109: Toxic Alcohols

Methanol was a component of the embalming fluid used in ancient Egypt. Robert Boyle first isolated the molecule in 1661 by distilling boxwood, calling it spirit of box.²⁹ The molecular composition was determined in 1834 by Dumas and Peligot, who coined the term “methylene” from the Greek roots for “wood wine.”²⁰² Industrial production began in 1923, and today most methanol is used for the synthesis of other chemicals. Methanol containing consumer products that are commonly encountered include model airplane and model car fuel, windshield washer fluid, solid cooking fuel for camping and chafing dishes, photocopying fluid, colognes and perfumes, and gas line antifreeze (“dry gas”). Methanol is also used as a solvent by itself or as an adulterant in “denatured” alcohol.¹³⁸ Most reported cases of methanol poisoning in the United States involve ingestions of one of the above products, with more than 60% involving windshield washer fluid,⁵⁸ although most inhalational exposures involve carburetor cleaner.⁸⁷ In a Tunisian series, ingested cologne was the most common etiology.³⁰ In a Turkish series, cologne was also most common, accounting for almost 75% of ingestions.¹²⁹ Perfume was one of several exposures in a patient with methanol poisoning in a report from Spain,¹⁷³ and methanol poisoning from cologne has also been reported in India.¹² There are sporadic epidemics of mass methanol poisoning, most commonly involving tainted fermented beverages.^23,130 These epidemics are a continuing problem in many parts of the world.^{16,146,153,166,187,218,257}

Ethylene glycol was first synthesized in 1859 by Charles-Adolphe Wurtz and first widely produced as an engine coolant during World War II, when its precursor ethylene oxide became readily available.⁷⁰ Today its primary use remains as an engine coolant (antifreeze) in car radiators. Antifreeze used in gas tanks generally contains methanol. Because of its sweet taste, it is often consumed unintentionally by animals and children. Aversive bittering agents may be added to ethylene glycol containing antifreeze to try to prevent ingestions by making the antifreeze unpalatable, an approach required by law in two states. However, there is no evidence that this strategy is effective, and comparisons in poison center data between ­ethylene glycol ingestions where bittering agents were required and where they were not have revealed no significant differences in frequency or ­volume of ingestion, or any other outcome variable (Chap. 135).^253,254

Isopropanol is primarily available as rubbing alcohol. Typical household preparations contain 70% isopropanol. It is also a solvent used in many household, cosmetic, and topical pharmaceutical products. Perhaps because it is so ubiquitous, inexpensive, and with a common name that contains the word “alcohol”, isopropanol ingestions are the most common toxic alcohol exposure reported to poison centers in the United States,³⁶ typically in cases where it was used as an ethanol substitute (Chap. 136).

Alcohols are hydrocarbons that contain a hydroxyl (-OH) group. The term “toxic alcohol” traditionally refers to alcohols other than ethanol that are not intended for ingestion. In a sense, this is arbitrary, since all alcohols are toxic, causing inebriation and end organ effects if taken in excess. The most common clinically relevant toxic alcohols are methanol and ethylene glycol (1,2-ethanediol). Ethylene glycol contains two hydroxyl groups; molecules with this characteristic are termed diols or glycols because of their sweet taste. Other common toxic alcohols include isopropanol (isopropyl alcohol or 2-propanol), benzyl alcohol (phenylmethanol), and propylene glycol (1,3-propanediol). Primary alcohols, such as methanol and ethanol, contain a hydroxyl group on the end of the molecule (the terminal carbon), whereas secondary alcohols, such as isopropanol, contain hydroxyl groups bound to middle carbons. Glycol ethers are glycols with a hydrocarbon chain bound to one or more of the hydroxyl groups (forming the basic structure R¹ O-CH₂-CH₂-O-R² or R¹ O-CH₂-CH₂-CH₂-OR²). Glycol ethers commonly encountered include ethylene glycol butyl ether (also known as 2-butoxyethanol, ethylene glycol monobutyl ether, or butyl cellosolve), ethylene glycol methyl ether (2-methoxyethanol), and diethylene glycol (2,2′-dihydroxydiethyl ether). Poisoning with these compounds may clinically resemble toxic alcohol poisoning, and diethylene glycol is discussed in detail in Special Considerations: SC7.

Alcohols are rapidly absorbed after ingestion^74,88 but are not completely bioavailable because of metabolism by gastric alcohol dehydrogenase (ADH), as well as by first-pass hepatic metabolism. Occasionally, delayed or prolonged absorption may occur.⁶⁸ Although methanol may also be absorbed in significant amounts by inhalation, poisoning by this route is uncommon. In workers exposed to methanol fumes from industrial processes for up to 6 hours at concentrations of 200 ppm (Occupational Health and Safety Administration {OSHA} permissible exposure limit {PEL}), there was no significant accumulation of methanol or its metabolite formate.¹⁴⁸ Another study showed that with methanol use in the semiconductor industry, ambient methanol concentrations generally do not approach this OSHA limit even in a room with poor ventilation due and with no local exhaust ventilation.⁸⁰ Surprisingly, concentrations far in excess of the OSHA PEL can be present within the passenger compartment of a car when using the windshield wipers with methanol-containing windshield washing fluid.²¹ No cases of human poisoning are reported from this type of exposure, probably because these concentrations are not sustained over a long time. Two patients with occupational inhalational exposure aboard a tanker carrying methanol developed consequential toxicity, including the death of one; both patients reportedly used appropriate personal protective equipment.¹³⁹ Additionally, cases of inhalational poisoning are reported with intentional inhalation of methanol as a drug of abuse, typically in the form of carb­uretor cleaning fluid (“huffing”) (Chap. 84), and with massive exposures of rescue workers responding to the scene of an overturned rail car filled with methanol.^{14,75,87,158,244,250} Two case series suggest that patients who present after chronic inhalation of methanol have good clinical outcomes with folate and ADH blockade alone and without need for hemodialysis,^20,158 although in another series, patients with inhalational exposure were as likely to require dialysis as patients with methanol ingestion.⁸⁷ Transdermal methanol exposure can be consequential if exposure is prolonged.¹³¹ Ethylene glycol has low volatility and is not reported to cause poisoning by inhalation. In one study, human volunteers inhaled vaporized ethylene glycol at a concentration of 1340 to 1610 ppm for 4 hours to simulate an industrial exposure. Afterward, the volunteers had detectable but not clinically significant concentrations of ethylene glycol and its metabolites.²⁴² Most alcohols have some dermal absorption, although isopropanol and methanol are able to penetrate the skin much better than ethylene glycol.^63,154,248 Most reported cases of toxic alcohol poisoning by this route involve infants⁵⁷ because of their greater body surface area–to–volume ratio, and likely this also involved simultaneous inhalation. One reported case of transdermal methanol poisoning involved a 51 year-old woman, but details of the exposure were not reported.²³⁰ Another case involved a 52 year-old woman who reportedly frequently massaged with methanol containing cologne and spirit over the course of 3 days. That patient suffered significant visual and neurologic sequelae despite aggressive treatment with ethanol and hemodialysis.² One methanol fatality was deemed to be caused by transdermal absorption (in addition to blunt trauma) when high tissue methanol concentrations were measured in the absence of detectable methanol in the gastrointestinal tract,¹⁵ but inhalational exposure could also conceivably have contributed. When human volunteers were exposed to 100% ethylene glycol applied to a 66 cm² area of skin under an occlusive dressing for 6 hours, detectable but not clinically significant amounts were absorbed.²⁴²

