure 155-2 Metabolism of ethylene glycol. GAO, glycolic acid oxidase; LDH, lactate dehydrogenase; NAD, nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.

Pathophysiology

Unmetabolized ethylene glycol has limited toxicity, yet all metabolites are toxic. In humans, 2.3% of a dose of ethylene glycol ultimately is converted to oxalic acid, most of which is excreted in the urine. A fraction of oxalic acid combines with calcium to form calcium oxalate crystals, which precipitate in renal tubules, brain, and other tissues. Studies have shown definitively that the accumulation of calcium oxalate monohydrate crystals in kidney tissue produces renal tubular necrosis that leads to kidney failure.²⁰ Other authors suggest that glycolate levels correlate better with disruption of CNS metabolism, development of renal failure, and mortality.²¹ Because the intermediate metabolite, glyoxylic acid, theoretically can be shunted toward pyridoxine-dependent or thiamine-dependent pathways to generate the nontoxic products glycine and α-hydroxy-β-ketoadipate (see Fig. 155-2), both pyridoxine and thiamine are routinely used in therapy.

On histologic examination, proximal renal tubular dilation with hydropic change and vacuolar degeneration, intratubular crystal deposition, and edema of the interstitium are seen. Relative sparing of the glomeruli is typical, although glomerular interloop space crystal deposition may occur. Glomerular function is preserved, but tubular dysfunction manifesting as protein leak is noted.²² Neuropathologic changes induced by ethylene glycol include diffuse calcium oxalate deposition with petechial hemorrhages in the retina, brain, vessel walls, and perivascular spaces, with evidence of cerebral edema and chemical meningoencephalitis. Similar changes also have been noted in the liver, spleen, pancreas, pleura, lungs, pericardium, and blood vessel walls throughout the body. Myonecrosis occurs in skeletal and myocardial muscle, and rhabdomyolysis and myocardial dilation occur. Fatty liver with focal necrosis has been noted.

The metabolism of ethylene glycol results in a profound anion gap metabolic acidosis, caused mainly by glycolic acid. Elevated lactate, triggered by the altered redox potential within cells and inhibition of the citric acid cycle by products of glyoxylate metabolism, is a minor contributing factor to the severe acidosis.

Clinical Features

The clinical syndrome with ethylene glycol ingestion is divided into four stages: (1) acute neurologic stage, (2) cardiopulmonary stage, (3) renal stage, and (4) delayed neurologic sequelae stage. The severity of illness in each stage and the progression through stages may vary. Stages may be skipped and patients may die in any stage of ethylene glycol poisoning. Poor prognostic factors include hyperkalemia, severe acidosis, seizures, and coma. Metabolic acidosis and symptoms typically occur within 4 to 8 hours but may be delayed for 12 hours or longer if ethanol has been coingested.

Stage I, the acute neurologic stage, occurs 30 minutes to 12 hours after ingestion. The parent alcohol causes approximately the same degree of inebriation as ethanol does, with CNS depression, slurred speech, nystagmus, ataxia, and vomiting. With large ingestions, more dramatic neurologic findings, such as hallucinations, seizures, and coma, may be present during the early phase of intoxication. Ocular findings including decreased pupillary reflexes, decreased visual acuity, optic disc blurring, papilledema, and loss of color discrimination have been reported, but methanol exposure was not ruled out in most of these case reports.

Stage II, the cardiopulmonary stage, occurs 12 to 24 hours after ingestion. Often, the patient exhibits mild hypertension and tachycardia. Tachypnea may reflect the underlying profound metabolic acidosis or may herald the onset of cardiogenic or noncardiogenic pulmonary edema.⁸ The mechanism of acute respiratory distress syndrome (ARDS) is unclear but may be related to the toxicity of glycolic and glyoxylic acids and to the deposition of calcium oxalate crystals within the lungs. Pulmonary infiltrates are described during this phase. Circulatory collapse may occur as a result of myocardial depression. Hypocalcemia, rarely associated with tetany or cardiac dysrhythmia, occurs in 30% of patients as a result of systemic chelation of calcium by oxalate. Myositis with muscle tenderness and creatine kinase (CK) elevation results from skeletal muscle inflammation and necrosis.

