Nephrology Hypertension

Pharmacology and Toxicology: Treatment of Poisons - Ethylene Glycol Intoxication

Does this patient have ethylene glycol intoxication?

Ethylene glycol is a sweet-tasting substance that is a common constituent of antifreeze and de-icing solutions. It can also be found in hydraulic brake fluid, many solvents and as an agent in chemical synthesis. Because of its sweet taste and its ability to intoxicate, it is sometimes used as a substitute for ethanol. Intoxication can also follow an accidental ingestion in children, or as a suicidal attempt. It accounts for approximately 0.3% of all exposures and 2.5% of all deaths due to poisonings. In 2009, there were 5977 exposures to ethylene glycol and 19 deaths reported to the National Poison Data System (NPDS) (Figure 1). This is a mortality rate of 0.3%.

Figure 1.

Exposures and fatalities from toxins that can be substantially removed by extracorporeal techniques.

The estimated minimum lethal dose for adults is approximately 100 ml. A number of patients have survived ingestions of over 2000 ml. In a case report by Johnson and co-workers, one patient who underwent rapid treatment with ethanol infusion and hemodialysis in the emergency room survived an ingestion of 3000 ml without long-term sequelae. The ethylene glycol level was found to be 1889 mg/dL.

Pharmacokinetics of ethylene glycol

Ethylene glycol reaches a peak serum level 2 to 4 hours after ingestion. It is water-soluble and has a volume of distribution that is equal to total body water (0.6 L/kg). It has a molecular weight of 62 g/mole. Figure 2 displays the metabolism of ethylene glycol to its end products. Ethylene glycol is oxidized by alcohol dehydrogenase in the presence of nicotinamide adenine dinucleotide (NAD) to glycoaldehyde, which is then rapidly oxidized to glycolate. Ethanol and fomepizole slow the metabolism of ethylene glycol by inhibiting the enzyme alcohol dehydrogenase.

Figure 2.

Metabolism of ethylene glycol.

Glycolate is the toxic metabolite and produces the high anion gap acidosis. Glycolate may be metabolized to oxalate, alpha-hydroxy-beta-ketoadipate, and glycine. Oxalate causes some of the end organ damage as a direct toxin and through calcium oxalate deposition. Some part of the acidosis stems from the production of lactate and is due to the reduction of NAD to NADH, which drives the conversion of pyruvate to lactate (Figure 2). Without treatment, the elimination half-life of ethylene glycol is 3 – 8 hours. Ethanol and fomepizole will prolong the half-life 5 fold to 15 – 20 hours.

What tests to perform?

Laboratory abnormalities

Anion gap

Ethylene glycol intoxication is characterized by a high anion gap acidosis, osmolar gap and hypocalcemia. The anion gap acidosis is due to both the production of glycolate and lactate. Lactate is formed because of the reduction of NAD to NADH during the oxidation of ethylene glycol to glycolate. A patient may have no acidosis soon after ingestion before the ethylene glycol has been converted to glycolate. The acidosis will worsen as the ethylene glycol is metabolized.

Osmolar gap

Ethylene glycol will also form an osmolar gap because it is osmotically active and has a relatively small molecular weight. In ethylene glycol intoxication, the serum level of the toxin can be estimated by multiplying the osmolar gap by 6.2 (Figure 3). An osmolar gap lacks the sensitivity and specificity to be an ideal screening test for intoxications. Glycolate does not contribute to the osmolar gap so that as the ethylene glycol is metabolized to glycolate, the osmolar gap will in fact fall. Therefore patients who present late after an ingestion, may have a normal osmolar gap.

Figure 3.

Osmolar contribution of various toxins and drugs.

Urine abnormalities

The urine may contain two forms of calcium oxalate crystals in ethylene glycol intoxication (Figure 4). The dumbbell-shaped monohydrate forms are more common but the octahedral-shaped dihydrate form is more specific for ethylene glycol intoxication. Individuals who ingest a large amount of vitamin C or urate-containing foods may have monohydrate calcium oxalate crystals in their urine. The dihydrate form requires higher oxalate concentrations for its formation and therefore is more indicative of intoxication with ethylene glycol. If the ethylene glycol ingestion is in the form of antifreeze, the urine will often fluoresce under ultra-violet light due to the addition of fluorescein to most antifreeze preparations.

Figure 4.

Urine from a patient after ethylene glycol ingestion. Shown are both types of calcium oxalate crystals. The arrows point toward the envelope shaped dihydrate calcium oxalate crystal. The arrowheads point toward the needle shaped monohydrate calcium oxalate crystals. Used with permission from Takayesu et al, 2006.