Once absorbed, alcohols are rapidly distributed to total body water. In human volunteers given an oral dose of methanol on an empty stomach, the measured volume of distribution was 0.77 L/kg, with a distribution half-life of about 8 minutes.⁸⁸ This is only slightly longer than the absorption half-life, so serum concentrations typically peak soon after ingestion and then begin to fall.

Without intervention, toxic alcohols are metabolized through successive oxidation by ADH and aldehyde dehydrogenase (ALDH), each of which is coupled to the reduction of NAD⁺ to NADH. Methanol is metabolized to formaldehyde, then to formic acid (Fig. 109–1). Ethylene glycol has two hydroxyl groups that are serially oxidized by ADH and ALDH, producing, in turn, glycoaldehyde, glycolic acid, glyoxylic acid, and finally oxalic acid (Fig. 109–2). Like ethanol, this metabolism follows zero-order kinetics, with a rate that is reported to be about 10 mg/dL/h.^50,118,169 Additionally, this rate is apparently unchanged in chronic ethanol users.^97,98 Alternate minor metabolic pathways such as catalase exist for methanol and ethylene glycol.

After methanol ingestion, the formate metabolite is bound by ­tetrahydrofolate and then undergoes metabolism by 10-formyltetrahydrofolate dehydrogenase to carbon dioxide and water. Ethylene glycol is also metabolized to ketoadipate and glycine using thiamine and pyridoxine as cofactors.¹⁷⁸ Because of the low toxicity of these ethylene glycol metabolites, these normally minor metabolic pathways are attractive targets for potential therapy.

Methanol and ethylene glycol are eliminated from the body as unchanged parent compounds. When kidney function is normal, ethylene glycol is cleared with a half-life of approximately 11 to 18 hours.^28,47,226 Methanol does not have significant renal elimination (about 1% of the ingested dose in patients with intact hepatic metabolism) and is cleared much more slowly than is ethylene glycol, presumably as a vapor in expired air (half-life, 30–54 hours).^34,144,188

Acute Central Nervous System Effects

All alcohols may cause inebriation, depending on the dose. Based on ­limited animal data, it appears that higher molecular weight alcohols are more intoxicating than lower molecular weight alcohols on a molar basis (therefore, isopropanol ≈ ethylene glycol > ethanol > methanol).²⁵¹ However, the absence of apparent inebriation does not exclude ingestion, particularly if the patient chronically drinks ethanol and is thereby tolerant to its central nervous system (CNS) effects.²³⁵ Additionally, serum methanol concentrations of 25 to 50 mg/dL may potentially be associated with toxicity, whereas in most states one may legally drive a car with a blood alcohol concentration of up to 80 mg/dL.

The CNS manifestations of toxic alcohol poisoning are incompletely understood. It is assumed by analogy that inebriation is similar to that of ethanol, where effects are mediated through increased γ-aminobutyric acid (GABA)–ergic tone both directly and through inhibition of presynaptic GABA, GABA_A receptors as well as inhibition of the N-methyl-d-aspartic acid glutamate receptors.^{10,42,90,105,172} Although the CNS effects of other alcohols are clinically similar, there is no direct evidence that they are mechanistically the same.

Metabolic Acidosis

Metabolic acidosis with an elevated anion gap is a hallmark of toxic alcohol poisoning. This is a consequence of the metabolism of the alcohols to toxic organic acids. The acids have no rapid natural metabolic pathway of elimination, and therefore they accumulate, unlike acetic acid resulting from ethanol metabolism, which can enter the Krebs cycle. In methanol poisoning, formic acid is responsible for the acidosis, whereas in ethylene glycol poisoning, glycolic acid is the primary acid responsible for the acid­osis, with other metabolites making a minor contribution. An exception to the formation of an acid metabolite is isopropanol, which is metabolized to acetone. Acetone is a ketone, not an aldehyde, and therefore cannot be ­further metabolized by ALDH (Fig. 109–3). Thus isopropanol has no organic acid metabolite and does not cause metabolic acidosis. In fact, ketosis without acidosis is essentially diagnostic of isopropanol poisoning. Occasionally, a non–anion gap (hyperchloremic) metabolic acidosis may result from ethylene glycol poisoning (almost 18% in one series), often concurrently with anion gap acidosis.²²⁹ The mechanism for this is unclear, but a similar pattern has been observed in the setting of diabetic ketoacidosis, alcoholic ketoacidosis, and toluene poisoning.

End-Organ Manifestations

Additional end-organ effects depend on which alcohol is involved. Methanol causes visual impairment, ranging from blurry or hazy vision or defects in color vision, to “snowfield vision” or total blindness in severe poisoning. Although it is counterintuitive, vision loss may not be symmetric.^48,161 On physical examination, central scotoma may be present on visual field testing, and both hyperemia and pallor of the optic disc, papilledema, and an afferent papillary defect are described as characteristic findings.^23,183,260 Electroretinography may demonstrate a diminished b-wave,²⁴⁰ a marker of bipolar cell dysfunction, and optical coherence tomography (similar in principle to ultrasound, but using reflected light waves to image translucent tissues) may demonstrate peripapillary nerve fiber swelling and intraretinal fluid accumulation.⁷⁷ Formate is a mitochondrial toxin, inhibiting cytochrome oxidase and it thereby interferes with oxidative phosphorylation.^69,179,180 Although it is unclear why this results in ocular toxicity while other tissues are relatively spared, retinal pigmented epithelial cells and optic nerve cells appear to be uniquely susceptible.^{66,165,239,240} Proteomic analysis of retinas in rats poisoned by methanol showed 24 proteins were different from baseline (14 increased, 10 decreased),⁴⁶ so the underlying pathophysiology of retinal toxicity from methanol may be more complex than is currently understood. Years after exposure, optic nerve atrophy, disc pallor and severe cupping may be still be present, even with normal intraocular pressure.²²¹

