Toxic Alcohols

Chapter 155


Toxic Alcohols




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.



Principles of Disease



Pharmacology and Metabolism


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.




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



Diagnostic Strategies


A severe anion gap metabolic acidosis is the hallmark of methanol poisoning. In some cases, this sign may be the only diagnostic clue. Because the onset of acidosis may be delayed 12 to 24 hours, a normal anion gap does not rule out methanol exposure. Absence of high anion gap acidosis has been described in cases with concomitant ethanol, lithium, or bromide ingestion. In methanol toxicity, this anion gap is due primarily to the presence of formic acid, with a variable contribution from lactic acid. Another classic laboratory finding in methanol toxicity is an elevated osmol gap. The osmolal gap is defined as follows:


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Serum osmolality depends on the presence of low-molecular-weight solutes, primarily sodium, chloride, glucose, and blood urea nitrogen (BUN). One formula for calculation of osmolality attributable to these solutes is as follows:


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The “normal” osmol gap is often cited to be less than 10 mOsm/kg when the preceding equation is used. This is an arbitrary number, and there is considerable variability in baseline osmolal gaps in patients, particularly children. An osmol gap significantly greater than 10 mOsm/kg may be a useful aid in the diagnosis of toxic alcohol ingestion. In addition to methanol, ethylene glycol, and isopropanol, other low-molecular-weight solutes, such as ethanol, acetone, propylene glycol, mannitol, glycerol, and ethyl ether, may cause elevated osmol gaps. Caution should be taken, however, in ruling out toxic alcohol ingestion with a normal osmol gap for several reasons. First, calculated serum osmolality results may vary among laboratories and must be done by the freezing point depression method. Also, delayed presentation after toxic alcohol ingestion may be associated with prior metabolism of most of the parent alcohol. Because only the parent compound is osmotically active and because the charged metabolites are electrically balanced by sodium, there may be little or no osmol gap elevation in this setting. Finally, a toxic level of either methanol or ethylene glycol may be present with a gap of only 10 mOsm/kg. If there is clinical suspicion of toxic alcohol ingestion, direct measurement of the serum toxic alcohol level is necessary, and if it is not readily available, empirical treatment is warranted.15 Rhabdomyolysis, pancreatitis, and metabolic derangements, such as hypomagnesemia, hypokalemia, and hypophosphatemia, are also described with methanol poisoning.


Computed tomography may be indicated in an intoxicated patient with altered mental status. The characteristic finding of bilateral putaminal lesions suggests methanol poisoning, but this finding also may be seen with Leigh’s syndrome, Wilson’s disease, hypoxic-ischemic insult, encephalitis, and certain metabolic disorders. Ischemic necrosis, cerebral edema, or brain hemorrhages also may be noted. Follow-up scans may have prognostic value because parkinsonian features are unlikely to develop in patients whose putaminal lesions resolve within a short time frame.16 MRI may also detect putaminal aberrations or optic neuropathy from methanol intoxication.



Differential Considerations


Methanol and ethylene glycol cause inebriation and are ingested as ethanol substitutes. The differential diagnosis of a patient with altered mental status includes hypoglycemia, head trauma, postictal state, carbon dioxide narcosis, hypoxia, infection, hepatic encephalopathy, other metabolic disorders, thiamine deficiency, endocrinopathy, drug abuse, and other poisoning. For patients who present with severe abdominal pain and altered mental status, the differential diagnosis could include a long list of intra-abdominal entities. When an anion gap acidosis is identified, however, the differential diagnosis should be tapered toward entities that cause this, and a primary decision should be made as to whether the acidosis is a result of an ingested toxin or some other cause (e.g., mesenteric ischemia, diabetic ketoacidosis). Toxic alcohol ingestion should be included in the differential diagnosis for patients with depressed mental status of unknown cause. Causes of an elevated anion gap in patients without evidence of renal failure, hypotension, hypoxemia, diabetes, seizures, or alcoholism include methanol, ethylene glycol, paraldehyde, isoniazid, iron, salicylates, toluene, and lactic acidosis from myriad toxicants, including metformin, carbon monoxide, cyanide, and cocaine. Isopropanol does not cause an increased anion gap. Ethylene glycol and methanol may cause a “double gap” (i.e., an osmol gap in addition to the anion gap). Other substances that contribute to an elevated osmol gap include isopropyl alcohol, ethanol, propylene glycol, mannitol, glycerol, and ethyl ether. Other situations in which double-gap acidosis may be encountered include diabetic ketoacidosis; alcoholic ketoacidosis; acetonitrile, methanol, ethylene glycol, and propylene glycol toxicity; multiple organ failure; chronic renal failure; and critical illness. Hyperlipidemia and hyperproteinemia, by decreasing the measured sodium concentration, can increase the osmolal gap.


Certain unique characteristics of methanol and ethylene glycol intoxication may lead to the specific diagnosis. The presence of ocular complaints unique to methanol poisoning is a valuable clue. Ethylene glycol ingestion often is associated with calcium oxalate crystalluria, which is not seen in methanol ingestion. Ultimately, a definitive diagnosis requires the documented presence of the parent alcohol through laboratory tests that may not be routinely available. It is often necessary to start treatment on the basis of clinical suggestion alone. Because the initial treatment for methanol and ethylene glycol is almost identical, identification of the specific toxic alcohol is not crucial to the initiation of therapy.




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).




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.

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Jul 26, 2016 | Posted by in ANESTHESIA | Comments Off on Toxic Alcohols

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