SC7: Special Considerations

HO—CH₂—CH₂—O—CH₂—CH₂—OH

Diethylene glycol (DEG) is a solvent with physical and chemical properties similar to propylene glycol used throughout the chemical industry. Pharmaceutical-grade propylene glycol is a safe and commonly used solvent for water-insoluble pharmaceuticals (Chap. 55). However, unlike propylene glycol, DEG is a potent nephrotoxic and neurotoxic chemical. Substitution of DEG for propylene glycol and other diluents such as glycerin in oral pharmaceutical elixirs has repeatedly caused epidemics of mass poisoning (Chap. 2). This substitution has occurred early in the pharmaceutical manufacturing process due to the intentional mislabeling of DEG as a replacement for the intended pharmaceutical-grade glycerin,⁴² for financial gain⁴⁹ and other reasons, without regard to safety.¹⁵ As medication-associated DEG mass poisonings have recurred, numerous quality assurance and control guidelines have been developed to identify DEG-contaminated materials.Failure to adhere to these guidelines throughout the pharmaceutical manufacturing and distribution process contributes to this public health ­problem.⁴⁹ In DEG poisoning, patients develop acute kidney injury (AKI) that can rapidly progress to renal failure and death. Those patients who do not die quickly after exposure, but who develop AKI, often become ­dialysis dependent and may go on to develop neurological signs and symptoms. These patients may deteriorate further after onset of neurotoxic signs and symptoms and subsequently die.

The metabolism of DEG and the pathophysiology of DEG-associated disease are incompletely understood and most of what is known comes from animal studies. Indeed, very little data are available in humans. Previously, DEG was thought to be metabolized to two ethylene glycol molecules which, when metabolized to glycolic acid and oxalic acid, caused AKI; this theory has been disproven.⁵⁷ Current evidence supports that the terminal DEG metabolite diglycolic acid (DGA) is nephrotoxic. Diglycolic acid appears to be neurotoxic as well based on a single, published case report of poisoning.⁴⁴ This chapter will provide a brief history and epidemiology of DEG poisoning, describe existing pharmacokinetic and toxicokinetic data collected primarily from animal studies, and then discuss available information on the toxic dose, pathophysiology, clinical manifestations, testing and treatment for DEG poisoning. When specific doses of DEG in the literature were reported in mL/kg, they were converted to g/kg by taking into account the density of DEG (1.118 g/mL) and the concentration. If information on concentration was not provided, then a 100% concentration was assumed. For the reader’s convenience, the original dose (if it was in mL/kg) and commensurate DEG concentration are provided following the converted dose in g/kg or mg/kg.

DEG is produced by the condensation of two ethylene glycol molecules forming an ether bond,¹ which yields a compound with a molecular weight of 106 g/mol.^1,46 It was first identified in 1869 and has been used in industry and manufacturing since 1928.¹ It has found use as an antifreeze, as a finishing agent for wool, cotton, silk, and other fabrics, as well as in dye manufacturing. DEG is chemically inert and has a higher boiling point than ethylene glycol.^20,58 Its other physical properties are quite similar to ethylene glycol, including a sweet taste.^20,58 It is often used as an intermediate in the production of polymers, higher glycols, morpholine, and dioxane.³⁵ Its physical properties enable it to serve as an excellent solvent for delivery of water-insoluble substances. Unfortunately, its use as a solvent for various pharmaceuticals intended for human consumption has resulted in the vast majority of reported cases of poisoning.^{6,8,9,12,14,15,17,18,28,32,38,42,50,52,58} In these recurring events, DEG was substituted for a safe and appropriate diluent such as glycerin or propylene glycol. DEG poisoning has also resulted from the intentional addition of DEG to wine as a sweetener^55,56 or when it was consumed as a substitute for ethanol.⁶⁰ Finally, there are numerous isolated case reports of DEG poisoning resulting from the consumption of DEG-containing products such as radiator fluid or antifreeze,³⁶ brake fluid,⁷ Sterno,⁴³ “fog solution,”¹⁹ cleaning solutions,¹ and wallpaper stripper.³⁴

Absorption and Distribution

In rodents DEG is highly (>75%) and almost immediately absorbed after ingestion. It is distributed primarily based on blood flow, with the kidneys receiving the most DEG, followed by the brain, the spleen, liver, and muscles.²⁰ The degree of protein binding and the volume of distribution (Vd) in humans is unknown but the Vd in the rat is approximately 1 L/kg.²⁰ Maximal DEG plasma concentrations occur within 4 hours of ingestion: the ratio of DEG in plasma to red blood cells is 3:2 (approximately 60% of a dose is found in the plasma).^3,20,58 DEG readily crosses the blood–brain barrier,^20,58 and concentrations peak in brain tissue (CSF concentration was not reported) within 3 to 4 hours of exposure.²⁰

Metabolism.