Interestingly, neurons in the basal ganglia appear to be similarly susceptible to this toxicity. Bilateral basal ganglia lesions, bilateral necrosis of the putamen (with or without hemorrhage), and less commonly, caudate nucleus are characteristically abnormal visualized on cerebral computed tomography (CT) or magnetic resonance imaging (MRI) after methanol poisoning.^{3,6,12,24,26,60,64,72,78,99,100,123,124,131,190,205,208,217,224,237,243} While lesions of this type are nonspecific, and may also occur in hypoxia, hypotension, and carbon monoxide poisoning, in methanol poisoning they occur in the absence of hypotension and hypoxia,¹⁶⁷ suggesting a direct toxic mechanism. Patients have developed parkinsonism after poisoning by methanol, a finding consistent with the lesions in the basal ganglia lesions.^92,166,200 In one series, typical radiological lesions were present in six of nine cases.²¹⁷ Other CNS lesions reported include necrosis of the corpus callosum¹³⁴ and intracranial hemorrhage.^13,216 Pathologic examination of the brain reveals lesions similar to those found radiologically.¹³² Increased glial fibrillary acidic protein and decreased CD34 expression are pathologic markers in affected ­tissues, although how these relate to the underlying pathophysiology is not yet clear.²⁴¹

Both retinal and neurological toxicity of methanol poisoning may be permanent. Among 86 survivors of a methanol poisoning outbreak in Estonia in 2001, 26 had died six years later (many from alcohol intoxication) and 33 could not be tracked down. Of the five patients who could be found out of 20 patients that had been discharged with retinal or neurologic sequelae, all had persistent effects. Interestingly, 8 out of the 22 patients found who were discharged without sequelae had newly identified neurological and visual sequelae 6 years later (among 66 initially discharged without sequelae). The newly identified visual sequelae may have actually been present initially but missed due to lack of ophthalmologic evaluation, or symptoms may have developed more gradually in these patients. New neurologic symptoms were probably due to continued drinking.¹⁸⁶ In another series from Iran, 37 of 50 survivors of methanol poisoning with retinal toxicity were followed 1 year later; 16 patients improved before discharge from the hospital. Seven patients had their visual disturbance resolve within 2 weeks; 5 were blind at discharge but partially recovered within 3 to 4 weeks; 5 were blind at ­discharge and had no improvement 1 year later; and 4 were blind at discharge, had partial recovery within 1 month, but then had worsening vision within the subsequent 9 months.²¹¹ This suggests that, long-term outcomes of retinal toxicity are difficult to predict.

Rarely, injury to other tissues may also occur. Both acute kidney injury (AKI) and pancreatitis are reported after methanol poisoning.^102,140 For unclear reasons, one case series showed a much higher incidence of pancreatitis (50%)¹⁰² and in another, 11 of 15 patients had pancreatitis,²⁴⁷ but this is not typical. Some of the AKI that results from methanol poisoning may be due to myoglobinuria.⁹¹ In one series of methanol poisoned patients with AKI about half had associated myoglobinuria, presumably due to atraumatic rhabdomyolysis. One reported patient with methanol poisoning had rhabdomyolysis severe enough to cause compartment syndrome in both legs, requiring fasciotomy.⁵¹ Patients with AKI were also more likely than a control group of patients to have severe poisoning, as manifested by low initial serum pH, high initial osmolality, and high peak formate concentration.²⁴⁷ Pathologic abnormalities of the liver, esophagus, and gastric mucosa are also found in some fatal cases of methanol poisoning.^4,44

The most prominent end-organ effect of ethylene glycol is nephrotoxicity. The oxalic acid metabolite forms a complex with calcium to precipitate as calcium oxalate monohydrate crystals in the renal tubules, leading to AKI.^{73,93,95,168,196,234,238} The diagnosis of ethylene glycol poisoning has been established at autopsy by demonstrating this abnormality, including in one homicide case^11,151; in another case, the diagnosis was established by kidney biopsy.¹³⁴ Although the intermediate products of ethylene glycol metabolism, and possibly ethylene glycol itself, are directly toxic to the renal tubules in some studies,^{49,73,195,198} this appears not to occur at clinically relevant concentrations.⁹³ Currently no explanation exists for the presence of necrotic lesions to the glomerular basement membrane on some pathology specimens⁷³ as oxalic acid generally does not cause glomerular injury.¹²⁵

Ethylene glycol can occasionally affect other organ systems. In severe poisoning, the oxalic acid metabolite may be present in sufficient amounts to cause hypocalcemia following precipitation as calcium oxalate. This can result in prolongation of the QT interval on the electrocardiogram and ventricular dysrhythmias.²¹⁵ Cerebral edema was present on CT scan in two patients who died of ethylene glycol poisoning.^76,238 Two reported patients had delayed neurological manifestations. One patient developed increased intracranial pressure, with papilledema and an abducens (CN VI) palsy approximately 9 days after recovering from acute ethylene glycol poisoning and without another clear etiology.⁵⁹ Another patient developed the same cluster of delayed effects (increased intracranial pressure, papilledema and an abducens palsy) on day 13 of hospitalization, after fomepizole, thiamine, pyridoxine, and hemodialysis. He subsequently developed a facial (CN VII) palsy, sensory neuropathy, and autonomic neuropathy, including postural hypotension and gastroparesis.¹⁹⁹ Precipitation of calcium oxalate crystals in the brain was found on autopsy after severe ethylene glycol poisoning^8,73,76 and may account for the multiple cranial nerve abnormalities that occasionally develop,^59,231 although there is as yet no direct evidence of causation. Peripheral polyradiculoneuropathy can be diagnosed by electromyography and nerve conduction studies in cases of ethylene glycol poisoning,^7,17 and intracranial hemorrhage involving the globus pallidus can occur.³⁹ A leukemoid reaction may also occur in the setting of severe ethylene glycol poisoning, but the mechanism remains unclear.^160,176 One pediatric case of hemophagocytic syndrome and liver failure in the setting of ethylene glycol poisoning resulted in fatality.¹⁴⁵ Parkinsonism can also occur.²⁰⁰ Two severe cases of unintentional ethylene glycol ingestion in the United Kingdom resulted in blindness and deafness; one with associated cranial neuropathies and one with multiple peripheral neuropathies.^41,62 One patient had a myocardial infarction with ST segment elevation while poisoned with ethylene glycol, but survived after cardiac catheterization and placement of five stents, as well as treatment with ethanol and hemodialysis.²³⁶ Finally, death can result from massive ethylene glycol ingestion with no elevation of its metabolites, suggesting direct toxicity of the alcohol, probably through respiratory depression.⁸¹

Hemorrhagic gastritis is associated with isopropyl alcohol intoxication. Although this is often assumed to be caused by a local irritant effect, one reported case of hemorrhagic gastritis after percutaneous isopropanol exposure suggests that this is not the only mechanism, and may in fact be a specific end-organ effect.⁶⁵ Hemorrhagic tracheobronchitis has occurred in fatal cases of isopropanol aspiration.⁵ The acetone metabolite of isopropyl alcohol may also interfere with some creatinine assays, causing a falsely elevated result,¹³⁷ but it does not actually cause AKI.