Stage III, the renal stage, occurs 24 to 72 hours after ingestion. In one epidemic of 36 patients, renal damage was noted in 67%. Awake patients may complain of flank pain or have costophrenic angle tenderness. Calcium oxalate monohydrate or dihydrate crystalluria is seen in only 50% of cases. Hematuria and proteinuria are common, however. As with other causes of acute tubular necrosis, oliguria is not always present, but it may develop 12 hours after ingestion and may progress to frank anuria. The outcome has not been well studied in patients who have renal failure. Prolonged hemodialysis may be necessary, although recovery of renal function has been reported. Delayed onset of ARDS has been reported to occur during this stage, but it is more typically seen in stage II. The degree of acidosis, delay in presentation, and glycolate levels correlate better than ethylene glycol levels with the development of renal failure.²³

Stage IV, the delayed neurologic sequelae stage, occurs 6 to 12 days after ingestion and typically is manifested as cranial neuropathy.²⁴ All cases have been associated with renal failure. Facial diplegia, occasionally with deafness, is most frequently encountered. Other reported findings include dysarthria, dysphagia, tongue deviation, visual deterioration, and internal ophthalmoplegia. Delayed and persistent cognitive and motor deficits, such as ataxia, chorea, coma, and late personality changes, are also reported. Total paralysis from severe axonal peripheral polyneuropathic degeneration with oxalate deposition²⁵ and polyradiculopathy from nerve root (not distal) disease are also reported. Although some improvement in neurologic status has been noted at follow-up, most patients are left with residual neurologic deficits. Some authors have coined the term facial auditory nerve oxalosis for this delayed syndrome on the basis of heavy calcium oxalate crystal deposition along the subarachnoid portions of the seventh and eighth cranial nerves seen at autopsy. Whether calcium oxalate deposition is a cause is unclear. Direct mechanical injury from crystals, inflammatory response triggered by ethylene glycol metabolites, meningitis, and pyridoxine deficiency have been proposed as mechanisms. Because the syndrome has been reported only since 1978, it is possible that the advent of hemodialysis has allowed more patients with potentially lethal ingestions of ethylene glycol to survive to display delayed neurologic complications.

Diagnostic Strategies

Useful laboratory tests for evaluation of a patient with potential ethylene glycol toxicity include serum electrolyte values; calcium, BUN, creatinine, and serum glucose concentrations; serum osmolality; blood ethanol level; arterial blood gas analysis; ethylene glycol level; electrocardiogram; and urinalysis. Although crystalluria is considered the hallmark of ethylene glycol ingestion, its absence does not rule out the diagnosis because less than half of patients have this finding. Crystalluria may take the form of envelope-shaped calcium oxalate dihydrate crystals or needle-shaped calcium oxalate monohydrate crystals, which are occasionally mistaken for hippurate crystals.⁸ Other crystal shapes and composites have been noted so that in the setting of combined anion and osmolal gap elevation, the presence of any type of crystalluria warrants a search for ethylene glycol. Monohydrate crystals are thought to be more specific for ethylene glycol poisoning. Irrigating the urinary bladder with 50 to 100 mL of saline, centrifuging the irrigant, and examining the sediment for crystals may yield the diagnosis in patients who are already anuric. Other findings reflecting tubular dysfunction include decreased specific gravity, proteinuria, microscopic hematuria, pyuria, and cylindruria. Falsely elevated ethylene glycol levels may be seen in the face of elevated lactate or lactate dehydrogenase with certain enzymatic assays.

Freshly voided urine can be examined for fluorescence with Wood’s lamp. Sodium fluorescein is added to antifreeze to aid in the detection of radiator leaks. Urinary fluorescence may be seen 6 hours after ingestion of fluorescein-containing antifreeze. Gastric contents and the patient’s skin or clothing also may fluoresce under Wood’s lamp. The lack of fluorescence does not rule out ethylene glycol ingestion, however, because examiner sensitivity, specificity, and inter-rater reliability are low.²⁶ One study found urinary fluorescence in all specimens from children evaluated for conditions unrelated to poisoning.²⁷ Specimens should be collected in borosilicate glass test tubes or deposited directly onto gauze or filter paper because many plastic specimen containers and some glass tubes are fluorescent. The urine pH also should be checked and adjusted to 4.5 or higher before Wood’s lamp examination.