Existing animal data demonstrate that as much as 40% of an ingested dose may undergo hepatic metabolism with most of that eliminated in the urine.^20,25,33 Diethylene glycol is metabolized by alcohol dehydrogenase (ADH) to 2-hydroxyethoxyacetaldehyde which is then further metabolized by aldehyde dehydrogenase (ALDH) to 2-hydroxy­ethoxyacetic acid (HEAA).^4,57 HEAA is either renally excreted, oxidized to DGA (also known as 2,2-oxybisacetic acid) or converted to 1,4-dioxan-2-one under extremely acidic conditions.⁵⁶ The predominant pathway depends on numerous factors such as dose, degree of kidney function, and acid-base status of the patient.^4,30,33,57 The DEG ether bond linking the two ethylene glycol molecules is stable and is not hydrolyzed. Ingestion of DEG and subsequent metabolism does not therefore result in ethylene glycol release.^4,35,57 However, a small amount of ethylene glycol may be formed as an intermediate after formation of 2-hydroxyethoxyacetaldehyde (Fig. SC7–1).⁴ Serum HEAA concentrations peak approximately 4 hours following small DEG ingestions (2 g/kg), but a delayed peak at 8 to 24 hours occurs with larger exposures (10 g/kg) in rodents. Rats which ingest relatively small doses of DEG (2 g/kg) and rats given larger amounts of DEG with coadministration of an ADH blocker (10 g/kg + fomepizole) do not accumulate DGA in their serum over time. Blood DGA concentrations in rats dosed with 10 g/kg of DEG and fomepizole are not significantly different from control rat blood DGA concentrations. Furthermore, DEG elimination half-lives in the two groups dosed with 10 g/kg (one with fomepizole and without) were not significantly different, and almost the entire DEG dose given to the DEG plus fomepizole group was recovered in the urine. This suggests that elimination from the body is mainly controlled by urinary elimination of DEG, rather than by metabolism. Larger doses (10 g/kg) in rat studies, without simultaneous coadministration of an ADH inhibitor, are associated with clinically significant serum DGA concentrations that peak at 24 hours postingestion. If kidney function is impaired, concentrations of both HEAA and DGA continue to climb in a dose dependent manner.³

Elimination

Animal studies utilizing DEG with radiolabeled carbon report that most (> 60%) of a dose is eliminated within 24 hours of ingestion and almost all (> 90%) within 72 hours.^33,35 The majority of a DEG dose is eliminated unchanged in the urine (> 60%).^20,33 The proportion of DEG excreted in the urine increases when compared to metabolites as the dose increases due probably to saturation of hepatic metabolism.^33,35 This effect persists for approximately 24 hours following exposure. This effect may not be demonstrable beyond 24 hours because either the dose was small enough such that it was rapidly eliminated or because the dose was large enough to induce AKI.³³ As the dose increases, the probability of developing AKI increases, which will result in a decreased elimination of both DEG and its metabolites. Up to 30% of a DEG dose may be eliminated via the kidneys as HEAA.^3,13,33,57 Most initial work did not either look for or detect DGA, probably due to small exposures in the range of 1.1 g/kg, which did not result in substantial DGA generation.⁵⁷ For those reasons DGA metabolic data was not available until recently.^3,4 Although both HEAA and DGA are taken up into the liver and the kidneys in a dose-dependent manner, the kidney tissue concentrations of HEAA are correlated directly with peak blood concentrations, but DGA concentrations are not. In fact, kidney tissue DGA concentrations are approximately 100 times greater than peak blood DGA concentrations suggesting much greater accumulation in the kidney.³ This accumulation explains the low concentrations of urinary DGA seen experimentally.⁴ In rodent studies of DGA ingestion limited to 48 hours, DGA is detected in the urine, but at concentrations 50 times lower than HEAA.⁴ However, biologic samples in DEG poisoned humans many days after exposure and in the presence of AKI demonstrated a predominance of urinary DGA concentrations and a relative absence of urinary HEAA.⁴⁸ These findings may be due to a number of different reasons such as the delayed blood peak of DGA when compared with HEAA, the greater time interval from exposure to sampling, which may have afforded a greater likelihood of HEAA metabolism to DGA (compared with experimental animal data), and saturation of kidney tubule cell uptake of DGA. Finally, small amounts of a given DEG dose are eliminated in a dose-dependent fashion via fecal excretion (< 3%) and exhalation (< 7%).^20,33,35,46 Animal studies also demonstrate that small amounts of DEG radiolabeled carbon is not eliminated but distributed to and collected in certain tissues such as muscle, fat, and skin (< 4% each) and the intestines, liver, and kidneys (< 2% each).^33,35