Toxic Alcohol and Metabolite Concentrations

Serum methanol, formate, ethylene glycol, oxalate, and isopropanol concentrations (as appropriate) would be the ideal tests to perform when toxic alcohol poisoning is suspected shortly after exposure. However, these concentrations are most commonly measured by gas chromatography with or without mass spectrometry confirmation, methodologies that are not available in most hospital laboratories on a 24 hour basis, if at all. In fact, in many hospitals these are only available as “send out” tests, so results arrive too late for early clinical decision making.¹³³ Enzymatic assays for methanol, formic acid, ethylene glycol, and glycolic acid have been developed,^27,232,249 and these may lead to more readily available clinical tests. However, the commercial product is currently approved for veterinary use only. This veterinary test is effective for confirming the qualitative presence of ethylene glycol in human poisoning, although false positives may occur with propylene glycol.¹⁵⁷ In a murine model, a commercially available ethanol in saliva point of care test can detect the presence of a low concentration of methanol but not ethylene glycol.⁹⁶ Unfortunately, it would not distinguish between methanol and ethanol, limiting the clinical utility of this test. A group in Finland described a point of care breath test for methanol, using a portable Fourier transform infrared (FT-IR) analyzer similar to the “breathalyzers” used by law enforcement agents.¹⁴⁷ Although analyzers like this are used to check for methanol as a combustion product in industry, they are not yet approved for medical use in the United States. Once approved, they would be useful for early clinical decision making because they are easy to use and provide a rapid result. They also can provide continuous monitoring of concentrations, a feature that would be very helpful during hemodialysis. Unfortunately, this methodology could not be used to detect ethylene glycol because of its low volatility.

Patients presenting late after ingestion may already have metabolized all parent compound to toxic metabolites and thus may have low or no measurable toxic alcohol concentrations. Fortuitously, the enzymatic assay for ethylene glycol is also capable of detecting glycolic acid, although as mentioned, this assay is approved only for veterinary use. Some authors have actually advocated for routine testing for glycolic acid in addition to testing for the parent compound when ethylene glycol poisoning is suspected.¹⁹⁸ Serum and urine oxalate concentrations may also be determined,²³³ although their clinical utility is unclear. Similarly, a formate concentration may be valuable when a patient presents late after methanol ingestion.^115,184 Formate was detected in blood samples from 97% of patients who died of methanol poisoning in one series; all of these patients also had detectable blood or vitreous methanol concentrations.¹²⁶ Clearly, a low or undetectable toxic alcohol concentration must be interpreted within the context of the history and other clinical data, such as the presence of acidosis and end-organ toxicity, with glycolate and formate concentrations as potentially valuable additions.

Samples must be handled correctly for accurate toxic alcohol results. Particularly with the more volatile alcohols methanol and isopropanol, concentrations may be falsely low if the sample tubes are not airtight. This commonly results in low concentrations if alcohol concentrations are done as “add on” tests to samples already opened for electrolyte or osmol determinations.

Other alcohols such as benzyl alcohol and propylene glycol are not routinely assessed for by gas chromatography. Thus these xenobiotics present a much greater diagnostic challenge than methanol and ethylene glycol. Enzymatic assays for methanol or ethylene glycol would also fail to detect these, although false positive ethylene glycol tests may occur if propylene glycol is present. Thus a high index of suspicion is critical to establishing the diagnosis in these cases. If suspected on the basis of history, specific toxic alcohol testing should be performed.

Once alcohol concentrations are obtained, their interpretation represents a further point of controversy. Traditionally, a methanol or ethylene glycol concentration greater than 25 mg/dL has been considered toxic, but the evidence supporting this as a threshold is often questioned. In a case series of methanol poisoned patients from the 1950s, a methanol concentration of 52 mg/dL was the lowest associated with vision loss.²³ This may have been the origin of the 25 mg/dL threshold, incorporating a 50% reduction as a margin of safety. However, the patient with the 52 mg/dL concentration presented 24 hours after his initial ingestion, and therefore was much more severely poisoned than suggested by his serum concentration at that point. In fact, almost all reported cases of methanol poisoning involve patients with delayed presentations who already have a metabolic acidosis.¹⁴¹ The only reported patient who went untreated after presenting early with an elevated methanol concentration (45.6 mg/dL) never developed acidosis or end-organ toxicity.^32,141 A systematic review found that 126 mg/dL was the lowest methanol concentration resulting in an acidosis in a patient who arrived early after ingestion and met the inclusion criteria. The authors concluded that the available data are currently insufficient to apply a 25 mg/dL treatment threshold in a patient presenting early after ingestion without acidosis.¹⁴¹ However, until better data are available demonstrating the safe application of a higher concentration, it seems prudent to use a conservative concentration such as 25 mg/dL as a threshold for treatment.

Because of the problems with obtaining and interpreting actual serum concentrations, many surrogate markers have been used to assess the patient with suspected toxic alcohol poisoning. The initial laboratory evaluation should include serum electrolytes, including calcium, blood urea nitrogen, serum creatinine concentrations, urinalysis, measured serum osmolality, and a serum ethanol concentration. Blood gas analysis with a lactate concentration is also helpful in the initial evaluation of ill appearing patients.

Anion Gap and Osmol Gap

For a full discussion of the anion gap concept, refer to Chap. 19. As previously discussed, anion gap elevation is a hallmark of toxic alcohol poisoning. In fact, the possibility of methanol or ethylene glycol poisoning is often first considered when patients present with an anion gap acidosis of unknown etiology, frequently with no history of ingestion. Unless clinical information suggests otherwise, it is important to exclude metabolic acidosis with elevated lactate concentration and ketoacidosis, which are the most common causes of anion gap acidosis, before pursuing toxic alcohols in these patients. This is because of the extensive evaluation required and expensive, potentially invasive course of therapy to which they are otherwise committed. However, elevated lactate concentrations may be present in the setting of both methanol and ethylene glycol poisoning.^163,170,219

The unmeasured anions in toxic alcohol poisoning are the dissociated organic acid metabolites discussed above. The acidosis takes time to develop, sometimes up to 16 to 24 hours for methanol. Thus the absence of an anion gap elevation early after reported toxic alcohol ingestion does not exclude the diagnosis. If ethanol is present in the body, the development of acidosis will not begin to occur until enough ethanol has been metabolized that it can no longer effectively inhibit ADH (see Ethanol Concentration, below).

