By Kathleen McMahon, DO, and Guhan Rammohan, MD
EXECUTIVE SUMMARY
- Patients who consume toxic alcohols may present with inebriation, similar to ethanol consumption.
- The major harm from toxic alcohols results from the formation of toxic metabolites.
- The biochemical hallmark of toxic alcohol poisoning is an elevated osmolar gap with an anion-gap metabolic acidosis (apart from isopropanol consumption, which typically does not lead to metabolic acidosis).
- The laboratory tests used to detect serum levels of the toxic alcohols are not often readily available in hospital laboratories.
- The initiation of antidotal treatment may be based on clinical suspicion and history, supported by commonly available biochemical tests.
- The standard treatment for most toxic alcohols (except isopropanol) is alcohol dehydrogenase blockade with ethanol or fomepizole to prevent the creation of toxic metabolites.
- Hemodialysis also may be indicated and is used most often for methanol and ethylene glycol poisoning to remove the toxic alcohol and correct the severe metabolic disturbances.
- Sodium bicarbonate bolus and infusion may be used as adjunctive therapy in patients with severe metabolic acidosis from methanol and/or ethylene glycol poisoning.
- Consultation with a local toxicologist and/or poison control center also can assist in patient management and disposition planning.
Case
A 30-year-old male with a history of alcohol use disorder and homelessness presents to the emergency department with altered mental status. He was last seen by a friend in his usual state of health approximately three hours prior and was found by this friend lying on the ground next to multiple empty containers in a garage. His initial vital signs included a respiratory rate of 7 breaths/minute, a heart rate of 100 beats/minute, and blood pressure of 100/70 mmHg. On physical exam, he was unresponsive to painful stimuli, with equal and reactive pupils and no external signs of trauma. He was emergently intubated for airway protection.
Computed tomography (CT) scan of the head demonstrated no abnormalities. An electrocardiogram (ECG) demonstrated prolonged QTc with normal QRS and T wave morphology. He was noted to have an elevated serum osmolar gap of 68 mOsm/L, serum calcium of 8.0 mg/dL, metabolic acidosis with a pH of 7.2, and serum bicarbonate of 10. The patient then was admitted to the intensive care unit for further evaluation and management.
Introduction
The term “toxic alcohols” often is used to refer to alcohols other than ethanol that may be ingested and result in toxicity.1 It commonly is used to refer to methanol, ethylene glycol, diethylene glycol, isopropanol, and propylene glycol.2 Poisoning from these substances may result from accidental or intentional ingestion, exposure through pharmaceutical agents, and adulteration of commercial or homemade products.3 Identification of toxicity caused by toxic alcohols may be challenging, since patients often are unable to provide a history of such an ingestion on presentation, and because the clinical presentation changes over time secondary to the metabolism of the alcohol into its toxic metabolites that exert end-organ effects.2 Exposure to toxic alcohols can lead to serious morbidity and mortality; thus, awareness of these substances, their clinical presentation, and treatment options is critical to prevent poor outcomes.2,3 More serious poisonings generally are noted in early to middle-age adults, and those at the younger end of this spectrum tend to be exposed through intentional misuse of these substances or self-harm.4 A significant metabolic acidosis or elevated osmolar gap in the setting of intoxication should raise suspicion for ingestion of one of these substances. This constellation of findings is not always present, though, and a normal anion or osmolar gap does not rule out exposure to a toxic alcohol.2,3 This is particularly true in exposures to small amounts of these substances or very early in the clinical presentation.3
General Alcohol Metabolism
Alcohols are readily absorbed from the gastrointestinal (GI) tract after oral ingestion, but first-pass metabolism in the liver generally limits the oral bioavailability of alcohols.1 Alcohols are distributed into the total body water compartment. Their volume of distribution is approximately 0.77 L/kg.1 Toxic alcohols are successively metabolized by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), producing toxic metabolites. Each of these reactions is coupled to the reduction of oxidized nicotinamide adenine dinucleotide (NAD+) to its reduced form where it carries a hydrogen ion, H+ (NADH).
Laboratory Testing
Although it may be tempting to check serum levels for toxic alcohols to secure a definitive diagnosis, several significant issues arise when ordering and interpreting such tests. Serum levels of these substances often are not rapidly available, taking hours to days to perform, and may need to be sent out to other laboratories to be analyzed. Gas chromatography is considered the gold standard test for toxic alcohols, and it typically is not performed in many hospital laboratories.5 Therefore, serum levels cannot be relied on to make real-time clinical decisions for acutely ill patients.3,6 Development of newer, faster tests for alcohols is upcoming but not currently of clinical use.7
The longer the lag period between ingestion and obtaining the specimen, the greater the amount of the parent alcohol that will be metabolized to other compounds. This may lead to reports of falsely low levels. Additionally, more volatile alcohols, such as isopropanol and methanol, may be measured falsely low if sample tubes are not airtight or have been used prior for other testing (such as in “add-on” testing) because the toxic alcohols may burn off.