How should patients with ethylene glycol intoxication be managed?

Diagnosis

Estimating serum levels in ethylene glycol intoxication

As discussed above, the alcohols will produce an osmolar gap when they are present in the serum in significant amounts. Although there are some cautions to be noted with its use, the osmolar gap can be used to estimate the serum concentration of the alcohols. If one keeps in mind that the osmolar gap may have fairly low specificity and sensitivity for the detection of alcohol intoxication due to variations in the normal gap in the general population, it can be helpful as a rapid way to estimate serum levels of the intoxicant. It should not be used as the sole criterion for deciding a treatment strategy in the case of a possible intoxication with one of the alcohols but it can be useful when other clinical data support the diagnosis.

Figure 3 describes the use of the osmolar gap to estimate the serum level of the alcohol intoxicant. An increase in the osmolar gap of 10 mOsm/L would be expected to be caused by a concentration of the drug listed in the figure. For example, if ethylene glycol were to cause an increase in the osmolar gap of 10 mOsm/L then the expected concentration of ethylene glycol would be 62 mg/dL. To estimate the concentration of the agent listed, the osmolar gap divided by 10 is multiplied by the factor listed in the table for the specific alcohol.

It is important to remember that a low gap does not always imply a low risk of intoxication. First, the gap will underestimate serum levels in some people who start out with a low serum osmolarity. Secondly, the gap will fall as the alcohol is metabolized and in the case of ethylene glycol and methanol, the metabolites are toxic and therefore a patient with a low gap may still have an indication for aggressive therapy including dialysis.

Although there are some cautions to be noted with its use, the osmolar gap can be used to estimate the serum concentration of the alcohols. If one keeps in mind that the osmolar gap may have fairly low specificity and sensitivity for the detection of alcohol intoxication due to variations in the normal gap in the general population, it can be helpful as a rapid way to estimate serum levels of the intoxicant. It should not be used as the sole criteria for deciding a treatment strategy in the case of a possible intoxication with one of the alcohols but it can be useful when other clinical data support the diagnosis.

Emergency management

Supportive treatment

Supportive treatment includes airway protection, circulatory support, correction of metabolic abnormalities and control of seizures. Bicarbonate is indicated for patients with pH < 7.3. Asymptomatic hypocalcemia is generally not treated because of the risk of increasing the formation of calcium oxalate crystals. Seizures may be due to hypocalcemia but should be treated first with standard anticonvulsants. There is no role for activated charcoal, cathartics or gastric lavage in ethylene glycol intoxication. Alcoholics and patients likely to be malnourished should be given thiamine and pyridoxine. The addition of thiamine, 100 mg intramuscularly (IM) or IV, and pyridoxine, 50 mg IV every 6 hours, will shunt the metabolism of ethylene glycol to less toxic metabolites. Thiamine promotes the metabolism of glyoxylate from glycolic acid to a nontoxic metabolite, alpha-hydroxy-beta-ketoadipate, pyridoxine premotes the metabolism of glyoxylate to glycine.

Bicarbonate therapy

Bicarbonate based intravenous fluids should be given to all patients with acidosis due to ethylene glycol intoxication unless there is a contraindication to the volume. The use of bicarbonate based fluids may help patients in two ways. Often, patients will present with some degree of volume depletion and volume replacement will help maintain kidney function and allow for renal clearance of ethylene glycol, glyoxylate and oxalate

Treatment

Fomepizole and ethanol will slow the metabolism of ethylene glycol to its more toxic metabolites. The indications for the use of one of the antidotes have been outlined by the American Academy of Clinical Toxicology. These indications include a plasma ethylene glycol concentration > 20 mg/dL, a recent ingestion of ethylene glycol and an osmolar gap > 10 mOsm/kg or a high clinical suspicion and two of the following: pH < 7.3, serum bicarbonate < 20 mEq/L, osmolar gap > 10 mOsm/kg or urinary oxalate crystals (Figure 5). The dosing schedule of each antidote is listed in Figure 6 and Figure 7.

As with methanol intoxication, fomepizole may be the preferred antidote in ethylene glycol poisoning because of its ease of administration and because it does not cause central nervous system (CNS) depression or hypoglycemia. Some patients treated with fomepizole may not need observation in an intensive care unit or hemodialysis if they have no acidosis and are otherwise clinically stable. Fomepizole is removed with dialysis and therefore needs to be dosed every 4 hours during dialysis

Figure 5.

Indications for fomepizole or ethanol therapy in methanol or ethylene glycol intoxication.

Figure 6.