A potential early surrogate marker of toxic alcohol poisoning is an elevated osmol gap (the principles and the calculations are discussed in detail in Chap. 19). However, it is important to recognize that osmol gap elevation is neither sensitive nor specific for toxic alcohol poisoning. Since a baseline osmol gap is generally not available when evaluating a patient (with rare exceptions),¹¹³ and a normal osmol gap ranges from –14 to +10 osmols, so-called “normal” osmol gaps cannot exclude toxic alcohol poisoning.¹⁰⁸ For example, in a patient with a baseline osmol gap of –10, a current gap of +5 potentially represents a methanol concentration of 47 mg/dL or an ethylene glycol concentration of 93 mg/dL, values that might require hemodialysis. Inversely, a moderately elevated osmol gap (+10 to +20) is not necessarily diagnostic of toxic alcohol poisoning because other disorders such as alcoholic ketoacidosis and metabolic acidosis with elevated lactate concentration, may raise the osmol gap.²¹⁴ Furthermore, mean osmol gaps vary within populations over time, further limiting their utility.¹⁴² However, a markedly elevated osmol gap (>50) is difficult to explain by anything other than a toxic alcohol.

Further complicating matters, the anion gap and osmol gap have a reciprocal relationship over time. This is because soon after ingestion, the alcohols present in the serum raise the osmol gap but do not affect the anion gap because metabolism to the organic acid anion has not yet occurred. As the alcohols are metabolized to organic acid anions, the anion gap rises while the osmol gap falls, because the metabolites are negatively charged particles that have already been accounted for in the calculated osmolarity by doubling of the sodium. Thus patients who present early after ingestion may have a high osmol gap and normal anion gap, while those who present later may have the reverse.^111,117 Figure 109–4 depicts a more intuitive visual representation of this process.

One retrospective and one prospective study have attempted to evaluate the performance characteristic of the osmol gap as a diagnostic test. Although in both cases, the osmol gap performed fairly well, the studies were small, 20 patients with toxic alcohol poisoning in the retrospective study and 28 patients with methanol poisoning in the prospective study, and the prospective study identified three patients with significant poisoning and acidosis but “normal” osmol gaps, defined in the study as less than 25.^111,162 Therefore, these data do not eliminate the concern that a patient with significant poisoning could be missed by relying on the osmol gap alone to exclude poisoning.

Ethanol Concentration

A serum ethanol concentration is an important part of the assessment of the patient with suspected toxic alcohol poisoning. As discussed in Chap. 19, the ethanol concentration is necessary to determine the calculated osmolarity. In addition, because ethanol is the preferred substrate of ADH (4:1 over methanol and 8:1 over ethylene glycol), a significant concentration would be protective if coingested with a toxic alcohol. In fact, ethanol concentrations near 100 mg/dL virtually preclude toxic alcohols as the cause of an unknown anion gap metabolic acidosis because the presence of such a concentration should have prevented metabolism to the organic acid. A possible exception would be ingestion of ethanol several hours after ingestion of a toxic alcohol.¹⁰⁶ If a breath alcohol analyzer is used to determine ethanol concentration, a false positive ethanol value may be obtained if significant methanol concentrations are present, and the machine may not indicate that an interfering substance is present (as it does with acetone).⁴⁰ Therefore, even if a prehospital breath alcohol analyzer indicates a significant ethanol concentration, this should be confirmed by determining the serum ethanol concentration.

Lactate Concentration

Both methanol and ethylene glycol poisoning can result in elevated lactate concentrations, for different reasons. Formate, as an inhibitor of oxidative phosphorylation, can lead to anaerobic metabolism and resultant lactate elevation. Additionally, metabolism of all alcohols results in an increased NADH/NAD⁺ ratio, which favors the conversion of pyruvate to lactate. Furthermore, hypotension and organ failure in severely poisoned patients can also produce an elevated lactate concentrations. However, lactate production by these mechanisms tends to result in serum concentrations no greater than 5 mmol/L.

In ethylene glycol poisoning, the glycolate metabolite may also cause a false positive lactate elevation when measured by some analyzers, particularly with whole blood arterial blood gas analyzers. The Radiometer ABL series (625, 700, 725, 825, 835) is most widely reported to result in a false positive lactate; other specific models implicated to varying degrees include: Beckman LX 20, Bayer/Chiron Rapidlab series (860, 865), Roche Modular, Architect c8000, Vitros Fusion 5.1, Cobas Integra, GEM Premier 4000 and Hitachi 911 analyzers, but not the Vitros 950 or Vitros 250 or the Beckman Coulter DxC-800 chemistry analyzer.^{35,45,53,71,163,170,175,191,197,213,256} In such cases, the degree of lactate elevation directly correlates with the concentration of glycolate present,^163,170 and the artifact results from the lack of specificity of the lactate oxidase enzyme used in these machines,^{170,175,197,256} although direct oxidation of glycolate at the analyzer anode is also suggested as a possible mechanism.²²² Thus the presence of a “lactate gap” might also be used to diagnose ethylene glycol poisoning in hospitals where lactate assays are available with and without sensitivity to glycolate, or two lactate assays with different sensitivities to lactate.^222,246 Ingestion of propylene glycol can also result in elevated lactate concentrations, but in this case, it is not a false positive lactate but rather an accurate measurement of a metabolite of ­propylene glycol.^127,128

Other Diagnostics

Serum glucose concentration is generally obtained as part of routine laboratory analysis. Hyperglycemia, defined as serum glucose greater than 140 mg/dL (7.77 mmol/L) in nondiabetic patients, portended a greater risk of death after methanol poisoning, with an odds ratio of 6.5 in one retrospective study.²¹⁰ This has not yet been prospectively validated.

The urine may provide information in the assessment of the patient with suspected ethylene glycol poisoning. Calcium oxalate monohydrate (spindle-shaped) and dihydrate (envelope-shaped) crystals may be seen when the urine sediment is examined by microscopy, although this finding is neither sensitive nor specific.^79,118,174 In fact, calcium oxalate crystals were present in the urine of only 63% (12 of 19) of patients with proven ethylene glycol ingestion in one series.³³

Some brands of antifreeze contain fluorescein to facilitate the detection of radiator leaks. If one of these products is ingested and the urine is examined with a Woods lamp within the first 6 hours, there may be urinary fluorescence.²⁵⁵ Gastric aspirate may also demonstrate fluorescence.⁵⁶ False positive fluorescence may result from examining the urine in glass or plastic containers due to the inherent fluorescence of these materials, so if this test is performed, an aliquot of the urine should be poured onto a piece of white gauze or paper. Recent work has suggested a lack of utility of this test. Almost all children had urinary fluorescence, and there was poor interrater agreement in determining fluorescence of specimens.^43,189

The evaluation of patients with known or suspected ethylene glycol poisoning should also include serum calcium and creatinine concentrations. Patients with methanol poisoning and abdominal pain also warrant an assessment of liver function tests and serum lipase because of the ­possibility of associated hepatitis and pancreatitis.