Most toxic alcohols characteristically cause an elevated osmolar gap and an elevated anion gap metabolic acidosis, and intoxication with these substances should be on the differential diagnosis for any elevation in osmolar gap. The osmolar gap is defined as the difference between measured serum osmolality and calculated osmolality based on sodium, glucose, and urea concentrations. The normal osmolality is 285 mOsm/L to 290 mOsm/L, with the normal osmolar gap traditionally cited as between -10 mOsm/L and +10 mOsm/L.5,6 Others have suggested alternative ranges, such as -9 mOsm/L to +19 mOsm/L in emergency department populations.3 Individual variations around the normal range exist, which may confound the identification of an abnormal osmolar gap.8 (See Table 1.)
Table 1. Laboratory Findings in Toxic Alcohol Toxicity |
Methanol
Ethylene Glycol
Diethylene Glycol
Propylene Glycol
Isopropanol
|
It also should be noted that the serum osmolality may be measured in a multitude of ways, depending on the laboratory, but the general consensus is that the best method is freezing point depression. However, this variability in testing may lead to a variation in values depending on the timing of testing.
Since these alcohols are not included in the standard calculation of serum osmolality, a difference between the measured and calculated serum osmolality will be present early in the clinical presentation.1,6 Toxic alcohols also can produce a metabolic acidosis with an elevated anion gap, with the exception of isopropanol, which produces an elevated osmolar gap without metabolic acidosis.6
As the toxic alcohols other than isopropanol are metabolized to organic acids, this translates into a decreasing osmolar gap and increasing anion gap over time. In other words, the osmolar and anion gaps have an inverse relationship over time following toxic alcohol ingestion. Alcohols do not raise the osmolar gap equally when compared to each other; methanol causes the greatest increase, followed by ethanol, isopropanol, ethylene glycol, propylene glycol, and finally diethylene glycol.6
Although other conditions may cause both an elevated osmolar gap and elevated anion gap, it is unusual for any condition other than toxic alcohol ingestion to lead to an osmolar gap of greater than 50 mOsm/L.1 A decreasing osmolar gap with rising anion gap over time should raise suspicion for a toxic alcohol ingestion.1,6 Given that it generally is the organic acid metabolites that exert the toxic effects of these substances, discordance between the osmolar gap and signs and symptoms is not unexpected.6
Testing for the presence of significant metabolic disturbance and end-organ dysfunction may help identify and guide management of these exposures. This may include evaluation of serum electrolytes, blood urea nitrogen (BUN), creatinine, lactate, and ethanol concentration in addition to consideration of urinalysis and serum blood gas to determine acid-base status. In patients with initially unremarkable laboratory studies but high suspicion for a toxic alcohol ingestion, repeat evaluation of serum acid-base status approximately every two to four hours may be considered based on case severity.3
Differential Diagnosis
Central nervous system (CNS) depression and metabolic acidosis with ketosis may be seen in alcoholic, diabetic, and starvation ketoacidosis. Many other conditions can cause an elevated osmolar gap, and the most common of these include alcoholic or diabetic ketoacidosis, large ingestions of ethanol, sepsis, and severe shock. Ingestions of sedative-hypnotic agents and salicylates also share some features with toxic alcohol poisoning.
General Notes on Treatment Options/Changes
Guidelines for treatment for methanol and ethylene glycol toxicity are more robust and supported by greater evidence than those for other toxic alcohols, although even these guidelines are subject to controversy and local practice variation.2 Therapies such as ADH blockade with or without dialysis and other adjunctive therapies are the cornerstones of treatment. While high-quality studies into the topic are lacking, the management of pediatric patients with toxic alcohol ingestions should follow the same general treatment algorithms as adult patients.9
Decontamination
Attempts at decontamination must occur within 30 to 60 minutes of ingestion to have any impact because of the rapid absorption of the alcohols from the GI tract following an oral ingestion.6 If performed within 60 minutes, aspiration via nasogastric tube of methanol or ethylene glycol following a very large ingestion may have some benefit. Activated charcoal does not significantly adsorb alcohols; thus, it plays no role in this setting. Other measures, such as syrup of ipecac and gastric lavage, likewise have no role.
ADH Blockade
Like toxic alcohols, ethanol and fomepizole (4-methylpyrazole or 4-MP) are substrates for ADH and can be used with similar effectiveness.10 Both ethanol and fomepizole can and should be used to treat pregnant and pediatric patients to prevent toxicity from the downstream metabolites of toxic alcohols.3
Early initiation is critical. ADH blockers do not prevent toxicity from metabolites that already have been generated; rather, they prevent the formation of further toxic organic acids.