Two studies have reported data on half-lives calculated from serial DEG concentrations. The first reported that oral doses of 6.7 and 13.4 g/kg (6 mL/kg and 12 mL/kg of assumed 100% DEG) result in half-lives of 8 and 12 hours, respectively.⁵⁸ The second report suggests that when animals are given DEG doses of 1.1, 5.5, and 10.9 g/kg (1, 5, and 10 mL/kg of 97.5% DEG), most (64%, 87%, and 91%, respectively) of the dose is eliminated in the first 16 hours after exposure with calculated half-lives of 3 to 4 hours.²⁰ The remainder is then eliminated much more slowly with half-lives ranging from 39 to 49 hours.²⁰

Several rodent studies have reported data on elimination half-lives collected from serial urinary DEG measurements in pharmacokinetic investigations. These same studies have demonstrated that a DEG dose-dependent osmotic diuresis occurs. As the ingested dose increases from 1.1 to 19.6 g/kg (–17.5 mL/kg of > 99% DEG), it induces a fourfold increase in urine production. This effect appears to plateau at approximately 19.6 g/kg (17.5 mL/kg of > 99% DEG).²⁰ DEG appears to undergo zero order kinetics for the first 9 to 18 hours following ingestion. This correlates temporally with the osmotic diuresis which may contribute to this phenomenon.^20,33 During this time, elimination half-lives range from 6 hours at doses of 1.1 to 5.5 g/kg (1–5 mL/kg of 97.5% DEG) to 10 hours for doses of 10.9 g/kg (10 mL/kg of 97.5% DEG).²⁰ First order kinetics ensue thereafter with elimination half-lives that are dose-dependent and range from 3 to 13 hours.^3,4,20,33 Based on some animal data, 12 hours may be sufficient to eliminate 94% of a dose assuming an elimination half-life of 3 hours at doses of 1.1 to 5.5 g/kg (1–5 mL/kg of 97.5% DEG).^20,24 However, several other studies with similar exposures (2 g/kg) suggest that urinary elimination half-lives may be as high as 5 to 6 hours, which suggests that more than 12 hours is needed to eliminate the majority of an similar dose.^4,20 Half-lives can be prolonged to at least 13 hours in more substantial poisonings (10 g/kg)³ and as kidney function becomes impaired DEG and its metabolites are unable to be excreted effectively, thereby prolonging elimination half-lives further. This information is of importance in determining the appropriate observation period for a suspected or known DEG exposure.