Although characteristic brain CT and MRI abnormalities are frequently reported in the setting of methanol poisoning, it is unclear what role they have in the routine evaluation of these patients. The presence of putaminal hemorrhage or insular subcortex white matter necrosis was associated with a greater odds ratio of death (8 and 10, respectively) in one study of patients with methanol poisoning.²³⁷ However, in the absence of neurological abnormalities on physical examination, routine CT or MRI are probably not indicated.

Diagnostic Testing and Risk Assessment

Increases in both anion gap and osmolar gap may be useful for risk stratification in methanol poisoning, and a venous or arterial blood gas should be performed. A review of reported toxic alcohol cases attempted to identify risk factors for mortality in adults with methanol or ethylene glycol poisoning. For methanol poisoning, no patient with an anion gap less than 30 mEq/L or an osmolar gap less than 49 osmols died. A pH less than 7.22 was an even better predictor of mortality, as no patient with a pH greater than 7.22 died. For ethylene glycol, the tests were less useful. One patient with an osmolar gap of only 25 osmols died, no patient with an anion gap less than 20 mEq/L died, and pH did not predict mortality with statistical significance.⁵⁴ This study has been criticized for missing a substantial number of patients,²⁰⁷ and it still needs to be validated in another population. Another retrospective study of risk factors for poor outcomes in methanol poisoning only found that pH less than 7.00 (as well as coma or a >24-hour delay to presentation) was associated with death.¹⁰³ In a large series from several epidemics of methanol poisoning, a pH less than 7.00 and coma were again identified as risk factors associated with death. In patients with a pH less than 7.00, PCO₂ greater than or equal to 23.3 mm Hg (3.1 kPa) was also a risk factor.¹⁸⁵ In methanol poisoned patients unlikely to die, the pH may still be useful for predicting retinal toxicity. Another retrospective study examined markers for poor visual outcome after methanol poisoning and again found pH to be the best predictor, with a pH greater than 7.20 associated with a high likelihood of only transient visual sequelae.⁶¹

As always, immediate resuscitation of critically ill patients starts with management of the airway, breathing, and circulation. Because alcohols may cause respiratory depression and coma, intubation and mechanical ventilation are commonly necessary for patients with severe poisoning. Alcohol-induced vasodilation combined with vomiting often lead to hypotension, and many patients will require fluid resuscitation with intravenous crystalloid. Gastrointestinal decontamination is rarely, if ever, indicated for toxic alcohols because of their rapid absorption and limited binding to activated charcoal. However, placement of a nasogastric tube and aspiration of any gastric contents is probably worthwhile in intubated patients, as absorption may sometimes be delayed after a large dose.⁶⁸

Alcohol Dehydrogenase Inhibition

The most important part of the initial management of patients with known or suspected toxic alcohol poisoning (after initial resuscitation) is blockade of ADH. This allows for the establishment of a definitive diagnosis and arrangement for hemodialysis while preventing the formation of toxic metabolites. Additionally, in some cases ADH blockade may itself serve as definitive therapy.

Teleologically, ADH exists for the purpose of metabolizing ethanol, so it is not surprising that the enzyme has a higher affinity for ethanol than for other alcohols. ADH metabolizes ethanol with a Km that is 15 to 20 times lower in vitro than its Km for methanol metabolism and 67 times lower than its Km for ethylene glycol metabolism.^55,192,193 Thus significant concentrations of ethanol prevent metabolism of other alcohols to their toxic products. Ethanol is the traditional method of ADH inhibition and may still be the only option in some institutions. A 10% solution is administered through a central venous catheter and titrated to maintain a serum concentration of 100 mg/dL (Antidotes in Depth: A31). Complications of the infusion include hypotension, respiratory depression (with supratherapeutic concentrations), flushing, hypoglycemia, hyponatremia, pancreatitis, and gastritis, as well as inebriation, so patients receiving intravenous ­ethanol require admission to an intensive care unit. The true incidence of these adverse events is unclear. In one study, complications of ethanol infusion in children were uncommon.²⁰³ However, in another review of 49 adults treated with ethanol infusions for toxic alcohol poisoning, 92% of patients had at least one adverse event.²⁵² Orally administered ethanol is also effective and may be considered when intensive monitoring is unavailable, particularly in rural areas where there may be a significant delay in getting the patient to a hospital.

Fomepizole is a competitive antagonist of ADH that has many advantages over ethanol. It reliably inhibits ADH when administered as an intravenous bolus every 12 hours, and concentrations do not need to be monitored as with an ethanol infusion.^33,34 It does not cause inebriation and is associated with fewer adverse effects, so it does not require intensive care unit monitoring.^{18,19,33,34,150} For these reasons, it has become the preferred method of ADH blockade, despite being significantly more expensive than ethanol.²²⁵ In theory, the savings in intensive care unit (ICU) monitoring and laboratory costs probably compensate for the higher drug cost of fomepizole, unless the patient requires intensive monitoring regardless based on the severity of illness.²⁸ However, one study showed that even after fomepizole was introduced to their hospital, 95% of patients received ICU admission and hemodialysis,⁸⁹ so this may not be a large area of ­savings. Additionally, the cost difference will vary depending on the setting of poisoning and the health care delivery system of the country involved. A series in Belgium found that treating with ethanol and dialysis was much less expensive than fomepizole without dialysis within their system.⁹

The dose of fomepizole is 15 mg/kg intravenously as an initial loading dose followed by 10 mg/kg every 12 hours. Bradycardia and hypotension may occur after fomepizole infusion, so vital signs should be monitored closely during and after each dose.¹⁴⁹ After 48 hours of therapy, fomepizole induces its own metabolism, so the dose must be increased to 15 mg/kg every 12 hours. Although one review advocates giving doses as high as 20 mg/kg every 12 hours with no adjustment for induced metabolism,²⁵ this dosing regimen is not supported by the manufacturer or any current clinical guideline. A review of reported cases in which fomepizole was used in children suggests that it is safe and effective with the same weight based dosing as adults.³² Pharmacokinetic data from a human volunteer study show that there is no significant difference in serum concentrations between oral and intravenous fomepizole.¹⁶⁴ However, there is currently no oral preparation of fomepizole on the market (Antidotes in Depth: A30).