Ethanol dosing in methanol and ethylene glycol intoxication.

Figure 7.

Fomepizole dosing in methanol and ethylene glycol intoxication.

Inhibition of alcohol dehydrogenase with ethanol

Ethanol has been used as an inhibitor of alcohol dehydrogenase in ethylene glycol intoxication for 50 years but has not been approved by the FDA. The standard loading dose of ethanol is 0.6 g/kg followed by a constant infusion to keep the blood ethanol level between 100 and 200 mg/dl. The average maintenance dose of ethanol is 100 mg/kg/hr but is significantly higher for alcoholics and must also be increased while the patient is on dialysis. Blood ethanol levels should be checked every 1 – 2 hours until a steady state has been reached and then every 2 to 4 hours (Figure 6). The potential adverse effects of ethanol include central nervous system depression, hypoglycemia, respiratory depression and aspiration.

Inhibition of alcohol dehydrogenase with fomepizole

Fomepizole should be given at a loading dose of 15 mg/kg followed by 10 mg/kg every 12 hours for 48 hours. After 48 hours, the dose should be increased to 15 mg/kg every 12 hours. Fomepizole should be continued until the serum ethylene glycol level is < 20 mg/dl and the patient is asymptomatic with a normal serum pH. Fomepizole is removed with dialysis and therefore needs to be dosed every 4 hours during dialysis. (Figure 7).

Inhibition of Alcohol dehydrogenase - conclusions

The dose of both inhibitors of alcohol dehydrogenase have to be increased during dialysis. Fomepizole may be the preferred antidote in ethylene glycol intoxication because levels do not need to be followed, it has fewer side effects, does not cause further sedation and it has a much simpler dosing scheme both with and without concurrent dialysis. Finally, because of the low side effect profile, some patients treated with fomepizole may not need observation in an intensive care unit if they are otherwise stable without significant acidosis.

Other studies have found an increase in cost with the use of fomepizole and recommend the use of ethanol when feasible. With either antidote, the treatment should be continued until the ethylene glycol level is undetectable or both symptoms and acidosis resolve and the level is < 20 mg/dL.

Hemodialysis

Ethylene glycol, like the rest of the alcohols (e.g, ethanol, methanol, and isopropyl alcohol), hascharacteristics that allow for rapid removal with hemodialysis. They all have low molecular weights, are hydrophilic, have small Vd and rapidly equilibrate with the intravascular space. The drug characteristics of these compounds are listed in Figure 8. Ethanol toxicity usually does not require hemodialysis because most patients will recover with supportive measures alone.

Figure 8.

Characteristics of drugs and toxins that are amenable to removal with extracorporeal therapy.

Hemodialysis is very effective at clearing ethylene glycol and its metabolites. The clearance rate of ethylene glycol ranges between 200 – 250 ml/min depending on the filter and blood flow. Glycolate, which is the major toxic metabolite, has a half-life of up to 18 hours without hemodialysis but the half-life is reduced by a factor of 6 with hemodialysis. Patients with acidosis may therefore still benefit from hemodialysis even in the face of a low serum ethylene glycol level if they have an anion gap acidosis suggesting high glycolate levels.

Estimating dialysis time

Like all of the alcohols, ethylene glycol has a small Vd and rapid equilibration with the vascular space, its elimination therefore closely follows first order kinetics during dialysis.

The elimination of all the alcohols will follow the formula for first order kinetics:

C1/C0 = e-kt/V

If we determine a final concentration C1 that we want to achieve, we can solve for the time required for dialysis to achieve this final concentration:

t (min) = - ln (C1 /C0) x Vd(L) / k (L/min)

As an example, if a 100 Kg man has an ethylene glycol ingestion with a level of 80 mg/dL and we want to perform dialysis with a membrane that can deliver a k = 0.3 L/min until his level is less than 20 mg/dL then

t = - ln ( 20/80) 60 L / 0.3 L/min = 277 min = 4 hrs 37 min

It is important to note that this estimation does not take into account endogenous clearance of the alcohol and therefore will overestimate the time needed if the patient has significant renal clearance.

Indications

The indications for hemodialysis include those patients who have or are likely to develop the major sequelae of ethylene glycol ingestion. These include patients with metabolic acidosis (pH < 7.3) or deteriorating clinical status with respiratory failure or hypotension. Patients with acute renal failure and a metabolic derangement that is unresponsive to standard therapy should be considered for hemodialysis as well (Figure 9). In the past, an ethylene glycol level of 50 mg/dl was considered an indication for hemodialysis. Recent experience suggests that patients with normal renal function and no acidosis may be treated with fomepizole without hemodialysis even in the setting of an ethylene glycol level > 50 mg/dl. Withholding dialysis in patients with a high ethylene glycol level should only be considered if all of the following conditions are met:

Figure 9.

ndications for dialysis in patients with ethylene glycol intoxication.