Ethanol
Ethanol competes with toxic alcohols for the active site on the enzyme, delaying transformation of the toxic alcohols to their metabolites.3 Although it does not carry Food and Drug Administration (FDA) approval for this purpose, ethanol has been used with success in this setting.6 Its affinity for ADH is approximately 10-20 times greater than that of other alcohols.6
Ethanol is administered intravenously as 10% ethanol in D5W. The goal serum concentration for ADH blockade using ethanol is 100 mg/dL.3,6 Intravenous (IV) ethanol is given as an initial bolus dose (0.6 g/kg) followed by a maintenance infusion (66 mg/kg to 154 mg/kg per hour).3 Higher doses may be required in patients with a history of alcohol abuse because of chronic induction of ADH at baseline.3 In austere settings, it also may be given therapeutically per os (PO) or using a nasogastric tube by administering commercially available spirits until the patient is transported to a higher level of care.11
Ethanol has a low volume of distribution and low protein binding, and thus it can be cleared by dialysis. When used in conjunction with intermittent hemodialysis, the dose of ethanol must be approximately doubled, and it must be increased by 20% if given in conjunction with continuous renal replacement therapies.3 Ethanol therapy may lead to longer elimination half-lives of toxic alcohols, which also may translate to a longer length of stay when used without extracorporeal removal techniques.3 Widely available and less costly than fomepizole, ethanol may be beneficial for prehospital treatment, especially in the setting of large outbreaks.10
Adverse effects of ethanol therapy include inebriation, CNS depression, and respiratory depression, occurring in about 50% of patients.3 In addition, it may be irritating to blood vessels on IV infusion. Lastly, hypoglycemia may occur, especially in pediatric populations, although administration with dextrose-containing solutions decreases this risk.3
Treatment with ethanol has several logistical challenges. Serum ethanol concentrations should be measured every one to two hours to ensure stable, therapeutic levels. This may be difficult to achieve because of local resource availability and laboratory constraints.3 Frequent testing of serum concentration is necessary because of the variation in elimination rates between individuals and changing pharmacokinetics in the presence of other therapies.3
Given the risk of respiratory depression and other complications, patients receiving ethanol infusion typically are managed in a critical care setting. A central venous catheter may be required, given irritation to peripheral blood vessels.
Fomepizole
Fomepizole has between 500 to 8,000 times greater affinity for ADH compared to ethanol.3,6,9 It is the most commonly used ADH blocker, given its greater ease of administration and more favorable side effect profile, although it is more costly than ethanol.12,13 Fortunately, the development of a generic version of this treatment has made it significantly more affordable.5 Internationally, fomepizole is used both orally and intravenously, but only the IV preparation is available in the United States.6
Fomepizole is administered as a 15 mg/kg loading dose followed by 10 mg/kg every 12 hours. The recommended therapeutic serum concentration of fomepizole is 0.8 mg/L.6,9 The dose must be increased after 48 hours of therapy because fomepizole auto-induces its metabolism by CYP450 enzymes after approximately two days of continuous therapy.3,9
Like ethanol, fomepizole’s small volume of distribution and low protein binding make it amenable to clearance by dialysis, and the dose of fomepizole must be increased if these treatments are used simultaneously.3,6 It also can be administered after dialysis.9
Adverse effects include pain and burning at the infusion site, nausea, vomiting, confusion, drowsiness, and dizziness.3,14 The presence of adverse effects should not preclude further treatment.14 Allergic reactions to methylpyrazoles are a contraindication to fomepizole administration, although this is rare.3
Dialysis
Toxic alcohol poisoning is one of the most common indications for hemodialysis as a treatment for toxicologic exposures.15 Alcohols and organic acid anions are amenable to removal by hemodialysis, given that they have low molecular weight, have low volume of distribution, and are distributed in the total body water.6 Hemodialysis also may aid in correcting severe metabolic disturbances and renal failure caused by toxic alcohols.2 In general, the presence of acidosis, acute kidney injury, and suspected or measured toxic alcohol concentrations above a certain threshold are criteria to initiate dialysis.9 Methanol and ethylene glycol toxicity have the greatest evidence and most specific guidelines for initiation of dialysis.2,9
Intermittent hemodialysis (IHD) is more effective than continuous renal replacement therapy (CRRT) in lowering levels of toxic alcohols and their metabolites. CRRT still may be used with success in patients who are too unstable or otherwise unable to tolerate IHD.3,6,16 Peritoneal dialysis has little use in this setting because of much lower clearance rates of toxic alcohols and their metabolites.6
Although serum alcohol levels may be used to trend response to therapy, these levels often are not available quickly enough to affect clinical decision making. Surrogate markers, such as renal function, electrolytes, and acid-base status, should be used instead.6 For those undergoing hemodialysis, return of osmolar gap to ≤ 10 mOsm/kg H2O has been suggested as an endpoint for therapy.9
Base Administration
Administration of sodium bicarbonate intravenously or via dialysis has been used to treat severe metabolic acidosis in the setting of toxic alcohol toxicity.6 An acidemic environment promotes the stability of organic acids in an uncharged state that more easily crosses cell membranes. Administration of base converts these substances back to a charged form that is less easily able to cross membranes and that can be more easily renally excreted. Intravenously, sodium bicarbonate is given at a bolus dose of 1 mEq/kg to 2 mEq/kg, followed by an infusion of 133 mEq of sodium bicarbonate (or approximately three standard ampules of sodium bicarbonate) in 1 L of D5W, infused at a rate of 150 mL/hr to 250 mL/hr in adult patients. Although formal recommendations for initiation and discontinuation of this therapy do not exist at this time, some have proposed a threshold of serum pH < 7.3 as an indication for this treatment.6 Close monitoring of serum pH, sodium, and potassium during bicarbonate infusion is prudent.