Rodent studies suggest that doses of up to 2 g/kg are minimally toxic and that doses of approximately 10 g/kg result in significant toxicity.⁴ However, rodents are relatively resistant to the clinical effects of DEG poisoning compared to humans. Human data are limited, established primarily from the history of affected patients from mass poisoning events, and usually represent an estimated cumulative exposure that occurred over a certain time period, rather than a single point of time. The median estimated toxic dose from the 1995 Haitian epidemic was approximately 1.5 g/kg (range, 0.25–4.94 g/kg) (1.34 mL/kg; range, 0.22–4.42 mL/kg of 100% DEG).³⁸ This estimation is similar to the doses reported for the elixir of sulfanilamide outbreak in the United States in the 1930s.⁸ The estimated toxic dose (0.35 g/kg) based on patient recall in the 2006 DEG mass poisoning in Panama was lower than previous events (personal communication, Nestor Sosa, MD). The lower toxic dose in this outbreak may be due in part to an older population with more chronic diseases when compared with other outbreaks that affected younger, presumably healthier persons (unpublished data from author). Postmortem DEG concentrations from an Argentinean outbreak reported a lethal dose ranging from 0.014 to 0.170 mg/kg,^12,14 although these data were suggested to be inaccurate, possibly by a factor of 1000.⁴⁵ In addition, the analytical testing techniques used in this report may have been subject to error due to cross-reactivity with other metabolites formed as the result of normal postmortem processes.¹⁶ These data also are also inconsistent with the fact that polyethylene glycol solutions with trace DEG concentrations yielding average total DEG exposures of 11 mg (range, 2–22 mg) administered for whole bowel irrigation in adults are without adverse effects.⁵⁹ The trace DEG concentrations found in these polyethylene glycol solutions may simply reflect a minor contamination or byproduct produced during the manufacturing process. This issue has not been studied. Quantities far in excess of the Argentinean analysis are estimated to occur in adults from nonprescription health products containing trace amounts of DEG (maximum value, 6.3 mg) currently sold in the United States.⁴⁸ There are no reports of DEG poisoning associated with these products.⁴⁸

In summary, the minimum toxic DEG dose in an acute, single dose exposure is unknown but limited data suggest that single, small total exposures of ≤ 22 mg in an adult are not associated with adverse health effects. Analysis of outbreaks of DEG poisoning suggests that cumulative exposures of as little as 250 mg/kg are associated with illness,³⁸ but the minimum toxic DEG dose may be lower.

The minimum toxic dose of DGA is unknown but ingestion of 100 g in an adult was fatal. The actual toxic dose is probably much less since the patient in this case report vomited immediately after ingestion but still died.⁴⁴

Accumulation of HEAA and DGA in the blood causes a metabolic acidosis that can be prevented by early administration of an ADH inhibitor such as fomepizole.^3,4 Although there are no published reports examining the efficacy of ethanol to block DEG metabolism, it would be expected to do this also. Inhibition of DEG metabolism with an ADH inhibitor prevents kidney and liver toxicity⁴ and decreases lethality in rodents.⁵⁷ The parent compound DEG does not appear to be toxic based on these same studies.^4,30,57 Digly­colic acid is likely to be the major if not sole cause of nephrotoxicity in DEG poisoning. Studies with human proximal tubule cells demonstrate that DGA induced cell death is due to necrosis via uptake by a sodium-dicarboxylate-1 transporter, which probably occurs due to its structural similarities to citric acid cycle intermediates. This results in interruption of mitochondrial respiration, leading to energy depletion and ultimately cellular necrosis. This study also suggests that neither DEG nor HEAA cause cellular toxicity in kidney tissue (in vitro proximal tubule cell testing) and that acidemia may enhance DGA toxicity.^30,31 Elevations in blood urea nitrogen and plasma creatinine concentrations correlate moderately well with elevations in tissue DGA concentrations.⁴ The histopathology of DEG associated nephrotoxicity primarily involves the proximal convoluted tubules as expected and affects the renal cortex where necrosis, hemorrhage and vacuolization can be seen.⁴⁶ Elevations in hepatic aminotransferases can also occur probably due to DEG, HEAA, and DGA accumulation in the liver.^3,34,46 The spectrum of DEG associated neurotoxicity is complex. Some case reports document primarily demyelinating peripheral neuropathies,^34,43 but data from the large numbers of patients who received nerve conduction testing from the Panama outbreak and other case reports^19,50 demonstrate that axonal sensorimotor neuropathy with secondary demyelination is probably the typical clinical course. Only those DEG poisoned patients who develop some degree of AKI seem to be at risk for developing neurotoxicity.^41,46 The mechanism of neurotoxicity of DEG is unknown but may also be related to DGA (unpublished data from author). The single reported human case of a pure DGA ingestion demonstrated clinical and pathologic findings very similar to DEG poisoning, supporting the notion that DEG poisoning is likely due in great part to DGA.⁴⁴

The signs and symptoms of DEG poisoning are dependent on duration of exposure, dose, and other intrinsic host factors such as the presence of comorbidities. Following ingestion, symptoms typical of ethanol intoxication such as lethargy, confusion, “drunkenness,” and altered mental status may begin rapidly and last for several hours.^5,46 This may be followed by clinical signs and symptoms of a metabolic acidosis including tachypnea and hypernea.^3,46 Although nausea, vomiting, abdominal pain, diarrhea, headache, and confusion are reported with DEG poisoning,^7,46 AKI remains the single consistent feature of all cases. This finding manifests over 1 to 3 days following ingestion^{6,9,12,14,18,28,38,42,46,50,52} as a progressive history of ­oliguria, anuria, or both develops.