Leukocytosis may be seen in ethylene glycol poisoning, with a typical white blood cell count of 10,000 to 40,000/µL, but it is neither a sensitive nor a specific finding and is not of diagnostic value. The hematocrit and platelet counts are normal. One third of patients have hypocalcemia, which is most likely caused by calcium precipitation with oxalate. QT prolongation on the electrocardiogram leads to the early diagnosis of hypocalcemia. Rarely, profound hypocalcemia resulting in seizures and tetany may occur. The CK level can be elevated as a result of toxic effects of ethylene glycol metabolites on muscle tissue.

Similar to methanol, ethylene glycol often causes a profound anion gap metabolic acidosis when the metabolites glycolic acid and glyoxylic acid (and, to some extent, lactic acid) accumulate. False elevations of lactic acid levels may occur in the presence of glycolate with certain analyzers.²⁸ Similar to methanol toxicity, an elevated osmolal gap as measured by freezing point depression can be a clue, but lethal concentrations can be associated with a normal or only slightly elevated osmolal gap. The cerebrospinal fluid may be normal or have a cloudy or bloody appearance, with increased protein or, most commonly, a polymorphonuclear pleocytosis.

Imaging studies show cerebral edema with decreased attenuation in the mediobasilar portions of the brain, typically with a return to isodensity within 1 week; this does not correspond to the clinical picture.⁸ MRI in one patient with delayed cranial neuropathy showed gadolinium enhancement of cranial nerve V bilaterally, possibly secondary to calcium oxalate deposition. Electroencephalographic findings have been nonspecific.

Differential Considerations

Classically, patients who ingest ethylene glycol appear intoxicated without the odor of ethanol and have an anion gap metabolic acidosis, increased osmolal gap, and calcium oxalate crystalluria. Without evidence of alcoholic ketoacidosis or diabetic ketoacidosis, the differential diagnosis of the double gap should include methanol and ethylene glycol. The hallmark finding with late presentation is renal toxicity. Toxicant-induced acute renal failure is extensively reviewed elsewhere; substances commonly implicated include antimicrobials, nonsteroidal anti-inflammatory drugs, acetaminophen, halogenated hydrocarbons, radiocontrast media, metals, antineoplastic agents, and myoglobin. Hypocalcemia and a prolonged QT interval are important diagnostic clues. Toxicant-induced hypocalcemia is unusual and may be related to aminoglycosides, calcitonin, cisplatin, loop diuretics, interferon alfa, mithramycin, pentamidine, and phosphate infusions. Healthy individuals with dietary excesses of vitamin C or foods rich in oxalate, such as tomatoes, garlic, spinach, rhubarb, cocoa, and tea, may exhibit calcium oxalate crystalluria.

Management

Methanol and ethylene glycol ingestions are treated essentially in the same manner, and the following recommendations apply to both. As in any overdose, resuscitation and stabilization are paramount, including naloxone, bedside glucose determination, and thiamine, if indicated. Specific blood levels that confirm the presence of these substances may not be readily available, and a delay in therapy can lead to irreversible organ damage or death. For any significant history of exposure, treatment should be initiated pending a confirmatory toxic alcohol blood level.

Methanol and ethylene glycol are absorbed rapidly from the gastrointestinal tract; because gastric emptying has not been shown to alter clinical course or outcome and may be associated with complications, its use is restricted to possible nasogastric suction for patients who have ingested more than a swallow and arrive in the emergency department within 30 to 60 minutes of ingestion.²⁹ Even in these cases, it is of unproven value. Forced diuresis is of no value and may cause pulmonary edema and ARDS. Early intubation may be indicated to protect the airway against aspiration and in anticipation of further deterioration in mental status.

Three treatment goals exist for patients with methanol or ethylene glycol toxicity: (1) correction of metabolic acidosis with bicarbonate; (2) ADH enzyme blockade, which inhibits the metabolism of methanol and ethylene glycol to toxic metabolites; and (3) removal of the parent alcohol and its metabolites by hemodialysis. The acidic metabolites of methanol and ethylene glycol can cause a profound bicarbonate-resistant metabolic acidosis, with several hundred milliequivalents of excess acid produced per hour. In contrast to lactic acid, these acids are not metabolized to bicarbonate, and massive amounts of bicarbonate may be necessary merely for partial correction of the acidosis.⁸ Early correction of metabolic acidosis may be beneficial in reversing methanol-induced visual impairment,³⁰ most likely related to the induction of a larger fraction of dissociated formic acid, which should decrease the amount of formic acid entering the CNS. Depending on the severity of the patient’s acidosis, bicarbonate can be administered intravenously by intermittent boluses, by an initial bolus followed by an infusion, or by infusion alone. Boluses of 1 to 2 mEq/kg to attain a target serum pH of 7.45 to 7.50 followed by an infusion of 150 mEq/L of sodium bicarbonate in 5% dextrose at 1.5 to 2 times the maintenance fluid rate are suggested. With ethylene glycol, the potential for worsened hypocalcemia during the administration of large amounts of sodium bicarbonate should be considered.