Supportive Care
The cornerstone of most toxicologic exposures is supportive care, and toxic alcohols are no exception. Hypotension caused by alcohol-induced vasodilation can be treated with IV fluids or vasopressors in refractory cases.1 Hemorrhagic gastritis due to isopropanol ingestion may be concomitantly treated with proton pump inhibitors. Inebriation and CNS depression may be treated supportively, with airway management as needed for airway protection or ventilatory support.
Disposition
Disposition depends on the alcohol, time since ingestion, and severity of symptoms. Patients may be discharged several hours after ingestion of certain alcohols if they have no evidence of end-organ damage and a low blood toxic alcohol concentration. Other patients may require intensive care monitoring for hemodynamic instability, significant metabolic acidosis, or evidence of end-organ damage. A continuous ethanol infusion also requires intensive care unit admission. Consultation with a medical toxicologist or poison control center is recommended. If the presentation is the result of an intentional ingestion with intent for self-harm, psychiatric evaluation is recommended before discharge.
Methanol
Epidemiology
Methanol is a colorless liquid found in numerous products, including windshield wiper fluid, antifreeze, solid cooking fuels, photocopying fluid, perfumes, shellacs, paint thinners or removers, and model airplane fuel. It also is used as a solvent and in some industrial applications.1,6,17 Epidemics of beverages inadvertently containing methanol have occurred, often with high mortality because of the severity of toxicity and delay in diagnosis.1,3,17,18 Only a few thousand cases of methanol poisoning occur in the United States each year, but sometimes with devastating consequences.6 If there is a delay in diagnosis, mortality figures are very high, up to 36% in one study.19 In another study, 603 patients hospitalized with a methanol toxicity from 2003 to 2014 were identified and analyzed to determine outcomes. The three most common complications were metabolic acidosis (44%), hypokalemia (18%), and visual impairment (8%). The three most common end-organ failures were renal failure (22%), respiratory failure (21%), and neurological failure (17%). In-hospital mortality was 6.5% in this cohort.20
Toxicology
Intoxication may result from oral ingestion, absorption across the skin, and inhalation of large amounts.1 Metabolism of methanol by ADH and aldehyde dehydrogenase ALDH produces formaldehyde and formic acid (formate), respectively.1,2 (See Figure 1.) The toxic effects attributed to methanol are caused by these metabolites. In the mitochondria, formic acid inhibits cytochrome oxidase and disrupts oxidative phosphorylation. An increase in oxidative stress and pro-inflammatory cytokines through other mechanisms also may promote cytotoxicity.17,21 For reasons not fully understood, the retina, optic nerve, and putamen are disproportionately affected compared to other tissues.1 Low levels of tetrahydrofolate may lead to increased formate levels and, thus, increased toxicity because of disruption in downstream metabolic pathways.6
Figure 1. Metabolism of Methanol |
 |
Clinical Presentation
Inebriation, due to methanol itself, develops within the first few hours after ingestion.22 In the absence of coingestion of other substances, signs and symptoms of toxicity typically develop approximately 12-24 hours after ingestion but may be more rapid.3 Symptoms may be delayed between six and 24 hours or longer if ethanol has been coingested.6
The hallmark of methanol toxicity is visual disturbance, which may include sensitivity to light, blurred vision, changes in color vision, “snowstorm vision,” or blindness. Loss of vision is permanent in 11% to 18% of patients, with other permanent visual deficits in as many as 30% to 40% of survivors.1,3,6,21 Papilledema or hyperemia of the optic discs may be noted on physical examination.1,6 Other symptoms include abdominal pain, GI bleeding, and neurologic symptoms ranging from confusion to coma.1,5,6 Pancreatitis has been reported.23 Necrosis of the putamen, likely because of formic acid accumulation and associated cytotoxicity, may manifest as muscular rigidity, tremor, monotonous speech, and masked facies.1,3,6 Cardiac toxicity, including acute myocardial infarction in severe cases, may occur.24 Some patients present with severe respiratory distress, and in severe cases, deaths may occur prehospital. Respiratory failure, profound CNS depression, and severe metabolic acidosis are associated with the highest rates of morbidity and mortality.18
Increased rates of cancer have been observed years after methanol poisoning, although a causative effect has not been definitively demonstrated.25
Laboratory Testing
Blood concentrations may be obtained, but results are not available quickly. Plasma concentrations greater than 20 mg/dL (6 mmol/L) are associated with end-organ damage. Blood formate concentrations have been used as a sensitive indicator of methanol exposure and to trend clinical condition.26
Management