In some of the reported DEG mass poisonings, patients have presented in AKI with profound acidosis and acidemia.³⁹ Many of these mass poisonings have occurred in children who received relatively high DEG doses in the form of a pediatric pharmaceutical such as liquid acetaminophen.^38,39 In the 2006 Panama mass poisoning, the overwhelming majority of patients were adults who probably ingested smaller doses per unit body weight when compared to child victims of past mass poisonings (although they were probably consumed for a longer period of time). Most of these patients presented to health care facilities with vague gastrointestinal or respiratory symptoms and were found to have AKI.^42,51 Many subsequently developed bilateral cranial nerve VII paralysis and peripheral extremity weakness, often within several days. Finally, many also rapidly developed encephalopathy, coma, and death in the subsequent 24 to 48 hours.⁵¹ This pattern of AKI followed days later by the appearance of neurological signs and symptoms such as unilateral or bilateral cranial nerve VII (facial nerve) paresis or paralysis, peripheral neuropathy, frank encephalopathy, autonomic nervous system instability, and coma is reported in several case reports, a case series, and two previous mass poisonings.^{1,18,19,43,46,51.}

Long-term outcomes among DEG poisoning survivors are not well characterized. Patients who develop AKI that does not improve quickly may become permanently hemodialysis dependent. Those who rapidly recover from their AKI appear to retain normal or at least adequate long-term ­kidney function. Patients with DEG-associated neurological findings tend to improve over time. In a study that followed DEG poisoning survivors for 2 years following their acute poisoning, delayed-onset renal and ­neurologic toxicity did not occur.¹¹

The clinician will likely have to rely on a high index of suspicion, a good exposure history and more commonly encountered “routine” testing methodologies including serum electrolytes, blood gas measurements, and renal function studies. Use of the osmol gap calculation has limitations²² but may be helpful in patients with acute ingestions.²³ Although the osmol gap should never be used to exclude the possibility of a toxic alcohol ingestion, if it is very large (> 50) it is unlikely to be due to anything else, especially in the setting of a suspected poisoning. The reader is referred to Chap. 109 for a complete discussion on this topic. Nerve conduction studies may prove helpful in establishing the pattern of neuropathy if present. ­Otherwise, ­routine laboratory and diagnostic tests should be used as needed to help evaluate end organ damage.

Although laboratory assays for DEG in whole blood, serum, plasma, and urine are commercially available at specialized toxicology testing laboratories, they are not available in most hospital laboratories. A study conducted during the 2006 Panama DEG mass poisoning demonstrated statistically significant differences (P < .001) in urinary DEG concentrations among cases (range, 50–4000 ng/mL) and controls (undetectable); unfortunately the assay used is not available.⁴² Biologic samples collected from the 2006 Panama investigation demonstrated that serum and urine DGA concentrations were significantly associated with case status (OR > 999; P < .0001).⁴⁸ Diglycolic acid holds promise as a potential biomarker for DEG poisoning, but further work validating the methodology is needed.⁴⁸

Treatment options include observation, gastrointestinal decontamination, supportive care, administration of an ADH inhibitor therapy, and hemodialysis. There is no evidence of clinical benefit or even reduced bioavailability of DEG following gastric or nasogastric lavage or the administration of oral activated charcoal.²⁶ Nevertheless, given the limited data regarding the role of gastrointestinal decontamination techniques in DEG poisoning, the profound dose-related clinical effects, and the liquid state of the xenobiotic, nasogastric lavage for an individual who presents soon after ingestion for a significant amount may help remove unabsorbed DEG. Since absorption begins immediately after ingestion, the efficacy of lavage after one hour is probably minimal.