To prevent further production of the toxic and acidic metabolites of methanol and ethylene glycol, metabolism of the parent compounds by the enzyme ADH must be blocked by either ethanol or fomepizole (Antizol). As experience has been gained with fomepizole, it is generally thought to be more advantageous than ethanol from a safety and convenience perspective. ADH blockade should be carried out in any adult or child with symptoms or with methanol or ethylene glycol levels greater than 20 mg/dL, even if the patient is asymptomatic. If ethanol is used to block ADH, the goal is to maintain the blood ethanol level between 100 and 150 mg/dL, which completely saturates ADH.⁸ The affinity of ADH for ethanol is 10 to 20 times greater than for methanol and 100 times greater than for ethylene glycol. When the metabolism of methanol and ethylene glycol is blocked by ethanol, their half-lives increase to more than 30 hours and 17 hours, respectively. Prevention of methanol and ethylene glycol metabolism by ethanol explains the delayed toxicity seen in patients who ingest ethanol in combination with either of these substances. In dosing of ethanol, it also is important to measure the patient’s initial blood ethanol level. If it is greater than 100 mg/dL, a loading dose is unnecessary, and a maintenance infusion can be started (Table 155-1). The required maintenance dose of ethanol may nearly triple during hemodialysis because ethanol also is efficiently removed. Ethanol may be given orally or intravenously. Potential side effects of intravenous administration include CNS and respiratory depression, hypotension, vomiting, hypoglycemia, and thrombophlebitis, although even in children, adverse effects are limited.³¹ Oral ethanol loading may be associated with gastritis. Initial close monitoring of serum ethanol and glucose levels every 1 to 2 hours is essential until a steady-state level of 100 to 150 mg/dL is achieved. Levels should be checked every 2 to 4 hours thereafter. Monitoring of ethanol therapy ideally is accomplished in the intensive care unit.

Table 155-1

Standard Range of Therapeutic Doses of Ethanol Based on Average Pharmacokinetic Values

^*Specific gravity 0.79.

^†Equivalent to 86 proof undiluted liquor (34 g/dL of ethanol).

^‡Equivalent to 7.9 g/dL of ethanol.

^§Assumes that initial ethanol concentration is zero; dose is independent of chronic drinking status.

Modified from Barceloux DG, Krenzelok EP, Olson K, Watson W: American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol 37:537, 1999.

Similar to ethanol, fomepizole blocks the metabolism of methanol and ethylene glycol by ADH and prevents the formation of toxic metabolites.19,32 When the metabolism of methanol and ethylene glycol is blocked by fomepizole, their half-lives increase to an average of 52 hours and 17 hours, respectively.³³ Although fomepizole is a pregnancy category C drug and not approved for pediatric use, it has been used in children.³¹ Advantages of fomepizole over ethanol include ease of administration, predictable pharmacokinetics, improved patient safety profile, standardized and less complicated dosing regimen that does not require direct observation or frequent blood monitoring, longer duration of action, and lack of CNS depression.³⁴ Nonetheless, simply blocking toxic alcohol metabolism does not alter the toxicity of preformed metabolites. The use of neither fomepizole nor ethanol supplants the need for hemodialysis. The main disadvantage of the use of fomepizole is its cost. The dosing regimen for adults and pediatric patients is 15 mg/kg, followed by 10 mg/kg every 12 hours for four doses. After five doses, the dose increases to 15 mg/kg every 12 hours until the ethylene glycol concentration is undetectable or less than 20 mg/dL and the patient is asymptomatic with a normal arterial pH. Dosing changes are required during hemodialysis. Side effects of fomepizole include headache, nausea, dizziness, inflammation at the site of infusion, rash, eosinophilia, and mild reversible transaminase elevation. A single case of hypotension and bradycardia related to the rapid infusion has been described.³⁵ No prospective clinical trials have compared the relative efficacy, safety, or cost of fomepizole and ethanol in the treatment of ethylene glycol or methanol toxicity; however, a 10-year review of adverse events in patients showed fomepizole to be safer than ethanol.³⁶