ADH-blocker therapy should be initiated under the following conditions: plasma methanol concentration > 20 mg/dL; serum osmolar gap > 10 mOsm/L with a recent history of methanol ingestion; or suspected methanol ingestion plus any two of either arterial pH < 7.3, HCO3- < 20 mEq/L, or osmolal gap > 20 mOsm/L.6,9 (See Table 2.) The serum concentration at which ADH-blocker therapy can be discontinued is not currently known.6 There are reports of patients who coingest ethanol with methanol, particularly in cases of adulterated alcoholic beverages, in which the consumption of ethanol is believed to have delayed the onset of severe toxicity and led to improved outcomes after definitive treatment.18
Table 2. Treatment Options for Toxic Alcohol Toxicity |
Methanol
Ethylene Glycol
Diethylene Glycol
Propylene Glycol
Isopropanol
|
ADH: alcohol dehydrogenase |
Based on recommendations by the American Academy of Toxicology, hemodialysis should be considered in the following situations: serum methanol concentration > 50 mg/dL, metabolic acidosis with pH between 7.25 and 7.3 or lower, visual disturbances, acute renal failure, and inability to correct electrolyte disturbances or acidosis with other therapies.6 However, it should be noted that fomepizole alone has been used successfully to treat patients with serum methanol concentration > 50 mg/dL.6,13
The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup has criteria for initiation of dialysis for methanol poisoning as well. It recommends dialysis if any of the following are present: coma, seizures, new vision deficits, blood pH < 7.15, metabolic acidosis refractory to other measures, serum anion gap > 24 mmol/L, methanol concentration > 70 mg/dL if undergoing fomepizole therapy or concentration > 60 mg/dL if undergoing ethanol therapy, concentration > 50 mg/dL in the absence of ADH blockage, or impaired renal function.16
EXTRIP advises the cessation of dialysis when the methanol concentration is < 20 mg/dL and the patient is clinically improving.16 Others recommend discontinuation of dialysis when the serum methanol concentration is < 16 mg/dL or is undetectable, osmolar gap has normalized, and/or blood pH is greater than 7.3.6,9 Some have suggested down-trending serum formate levels as an indicator of response to dialysis, although these results often are not readily available.6
Sodium bicarbonate should be administered. Using base therapy to reverse metabolic acidosis within the first several hours after presentation has been described, although this treatment rarely is given alone.18
Folic acid 50 mg to 70 mg IV every four to six hours or folinic acid 1 mg/kg (max dose 50 mg) every four to six hours may be given as an adjunctive therapy for methanol toxicity, since it enhances the metabolism of folate to carbon dioxide and water.5,6,27 This can be continued even if the patient undergoes hemodialysis.16
Ethylene Glycol
Epidemiology
Of all toxic alcohols, intoxication with ethylene glycol is the most common.3,6 Ethylene glycol is found in automobile coolants, deicing products, cosmetics, detergents, paints, hydraulic brake fluids, and heat transfer fluids.17 Clinically, it is encountered most commonly in patients with intentional ingestion of ethylene glycol as an ethanol substitute or for intentional harm to self or others.3 Epidemics of exposure through adulterated products also have occurred.3 It characteristically has a sweet taste, is colorless, and has no distinct odor. Toxicity may result from ingestion or exposure to topical products applied to broken skin.6
Toxicology
Ethylene glycol itself does not cause significant signs or symptoms; the harm comes from the formation of toxic metabolites.2 It is metabolized by ADH to ALDH to glycolaldehyde and glycolic acid, the latter of which is metabolized into glyoxylic acid by lactate dehydrogenase or glycolate oxidase.1,2 (See Figure 2.) Glycolate oxidase is transformed into several compounds, including oxalic acid.1 Oxalic acid combines with calcium in the body to form calcium oxalate monohydrate, which is insoluble and may deposit in renal tubules and other tissues, causing tissue damage.3 Glycolic acid inhibits cellular respiration and contributes to metabolic acidosis through promoting anaerobic metabolism.5,6 Its half-life is prolonged at concentrations greater than 250 mg/dL, at which point its metabolism changes from first order to zero order elimination.17
Figure 2. Metabolism of Ethylene Glycol |
 |
In the presence of thiamine, glyoxylic acid may be transformed into alpha-hydroxy-beta-ketoadipic acid. Pyridoxine promotes transformation into glycine and hippuric acid. These downstream metabolites are considered nontoxic.1
Clinical Presentation
There may be a six- to 12-hour latency period after an isolated ethylene glycol ingestion before the onset of signs and symptoms.3 Ethylene glycol toxicity is suggested to occur in three stages, which may overlap.6 Like with methanol, initial mental status changes consistent with inebriation may predominate. Over the initial 12 to 24 hours, neurologic symptoms may worsen, and the development of focal neurologic signs, proteinuria, and hematuria may occur.5,6 Initial neurologic symptoms are followed by cardiopulmonary dysfunction between hours 12 and 36, which then is followed by more prominent renal dysfunction. Significant metabolic acidosis develops during this second stage.28 Renal failure may develop 24 to 72 hours after ingestion. Delayed presentation of cranial neuropathies around days 8 to 15 following ingestion may occur, and these usually are transient.6