Indications for fomepizole or ethanol therapy may be based on the ­history or on laboratory data. Any patient with a believable history of methanol or ethylene glycol ingestion should be treated until concentrations are available because, as previously discussed, early symptoms and laboratory markers other than serum concentrations may be absent. In addition, any patient with an anion gap acidosis without another explanation or a markedly elevated osmol gap should also be treated. Once concentrations are available, therapy should be continued until the serum toxic alcohol concentration is predicted or measured to be below 25 mg/dL, although as ­discussed previously, this value is based more on consensus opinion than on data.

The antiretroviral medication abacavir is a substrate for ADH and seemed to delay metabolism of methanol in one case.⁸⁴ It has been suggested that abacavir could have potential as an alternative to fomepizole in places where fomepizole is unavailable.²¹² Similarly, ranitidine is an inhibitor of gastric and hepatic ADH, and in a rat model, ranitidine improved pH, formate concentrations, and retinal histopathology.⁶⁷ Although these are intriguing possibilities, there are currently no data to support the use of either abacavir or ranitidine in human poisoning.

Hemodialysis

The definitive therapy for symptomatic patients poisoned by toxic alcohols is hemodialysis. Hemodialysis clears both the alcohols and their toxic metabolites from the blood and corrects the acid–base disorder. The indications for hemodialysis have become more restricted with the advent of fomepizole because of its effectiveness combined with its low incidence of adverse effects. Particularly for ethylene glycol, which can generally be expected to be cleared within a few days once ADH is blocked as long as the glomerular filtration rate is normal,^37,152,245 some have argued that the risks of an invasive and costly procedure such as hemodialysis are not warranted in minimally symptomatic patients with normal kidney function and without acidosis.^38,82 Even a patient with a moderately elevated serum methanol concentration, 80 mg/dL (2.5 mmol/L), was successfully treated with fomepizole alone.²⁰⁴ Based on toxicokinetic data, some patients with methanol poisoning might be treated without dialysis or with delayed dialysis, particularly in epidemic scenarios, where the need for hemodialysis may exceed the availability.¹¹² However, patients with end-organ toxicity or severe acidosis have significant amounts of toxic metabolites, a problem not addressed by ADH blockade, and acidosis is associated with poor prognosis.¹⁵⁶ Additionally, although formate is normally cleared rapidly once ADH is blocked, the half-life increases with higher serum methanol concentrations and varies from 2.5 to 12.5 hours.^101,110 In one patient with severe poisoning, formate was eliminated at an extremely slow rate with a half-life of 77 hours until hemodialysis was initiated,¹¹⁴ underscoring the importance of hemodialysis in patients with significant metabolic acidosis. In addition, patients with AKI will not eliminate the parent compound once ADH is blocked, except very slowly in expired air in the case of methanol. Therefore, the consensus is that metabolic acidosis, signs of end-organ toxicity, including coma and seizures, and AKI are indications for hemodialysis. A “toxic concentration” and possibly a very high osmol gap¹⁹⁴ are more relative indications for hemodialysis, and decisions must be based on the judgment of the clinician for the specific clinical scenario, considering the available resources. Some authors have advocated using toxic metabolite concentrations if available as additional criteria for hemodialysis. In data from one case series, an elevated formate concentration appears to be a better predictor of clinically important toxicity than methanol concentrations.¹⁸⁴ Similarly, glycolate concentrations are a better predictor of death and AKI than ethylene glycol concentrations.¹⁹⁸ However, although clearance of formate by hemodialysis is substantial,^121,122,136 the overall clearance in one case series did not appear to increase significantly above endogenous clearance in patients also treated with folate and bicarbonate.¹³⁶ Some have questioned the data quality in this series, pointing out that (a) the predialysis clearance in two patients was calculated using only two data points and in the three others was calculated using three points, generally considered the minimum; (b) several patients actually had decreased clearance during dialysis, contradicting all previous data; and (c) two of the patients had variable blood flow during dialysis.^112,258

The American Academy of Clinical Toxicology (AACT) practice guidelines are ambiguous with respect to a threshold methanol concentration for hemodialysis in the absence of acidosis, AKI, end-organ effects, or worsening clinical status.¹⁸ However, until additional investigations are completed, a methanol concentration of 50 mg/dL remains a reasonable indication for consideration of hemodialysis in the absence of significant acidosis or end-organ effects. The AACT guidelines for ethylene glycol actually advise against hemodialysis for a concentration alone without any of these clinical indications.¹⁹ Still, ethylene glycol remains the second most common toxin to be removed by hemodialysis in the US.¹⁰⁹ Clearly, there are still insufficient data to establish threshold concentrations of alcohols or their metabolites where dialysis is absolutely indicated, and the decision is ultimately a subjective one based on the overall clinical scenario.¹⁰⁷

Although hemodialysis effectively clears isopropanol and acetone from the blood, it is rarely if ever indicated for this purpose. Because isopropanol does not cause a metabolic acidosis and very rarely results in significant end-organ effects, the risks of hemodialysis likely outweigh the benefits.

Many patients will require multiple courses of hemodialysis to clear the toxic alcohol. Nephrologists may estimate the dialysis time required using the formula:

where t is the dialysis time required to reach a 5 mmol/L toxin concentration, V is the Watson estimate of total body water (liters), A is the initial toxin concentration (mmol/L), and k is 80% of the manufacturer ­specified dialyzer urea clearance (mL/min) at the observed initial blood flow rate.^104,259 Additionally, the normalization of the osmol gap may guide the required duration of dialysis, but this has not been validated.¹¹⁶ Regardless of how the duration of dialysis is determined, ADH blockade should be continued during and after hemodialysis until a subsequent concentration of the offending alcohol is confirmed to be nontoxic. Ethanol infusion rates must be increased during hemodialysis to maintain a therapeutic serum concentration as the ethanol is cleared (Antidotes in Depth: A31). Fomepizole should be redosed every 4 hours during hemodialysis to maintain therapeutic serum concentrations.^18,19

Continuous renal replacement therapy (CRRT) such as venovenous hemodiafiltration has occasionally been used in patients with toxic alcohol poisoning. Hemodialysis is much more efficient at clearing xenobiotics than CRRT and is virtually always the preferred modality if available. However, if there is a contraindication to hemodialysis, such as hemodynamic instability or severe cerebral edema,⁸⁶ or if hemodialysis is unavailable, CRRT may be considered as an intervention that may offer some advantage over no extracorporeal removal at all. In a pharmacokinetic model, the addition of CRRT can decrease the treatment time by 40%.⁵⁵

Adjunctive Therapy

There are several therapeutic adjuncts to ADH blockade with or (especially) without hemodialysis that should be considered for these patients. One of the differences that has been invoked to explain the absence of retinal toxicity from methanol in some species is the relative abundance of hepatic folate stores in these species such as the rat. Folate and leucovorin enhance the clearance of formate in animal models.^181,182 Thiamine enhances the metabolism of ethylene glycol to ketoadipate, and pyridoxine enhances its metabolism to glycine and ultimately hippuric acid (Fig. 109–2).¹⁷⁸ While all of these modalities offer theoretical advantages, they have yet to be proven to change outcome in humans. However, there is one human case report showing enhanced formate elimination with folinic acid therapy.¹²⁰ Additionally, some have suggested that the apparent lack of an increase in formate clearance by hemodialysis was because it was dwarfed by the effectiveness of folate supplementation in both the study group and the control group.¹³⁶ Because of the safety of vitamin supplementation, the potential benefit likely outweighs the risk of therapy (Antidotes in Depth: A10, A14, and A24).