Animal evidence suggests that the osmotic diuretic effect of DEG can cause large urinary volume losses in the immediate postexposure period which may not be effectively corrected due to concurrent inebriation. Adequate volume repletion and resuscitation should be performed as soon as possible. The patient should be closely monitored for decreases in urine output, fluid input and output recorded, their function tests closely followed, and appropriate fluid adjustments made for any signs of AKI. There is currently no evidence for forced diuresis; however, all patients should be aggressively hydrated (after appropriate resuscitation if needed) to ensure maintenance of euvolemia and a steady urine output. This is for several reasons, including (1) DEG is primarily eliminated unchanged in the urine via the kidneys, (2) inadequate resuscitation and/or suboptimal hydration beyond the initial fluid resuscitation period may contribute to prerenal ­azotemia thereby decreasing elimination of unchanged DEG, (3) any impairment in kidney function will result in decreased elimination of unchanged DEG with a corresponding increase in available DEG for metabolism to toxic metabolites such as DGA, and (4) animal studies suggest that when doses associated with adverse health effects (10 g/kg) are given in addition to fomepizole, almost the entire dose is eliminated unchanged in the urine.^3,30 Careful attention to acid-base status is advised since limited in vitro work with DGA and human proximal tubule cells suggest that acidemia may enhance DGA’s toxicity.^30,31 Intravenous bicarbonate therapy may be of benefit in treating DEG-associated metabolic acidosis for this reason, but this is unstudied.

Available evidence supports the use of an ADH inhibitor such as fomepizole in suspected or known DEG poisoning to prevent nephrotoxicity, although most of this evidence is from animal studies. This same evidence suggests that the parent compound is not nephrotoxic.^4,30,57 However, there is no evidence demonstrating that the parent compound is not neurotoxic (the mechanism of DEG associated neurotoxicity is still completely unstudied). Because neurotoxicity seems to only appear following DEG metabolite-associated AKI, the likelihood of the parent compound being neurotoxic seems low. Fomepizole monotherapy for DEG poisoning may be entirely appropriate (similar to other toxic alcohols); however, definitive evidence is lacking. Furthermore, data to guide dosing and duration of administration are also lacking. Considering the aforementioned factors and the current lack of human data confirming safety and efficacy of fomepizole in DEG poisoning, patients presenting soon after (within a few hours) a highly suspected or known moderate to large ingestion of DEG should be started on fomepizole therapy and then urgently hemodialyzed if available. If hemodialysis is not available the patient should be transferred to a facility with that capability. Although the minimal toxic dose is unknown, cumulative exposures at or above 250 mg/kg (the lower limit of the range reported in the Haiti mass poisoning) should be considered potentially life threatening. A single report documented higher prehemodialysis and lower posthemodialysis concentrations of DEG suggesting that it is cleared by hemodialysis, although the gradient was relatively small (0–1.6 mg/dL).⁷ Nevertheless, the volume of distribution and molecular weight of DEG suggest that hemodialysis should be effective.^20,46 The endpoint of fomepizole therapy or need for additional rounds of dialysis is unclear, but the relatively new commercial availability of techniques for the determination of whole blood, plasma, serum and urine DEG concentrations with careful attention to acid-base status should be helpful in guiding therapy. Considering the lack of fomepizole data in DEG poisoning, dosing should be comparable with the treatment regimens for the other toxic alcohols (Antidotes in Depth: A30).

Exposures to amounts less than those known to be associated with poisoning present management dilemmas. The following sections consist of suggested guidelines which may need to be modified depending on the individual situation. In all exposures, a toxicologist should be consulted as the circumstances surrounding the exposure are invariably different and may affect management.

Outbreak-derived toxic doses of DEG are not reliable measures for excluding poisoning. Patients with a reliable history of a minimal ingestion, such as an unintentional sip of a low concentration DEG containing product, are unlikely to be at risk for toxicity. Those adult patients with slightly larger DEG ingestions with relatively low concentrations liquids (< 10%) such as exposures consisting of more than a sip but less than a “mouthful” can be considered for careful observation alone, as long as it is coupled with serial chemistries and blood gas measurements to rapidly identify onset of renal function and acid-base abnormalities. Although the true minimum toxic dose of DEG is unknown, an example of the aforementioned situation might involve an unintentional ingestion of 30 mL (mouthful) of a 5% DEG product by volume in an adult. This is approximately 1.5 mL of DEG which is equivalent to about 1.7 g, which in an 80-kg adult is about 21 mg/kg. The lower end of the estimated toxic dose range in Haiti was 250 mg/kg, which is more than 10 times higher (1090% increase). Therefore careful observation might be reasonable in this situation if you believed you had correct values for the dose and product concentration and there were no other potential risk factors for DEG-associated illness (eg, preexisting renal disease). Such an exposure in a 3 year-old child weighing 16 kg would yield a dose of 110 mg/kg, an exposure of greater concern that might warrant more aggressive treatment. Unfortunately, ascertainment of the true volume ingested and product concentration may be difficult, which contributes to the problem of estimating risk based on patient history.