End-organ dysfunction is the result of acidosis and deposition of calcium oxalate complexes in tissues such as the glomerulus and renal tubules, heart, brain, and lungs.6 The impairment of cellular respiration by glycolate also contributes to toxicity.6 Hypocalcemia resulting from the formation of calcium oxalate complexes may lead to depression of myocardial function, myocarditis, congestive heart failure, and hypotension. End-organ toxicity is exacerbated by severe metabolic acidosis.6
While calcium-oxalate crystals may deposit in renal tubules, it is the direct effects of these complexes on the glomerulus that result in acute tubular necrosis and impairment in renal function.1 Oxalic acid is not directly nephrotoxic.1
Laboratory Testing
Peak serum concentrations occur one to two hours after ingestion.5 Plasma concentrations greater than 20 mg/dL (3 mmol/L) are associated with end-organ damage. Lethal ethylene glycol doses are reported to be 1.4 mL/kg to 1.6 mL/kg body weight, although death at lower concentrations and survival at higher concentrations have been reported.6,28
In the past, calcium oxalate crystals and fluorescence of urine were used as markers of ethylene glycol exposure, but such tests may be misleading. Calcium oxalate crystals appear in the urine starting several hours after ethylene glycol ingestion and may persist for a few days, but this finding is neither sensitive nor specific.1,3 Urine fluorescence under Wood’s lamp may result in false positives resulting from the presence of sodium fluorite (SF), which is found not only in some brands of antifreeze but also in some drugs and food products.1,5 SF is not present in all antifreeze products and has a relatively short half-life; thus, the absence of fluorescence does not rule out ethylene glycol exposure.5,8,29,30 Propylene glycol also has been noted to cause false-positive testing for ethylene glycol.1
Serum lactate levels may be falsely elevated in the presence of ethylene glycol if using the lactate oxidase-based laboratory method because of cross-reactivity of the enzyme with this alcohol.6
Glycolate levels may be measured as a marker of ethylene glycol toxicity and have been used to provide treatment response and prognostic information. Patients with glycolate levels greater than or equal to 8 mmol/L to 10 mmol/L are more likely to develop renal failure or die.6,28
Management
ADH blockers are used to prevent the creation of toxic metabolites if the ethylene glycol concentration is greater than 20 mg/dL. (See Table 2.) The exact concentration at which ADH-blocker therapy can be discontinued in this setting is not currently known.6
According to the American Academy of Clinical Toxicology and National Kidney Foundation, dialysis may be considered in the following scenarios: serum ethylene glycol concentration > 20 mg/dL; history of ingestion of a toxic amount of ethylene glycol with an osmolal gap > 10 mOsm/L; or strong suspicion of ethylene glycol toxicity with at least two of the following: arterial pH < 7.3 with serum bicarbonate < 20 mEq/L, osmolal gap > 10 mOsm/L, or the presence of oxalate crystals in the urine.6,9 High ethylene glycol concentration should not be used alone to determine the need for hemodialysis, since these patients still may be treated effectively with ADH blockade.13,31 Other indications for dialysis may include metabolic acidosis, renal failure, or electrolyte disturbance refractory to other measures, or a serum glycolic acid level > 8 mmol/L to 10 mmol/L.6
Other treatments for ethylene glycol toxicity may include volume expansion with mannitol and bicarbonate to decrease the severity of oxalate-induced renal disease, although there is a lack of evidence supporting this intervention.6 Similarly lacking evidence is thiamine and pyridoxine supplementation to promote conversion of glycolic acid to a-hydroxyl-b-ketoadipate and of glyoxylate to glycine, respectively.6 Despite the lack of evidence, the relative safety of thiamine and pyridoxine and their potential benefits generally support their use in clinical practice.6
Isopropanol
Epidemiology
A primary constituent of rubbing alcohol, isopropanol also is used in cosmetics, pharmaceutical products, and industrial applications. It also is used as a deicing fluid and cleaning agent.1,2,6
Toxicology
Isopropanol is metabolized to acetone by ADH. (See Figure 3.) Acetone is further degraded into products including propylene glycol, acetate, and formic acid, although these are thought to contribute little to clinical toxicity.32 Isopropanol itself may cause inebriation, CNS depression, and hemorrhagic gastritis in severe cases. Acetone itself may cause respiratory depression. Since acetone is not an organic acid, but rather a ketone, it does not result in metabolic acidosis or elevated anion gap in the absence of severe systemic toxicity. Acetone is eliminated renally and via the lungs.