Rapid removal of the methanol or ethylene glycol through hemodialysis before it has been metabolized remains the cornerstone of therapy. In addition, hemodialysis, preferably with use of a dialysate high in bicarbonate, corrects acidosis and uremia, aids in fluid management and cardiovascular stabilization, and removes the toxic metabolites in late presenters. Hemodialysis decreases the half-life of methanol and ethylene glycol to 2.5 to 3.5 hours. Peritoneal dialysis and hemoperfusion are much less effective.³⁶

Indications for hemodialysis in patients with methanol or ethylene glycol toxicity are controversial. In general, hemodialysis is indicated for patients who have metabolic acidosis, renal insufficiency, deterioration despite intensive care, electrolyte disturbance, or visual disturbances with methanol.⁸ In addition, a blood level of either substance greater than 50 mg/dL usually calls for dialysis,^35,37 but in patients with normal kidneys, prolonged fomepizole treatment alone has been used without hemodialysis.^38,39 For ethylene glycol, a glycolic acid level greater than 8 mmol/L, an anion gap greater than 20 mmol/L, or an initial pH less than 7.30 predicts renal failure and the need for hemodialysis.⁴⁰ Methanol and ethylene glycol levels should be interpreted in the context of the clinical status and the time after ingestion. An acidotic patient with a low blood level after a delayed presentation requires more aggressive treatment than an asymptomatic patient with a high level.

The endpoint for hemodialysis is an undetectable serum ethylene glycol or methanol concentration and the disappearance of acid-base abnormalities and signs of systemic toxicity. Resolution of the anion gap also may serve as an endpoint for hemodialysis in situations in which levels are not available or reliable (i.e., in patients with delayed presentation).

In methanol poisoning, the rate of the final degradation reaction of formic acid to carbon dioxide and water depends on the cofactor folate in primates (see Fig. 155-1), so 50 mg of leucovorin (folinic acid) should be given intravenously (IV) every 4 hours to adults with methanol toxicity. Likewise, the cofactors thiamine and pyridoxine have theoretic benefit on the basis of their use in humans with primary hyperoxaluria, although no clinical trials have studied their efficacy in the treatment of ethylene glycol toxicity. Adequate cofactor levels minimize oxalic acid production by favoring the production of other, less toxic metabolites (see Fig. 155-2). The recommended adult doses are thiamine, 100 mg IV every 6 hours, and pyridoxine, 50 mg every 6 hours for 2 days. With symptomatic hypocalcemia, IV calcium should be supplemented, albeit cautiously, to avoid further precipitation of calcium oxalate crystals in tissues. Asymptomatic hypercalcemia need not be treated. Magnesium is a cofactor along with thiamine for the detoxification of glycolic acid and should be replaced in patients who are deficient.

Disposition

Admission is generally necessary for patients undergoing treatment for ethylene glycol or methanol exposure. In addition, all patients with clinical or laboratory findings consistent with these ingestions should be admitted, even when the history is lacking or unavailable. Early consultation with a nephrologist for possible hemodialysis is necessary in the management of suggested toxic alcohol ingestion. If such services are not available, the patient should be given an ADH inhibitor and transferred to a setting where dialysis is available. A regional poison center (800-222-1222) or medical toxicologist may be contacted to guide management. An ophthalmologist can evaluate visual injury fully in patients with methanol poisoning. Neurologic consultation and follow-up monitoring of patients with either methanol or ethylene glycol toxicity are prudent given the potential for delayed or persistent neurologic sequelae.

Prevention

The bittering agent denatonium benzoate (Bitrex) has been added to consumer automotive products containing 10% or more ethylene glycol or 4% or more methanol, but the effect of this effort has not yet decreased the frequency or severity of pediatric antifreeze poisoning.⁴¹ Another opportunity for prevention is the substitution of less toxic glycols, such as propylene glycol, into commercial antifreezes.