Patients with signs or symptoms of alcohol intoxication, but who did not consume ethanol should be suspected of having a potentially life threatening DEG ingestion and treated as discussed in the previous section. Asymptomatic patients with ingestions beyond the “unintentional sip or taste” should probably be observed for at least 24 hours regardless of therapy offered. Serial laboratory determinations should be obtained and evaluated for at least 24 hours following exposure based on what is known of DEG toxicokinetics.

Fomepizole monotherapy (without hemodialysis) can be considered at the discretion of the attending physician and consulting toxicologist or poison center, as emerging evidence suggests that fomepizole can prevent nephrotoxicity. However, if the decision to use fomepizole monotherapy is made, the physician should remember that, albeit unlikely, the safety and efficacy of fomepizole monotherapy in DEG poisoning is not yet established, thereby necessitating that the risks be explained to the patient.

Unless laboratory testing documents a minimal or nonexposure, the patient’s clinical, acid-base, and kidney function status should probably be followed for at least 24 hours for evidence of DEG poisoning. For patients receiving fomepizole, this 24 hour period should begin 12 hours following the last dose of fomepizole. If signs and symptoms of nephrotoxicity begin to appear, then fomepizole should be given and the patient hemodialyzed.

For those patients presenting to health care facilities with a metabolic acidosis, oliguria or anuria within 24 to 36 hours of an DEG ingestion, fomepizole should be given and emergent hemodialysis should be performed, regardless of the patient’s acid-base and electrolyte status. This suggestion is based in part on animal studies showing that serum DGA concentrations peak at 24 hours following ingestion, DGA sequesters in kidney tissue, it is nephrotoxic,^3,30 and half-lives increase with larger doses.³ Early presentation to health care facilities (< 10 hours from ingestion) and aggressive treatment (gastrointestinal decontamination, fomepizole, and hemodialysis) appeared to be associated with better outcomes in the five reports in which fomepizole or ethanol was administered for DEG exposure.^1,5,7,19,43 In one of these cases, a 15 year-old girl who was witnessed to ingest approximately 22.4 g of DEG (patient’s weight was not reported) was managed with orogastric lavage and early (< 3 hours) fomepizole therapy alone; the patient had a good outcome with no renal or neurological dysfunction (other than inebriation).⁵ For those patients presenting later than 36 to 48 hours after a DEG ingestion with the aforementioned signs and symptoms, fomepizole and hemodialysis should be considered, but may be too late to be beneficial with regard to removal of DEG and toxic metabolites. However, it may be of value with regard to electrolyte imbalances and or AKI.

Although there are no published reports examining the efficacy of ethanol to block DEG metabolism, it is expected to act similarly to fompeizole. Hence, it may be an alternative therapy if fomepizole and hemodialysis are unavailable and a rapid transfer to another hospital is not possible.

• Patients with suspected or known exposures to DEG present a diagnostic and therapeutic challenge.

• Emerging work shows that the DEG metabolite DGA, and not the parent compound, is nephrotoxic.

• Alcohol dehydrogenase inhibitor therapies such as fomepizole have a role in treating DEG poisoning, but urgent hemodialysis is still indicated for substantial ingestions.

• Diethylene glycol poisoned patients who develop AKI are at risk for severe neurotoxicity.

• The etiology of DEG associated neurotoxicity is unclear. Diethylene glycol ingestion should be suspected in patients presenting with AKI and neurological signs and symptoms such as cranial nerve VII paresis or paralysis, or extremity weakness consistent with a peripheral ­neuropathy.

Disclaimer

The findings and conclusions in this article are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention or the Agency for Toxic Substances and Disease Registry.

References