Figure 3. Metabolism of Isopropanol |
 |
Clinical Presentation
Toxicity caused by isopropanol tends to be less severe than that of other toxic alcohols. Acetone and isopropanol both may cause CNS depression, but, in contrast to other toxic alcohols, the parent compound causes the majority of the clinical effects.1,2,6 Signs and symptoms typically present between 30 minutes and four hours after ingestion.6 Toxicity may present as inebriation and altered mental status, respiratory depression, abdominal pain, nausea, vomiting, acute pancreatitis, hemorrhagic gastritis, and, at high levels, hypotension.1,2,6 It is unknown whether the hemorrhagic gastritis predominantly is caused by local irritant effects or another mechanism.1
Laboratory Testing
Although some evidence suggests that levels of 150 mg/dL to 200 mg/dL are associated with increased mortality, other evidence suggests that levels of 400 mg/dL or greater are required to cause significant lasting effects.5 As with ethylene glycol, isopropanol ingestion may confound measurements of other laboratory tests. Elevated serum acetone may result in falsely elevated serum creatinine levels when the latter is measured using colorimetric techniques.6
Management
Treatment of isopropyl alcohol toxicity generally is supportive.1,2 (See Table 2.) ADH blockade generally is neither required nor helpful. In the case of a significantly intoxicated patient with severe CNS depression, hypotension refractory to supportive care, renal failure, or severely elevated isopropanol level (> 200 mg/dL), hemodialysis may play a role.2 Careful consideration of the relative risks and benefits in this case is prudent, since the former often may outweigh the latter, given that end-organ effects generally are not severe or persistent.1,2,6
In the case of small ingestions, the absence of symptoms two hours after exposure predicts an extremely low likelihood of significant poisoning. Ingestions of greater than one ounce of isopropanol and the development of mental status depression both are predictors of clinically significant toxicity.33
Propylene Glycol
Epidemiology
Propylene glycol is encountered primarily in pharmaceutical products, although it also may be found in cosmetics, solvents, antifreeze, and hydraulic fluids.6,9,17 Pharmaceuticals that include propylene glycol include phenytoin, phenobarbital, diazepam, lorazepam, etomidate, nitroglycerin, digoxin, and hydralazine. Intravenous lorazepam and diazepam may be associated with a higher risk of propylene glycol toxicity than IV midazolam, since the former contain up to 40% propylene glycol.9,34
Toxicology
Propylene glycol is successively metabolized by ADH and ALDH to lactic acid, which may result in extremely high serum lactate levels when measured.1 Lactic acid subsequently is converted to pyruvate through oxidation, which then joins normal metabolic pathways.1
Clinical Presentation
Renal failure in the setting of propylene glycol toxicity has been described, although its mechanism is unclear.6 Intravenous administration of medications containing propylene glycol has been reported to result in CNS depression, cardiac dysrhythmias, hypotension, seizures, and hemolysis in addition to soft tissue necrosis due to extravasation.35 Some of these effects may be attributed partly to the pharmaceutical agent itself.6
Laboratory Testing
Serum propylene glycol concentrations greater than 18 mg/dL to 25 mg/dL are associated with toxicity.35 In cases in which levels are not readily available, serum osmolar gap has been used as a surrogate marker for propylene glycol concentration in patients receiving propylene glycol-containing infusions. Serum lactate levels may not directly correlate in the same manner.36 Propylene glycol may cause a false-positive test for ethylene glycol.1
Management
Treatment of propylene glycol toxicity consists primarily of removing the patient from further exposure to the offending medication or propylene glycol-containing agent.6 (See Table 2.) While hemodialysis can effectively remove propylene glycol from the serum, the benefit typically is outweighed by the risks associated with the procedure. Only in the setting of renal failure, severe metabolic acidosis, or electrolyte disturbance, or the presence of extremely high serum concentrations may dialysis be indicated.6 In these extreme cases, fomepizole and base therapy also may be administered, although the exact management of these patients remains controversial.6 In less extreme cases, supportive care and removal of exposure should lead to clinical improvement within 24 hours in most patients.6
Diethylene Glycol
Epidemiology
Diethylene glycol is used in brake fluid, wallpaper strippers, fabric and dye manufacturing, some pharmaceuticals, and other industrial applications.6,17 Although an infrequent cause of poisoning, epidemics have occurred in instances when diethylene glycol is used as an illicit substitute for propylene glycol or glycerin in liquid medications.3 It has been associated with epidemics of poisoning in children.1 Of historical note, the 1938 Food, Drug, and Cosmetics Act was passed to protect consumer safety after the deaths in 1937 of 105 people poisoned by sulfanilamide elixir containing diethylene glycol.3
Toxicology
Diethylene glycol is metabolized to 2-hydroxyethoxyacetic acid (HEAA), which is believed to mediate the toxic effects of the parent alcohol. The exact mechanism of HEAA is not yet proven, but its metabolism to diglycolic acid may inhibit the citric acid cycle.1,3,6,17,37
Clinical Presentation
Because of the frequent delay from the time of ingestion to diagnosis, it has been difficult to establish the time course of evolution of signs and symptoms for diethylene glycol exposures.6 Clinical findings include renal failure (oliguric or nonoliguric), hepatitis, pancreatitis, abdominal pain, diarrhea, headache, and altered mental status. These symptoms may occur in three phases that have been described in the literature. Gastrointestinal symptoms and metabolic acidosis occur during the first stage, followed by the development of kidney injury after about one to three days. It is during this second stage that death results if treatment is not undertaken. Stage three is marked by neurologic symptoms and starts at days 5-7. Neurological features may include facial and peripheral nerve palsies, which may be bilateral paralysis, CNS depression, and coma.3 As is the case with ethylene glycol, cranial neuropathies may develop approximately 10-14 days after initial ingestion, although this is rare.