Formate is much less toxic than undissociated formic acid, likely because formic acid has a much higher affinity for cytochrome oxidase in the mitochondria, the ultimate target site for toxicity.¹⁵⁵ In addition, the undissociated form is better able to diffuse into target tissues.¹²² Alkalinization with a bicarbonate infusion shifts the equilibrium to favor the less toxic, dissociated form, in accordance with the Henderson-Hasselbalch equation. This also enhances formate clearance in the urine by ion trapping.¹²² Data from uncontrolled case series demonstrate that patients treated with bicarbonate alone had better than expected outcomes after severe methanol poisoning,¹⁷⁷ but the results are equivocal in patients also treated with ADH blockade and hemodialysis.^34,119,171 Additionally, the severity of the metabolic acidosis after methanol poisoning is a good predictor of severe neurological effects such as coma and seizures,¹⁵⁶ although it is not proven that alkalinization prevents these effects. However, in the absence of contraindications to a bicarbonate infusion (eg, hypokalemia, volume overload), alkalinization should be used in the patient with suspected methanol poisoning and a significant acidemia. A blood pH greater than 7.20 is a reasonable endpoint. Alkalinization should also be considered for patients with ethylene glycol poisoning and life-threatening metabolic acidosis.

Aluminum citrate has potential promise as an adjunctive therapy for ethylene glycol poisoning. It interacts with the surface of calcium oxalate monohydrate crystals and prevents their aggregation. This decreases tissue damage from calcium oxalate monohydrate crystals in an in vitro model of human proximal tubule cells.⁹⁴ However, there are not yet any in vivo human studies or even case reports, so it cannot be recommended for clinical use.

Some have suggested a possible benefit of corticosteroids for retinal injury following methanol poisoning. In an uncontrolled case series, 13 of 15 patients showed improvement in their vision after treatment with 1 g of methylprednisolone daily for 3 days, with one having worsening vision and one unchanged.²²³ A patient in another case report had permanent vision loss despite corticosteroid therapy using the same regimen.⁷⁷ Another uncontrolled case series used a slightly different dosing regimen, with 250 mg of intravenous methylprednisolone administered every 6 hours followed by oral prednisolone 1 mg/kg daily for 10 days. After treatment, the mean best corrected visual acuity improved, but methanol concentrations were not reported so exposure was not confirmed, and acuity data were not reported for individual patients, so it is unclear whether any worsened.^1,209 Another series of four patients with mild methanol poisoning given the same treatment regimen showed some improvement in vision.²²⁸ An uncontrolled case series with delayed presentations, incomplete follow up, and an inconsistent corticosteroid regimen showed improvement in some patients.^206,220 In a series of 63 patients with methanol poisoning from a 2009 epidemic in India, all patients with evidence of optic neuritis (at least 60% of 46 survivors), were treated with retrobulbar injections of triamcinolone (dose not reported); 75% had some improvement.²¹⁸ Currently, however, these data are insufficient to support the routine use of corticosteroids in methanol poisoning.²²⁷

Pregnant Women and Perinatal Exposure

There are very few reported cases of pregnant women with toxic alcohol poisoning, but some conclusions can be drawn from the available data. Toxic alcohols readily cross the placenta, and perinatal maternal methanol ingestion has resulted in death of a newborn.²² One woman was initially misdiagnosed with eclampsia after ingesting ethylene glycol and presenting with seizures and metabolic acidosis in her 26th week of pregnancy. An emergency cesarean section was performed, and she was later treated with hemodialysis and ethanol once the correct diagnosis was recognized. The child was severely ill, with an initial pH of 6.63 and an initial serum ethylene glycol concentration of 220 mg/dL. The baby was treated with exchange transfusion and ultimately survived without sequelae after a long hospital course.¹⁴³ In rat but not rabbit models of chronic high dose ethylene glycol exposure, fetal axial skeletal malformations occur and are thought to be caused by ­glycolate.⁵² No human case of chronic exposure has yet been reported.

Propylene Glycol

Propylene glycol is commonly used as an alternative to ethylene glycol in “environmentally safe” antifreeze. It is also used as a diluent for many pharmaceuticals (such as phenytoin and lorazepam). This alcohol is successively metabolized by ADH and ALDH to lactate, so a metabolic acidosis results. This can result in extremely high lactate concentrations typically that would be incompatible with life if generated by any disease process. In other diseases associated with lactate accumulation and acidosis, the lactate is a reflection of underlying anaerobic metabolism, a marker of severe illness rather than part of the underlying pathophysiology. Lactic acidosis from propylene glycol is surprisingly well tolerated because it represents nothing more sinister than its own metabolism, and it is rapidly cleared by oxidation to pyruvate, which then undergoes normal carbohydrate metabolism (Chap. 55).

Benzyl Alcohol

Benzyl alcohol is used as a preservative for intravenous solutions. Although it is no longer used in neonatal medicine, it has been responsible for “neonatal gasping syndrome,” involving multiorgan system dysfunction, metabolic acidosis, and death because of its metabolism to benzoic acid and hippuric acid (Chap. 55).^83,159

• Early symptoms of toxic alcohol poisoning may include inebriation, and subsequent toxicity results from metabolism to organic acid anions that cause metabolic acidosis and end organ effects.

• The time required for this metabolism results in a delay before toxicity is clinically manifest.

• Until serum concentrations are available, the serum anion gap and osmol gap may help with decision making but do not exclude toxicity if the history is concerning.

• Therapy consists of ADH antagonism with fomepizole or ethanol, as well as adjunctive therapy with bicarbonate, folate or folinic acid, pyridoxine, and thiamine.

• Hemodialysis is the definitive therapy for clinically ill patients as it removes the alcohol as well as toxic metabolites while correcting the metabolic acidosis and electrolyte abnormalities.

Acknowledgments

Neal E. Flomenbaum, MD, Mary Ann Howland, PharmD, Neal A. Lewin, MD, and Adhi N. Sharma, MD, contributed to this chapter in previous editions.

References