Isopropyl Alcohol

Perspective

Isopropyl alcohol (isopropanol) is a clear, colorless liquid with a slightly bitter taste. It is the second most commonly ingested alcohol after ethanol. In 2009, the American Association of Poison Control Centers reported 20,902 isopropanol exposures: 83% were unintentional, and 3% involved moderate or major effects; there was one fatality. Rubbing alcohols, which contain 70 to 91% isopropanol or ethanol, are frequent sources of exposure and may be tinted green or blue. Other sources include skin and hair products, nail polish removers, disinfectants, window and pine household cleaners, and antifreeze. Children experience toxicity most commonly from accidental ingestion, but inhalation and transdermal absorption during sponge bathing may occur. Isopropanol and its major metabolite acetone cause twice the CNS depression of ethanol, so intentional ingestion as an alcohol substitute is encountered frequently in adults. Isopropanol is not associated with the toxicity of ethylene glycol or methanol poisoning, and death after exposure is rare. The typical fatality involves a chronic, older alcoholic with mixed ethanol-isopropanol intoxication after a drinking binge.⁴²

Principles of Disease

Pharmacology and Metabolism

Absorption of isopropanol is rapid and complete; 80% of a dose is absorbed within 30 minutes of ingestion. The kidneys excrete 20% as unchanged isopropanol. A small portion is re-secreted into the stomach and saliva; the remaining 80% is metabolized in the liver to acetone by ADH (Fig. 155-3). Acetone is excreted primarily by the kidneys, with small amounts expired through the lungs.

Figure 155-3 Metabolism of isopropanol.

Isopropanol blood levels peak 30 minutes to 3 hours after ingestion, and elimination follows first-order kinetics, with a half-life of 3 to 7 hours. In children, the half-life may be slightly shorter. Acetone is eliminated more slowly, with a half-life of 22 hours. The rate of elimination of isopropanol may be increased by chronic ethanol abuse and decreased by hepatic damage.⁴² A potentially lethal dose in adults is 150 to 240 mL (2-4 mL/kg), but adults have survived ingestions of 1 L (8-15 mL/kg).

Pathophysiology

Isopropanol is a potent CNS depressant, but the mechanism of action is unclear. Acetone is also a CNS depressant, and it has been suggested that coma may be prolonged by the extended elimination of this metabolite. The extent to which acetone contributes to coma is brought into question by the report of a patient who was awake and conversant with acetone levels of 200 mg/dL. In large doses, isopropanol causes hypotension from peripheral vasodilation and direct myocardial depression. Topical effects include corneal de-epithelialization and dermal burns, described in premature infants as a result of skin de-esterification. Acetone does not seem to be shunted into the formation of acetoacetate or β-hydroxybutyrate; the finding of ketosis without acidosis is characteristic of isopropyl ingestion. No pathognomonic postmortem features are seen in isopropanol intoxication. Pulmonary congestion at autopsy is nonspecific and typical of deaths involving drug-induced CNS depression.

Clinical Findings

Gastrointestinal and CNS complaints predominate clinically. Intoxication may be suggested by apparent inebriation with the odor of acetone rather than of ethanol detected on the breath. The patient may have headache or dizziness and may exhibit neuromuscular incoordination, confusion, and nystagmus. Severe ingestions may result in deep coma, which is prolonged compared with ethanol. Respiratory depression or failure may occur. Patients may have a loss of deep tendon, corneal, or protective airway reflexes and have an extensor response to plantar reflex testing. Pupillary size varies, but miosis is most common.⁴³ Because isopropanol is a gastrointestinal irritant, the patient may complain of abdominal pain, nausea, and vomiting. Gastritis can occur with dermal and oral exposure.⁴⁴ Hematemesis and upper gastrointestinal bleeding stem from gastritis but are rare.

Hypotension, although rare, signifies severe poisoning, with a mortality rate of 45%. One case series found mortality only when coma and hypotension were present.⁴³ Sinus tachycardia is common, but other atrial and ventricular dysrhythmias are rare and generally found only with confounding hypoxia, acidosis, or shock. Hypothermia is frequent.⁴³ Rarely, myoglobinuria, acute tubular necrosis, hepatic dysfunction, and hemolytic anemia have been reported. A distinguishing feature is that metabolic acidosis is not present with isopropanol intoxication unless it is accompanied by hypotension, gastrointestinal bleeding, or coingestants. Hyperglycemia may be noted, but hypoglycemia has not previously been described, even though it should be sought in patients who have altered mental status.