Laboratory Testing
A fatal dose of diethylene glycol in an adult is estimated to be 1 mL/kg, but both higher and lower concentrations have been reported in the literature.37,38 A significant metabolic acidosis may not be present until 12 hours or more after exposure.39 In the case of diethylene glycol ingestion, osmolality may be high because of its high molecular weight.6
Management
Diethylene glycol toxicity has been treated with both ADH inhibitors and dialysis, although criteria for initiation and discontinuation of these therapies have not been formally established.2,3,6 (See Table 2.) Animal studies have demonstrated the promise of ADH-inhibitor therapy in this scenario, as have case reports of treatment in humans.3,13 Dialysis typically is reserved for patients with multiorgan failure and severe metabolic acidosis refractory to other measures.2
Hand Sanitizer
Several thousand poison center calls for hand sanitizer exposure are made per year, a figure that has risen through the COVID-19 pandemic.40
Hand sanitizers may be alcohol-based or non-alcohol-based, and alcohol-based products are associated with more severe toxicity.41 Whereas the active ingredient in non-alcohol-based hand sanitizers typically is benzalkonium chloride, alcohol-based hand sanitizers may contain ethanol, isopropyl alcohol, n-propanol, and other non-alcohol ingredients.42,43 Alcohol-based products may be consumed as an ethanol substitute or ingested accidentally.42,43 The most effective and the most frequently encountered products contain between 60% and 95% alcohol by volume (> 60% ethanol or > 70% isopropyl alcohol).42,43
As expected, ingestion of significant quantities of hand sanitizer containing ethanol or isopropyl alcohol leads to signs and symptoms consistent with ethanol or isopropyl alcohol toxicity, respectively. Unfortunately, products containing methanol as a substitute for other alcohols are illicitly produced. These products have been noted to cause severe methanol poisoning, which may lead to severe morbidity or mortality.43 One such epidemic occurred in 2019 and 2020 in Arizona and New Mexico and was associated with the deaths of multiple adult patients.43,44 The treatment of toxicity from alcohols contained in hand sanitizer products follows the same guidelines as that of the alcohol in question, although deaths occur in some cases despite maximal therapies.43,44
Conclusion
It is critical to have a high index of suspicion for toxic alcohol toxicity to make an accurate and timely diagnosis. This, in turn, facilitates expeditious treatment that may prevent morbidity and mortality in these patients. Treatment may need to be initiated based on clinical suspicion and readily available laboratory tests before making a definitive diagnosis. Current mainstays of treatment include ADH inhibitors, such as fomepizole and ethanol, hemodialysis, and other adjunctive therapies. There generally is a lack of robust evidence for criteria for initiating and discontinuing treatments in many situations, particularly for patients who ingested an alcohol other than methanol or ethanol. More research is needed to further define these parameters.
Case Conclusion
Over the first day of his admission to the intensive care unit, the patient’s serum osmolar gap improved while his metabolic acidosis worsened, and he developed acute renal failure, hypotension, and depressed myocardial function. Because of concern for poisoning, the medical toxicology service was consulted. A diagnosis of likely ethylene glycol ingestion was made through history, physical exam, and review of laboratory studies. Ultimately, he was started on fomepizole in addition to intermittent hemodialysis. Over the subsequent days, his renal function, mental status, and cardiovascular function improved significantly. On hospital day 8, he was discharged to an alcohol rehabilitation facility.
Kathleen McMahon, DO, is Emergency Physician, Cedars-Sinai Marina del Rey Hospital, Marina del Rey, CA.
Guhan Rammohan, MD, is Assistant Chief, EM/Critical Care Faculty, St. Luke’s Hospital, Bethlehem, PA.
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It is critical to have a high index of suspicion for toxic alcohol toxicity to make an accurate and timely diagnosis. This, in turn, facilitates expeditious treatment that may prevent morbidity and mortality in these patients.
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