1. The patient is receiving fomepizole.

2. The patient is clinically stable, awake and alert.

3. The patient has normal kidney function.

4. The serum bicarbonate and anion gap are normal.

5. There is no evidence of end organ damage such as neuropathy, ischemic bowel or cardiac dysfunction.

These patients would require close monitoring for the development of renal insufficiency or acidosis.

Details on the dialysis prescription

Clearance constants with high efficiency membranes have been as high as 250 ml/min for ethylene glycol, glyoxolate and oxalate. Both fomepizole and ethanol are cleared during dialysis and therefore the dose of each has to be changed during dialysis therapy. The addition of ethanol to the dialysate has been shown to maintain blood ethanol levels during dialysis. The use of fomepizole during hemodialysis is more straightforward and only requires an increase in the frequency of the doses to every 4 hours to maintain adequate levels.

Dialysis should be continued until the ethylene glycol level is less than 20 mg/dL, the acidosis has resolved and there are no signs of systemic toxicity or until the ethylene glycol level is undetectable. If an ethylene glycol level can not be quickly obtained, dialysis should be continued until the serum osmolar gap and anion gap return to normal suggesting that ethylene glycol and glycolate levels have dropped. A confirmatory ethylene glycol level should be drawn since the normal osmolar gap suggests but does not guarantee a low ethylene glycol level.

Prolonged dialysis up to 8 to 10 hours may be required for very high ethylene glycol levels and severe acidosis. See estimating dialysis time for alcohol intoxication above for an example of how to approximate the necessary dialysis time. As with dialysis for methanol intoxication, these patients are prone to severe hypophosphatemia and need close monitoring of their phosphate level with replacement when indicated.

Finally, because of the low side effect profile, some patients treated with fomepizole may not need observation in an intensive care unit if they are otherwise stable without significant acidosis. Other studies have found an increase in cost with the use of fomepizole and recommend the use of ethanol when feasible. With either antidote, the treatment should be continued until the ethylene glycol level is undetectable or both symptoms and acidosis resolve and the level is < 20 mg/dL.

The dose of both inhibitors of alcohol dehydrogenase have to be increased during dialysis. Fomepizole may be the preferred antidote in ethylene glycol intoxication because levels do not need to be followed, it has fewer side effects, does not cause further sedation and it has a much simpler dosing scheme both with and without concurrent dialysis.

What happens to patients with ethylene glycol intoxication?

Clinical and laboratory findings in ethylene glycol intoxication

The clinical course of ethylene glycol intoxication can be divided into three phases (Figure 10). The first phase occurs less than an hour after ingestion and is characterized by mental status depression similar to alcohol intoxication. In severe intoxication, coma, seizures and respiratory depression can complicate this phase.

Figure 10.

Clinical effects of ethylene glycol intoxication.

This stage lasts about 12 hours as the ethylene glycol is oxidized to glycoaldehyde and glycolate.

In the second phase, glycolate has a toxic effect on the cardiopulmonary system. In severe intoxications, patients can develop acidosis, heart failure, pulmonary edema or adult respiratory distress syndrome (ARDS). The timing of this stage depends on the metabolism of the ethylene glycol to glycolate and usually starts approximately 12 hours after ingestion but will be delayed by alcohol co-ingestion. Review of data from NPDS suggests that most deaths occur during this stage.

The final stage occurs 24 to 72 hours after ingestion and is characterized by flank pain, acute tubular necrosis, hypocalcemia and renal failure. During this stage, the production of oxalate leads to calcium oxalate precipitation in the kidney and other tissues and hypocalcemia. The renal toxicity is probably due to a combination of hydronephrosis from calcium oxalate crystals and a direct toxic effect from the metabolites of ethylene glycol. Most renal damage is reversible and renal recovery, which may take a few months, is the norm even after anuria. The toxicity to other tissues due to calcium oxalate deposition include persistent cognitive and motor deficits, cranial neuropathy, polyradiculoneuropathy, ischemic bowel, hepatitis and cardiac ischemia.

There is very little correlation between serum ethylene glycol levels and clinical outcome. Indeed, patients may have a very high mortality if they present after their serum levels have begun to decrease and the ethylene glycol has been converted to its toxic metabolites. There is better correlation between the arterial pH, serum bicarbonate or glycolate level and the clinical outcome. A number of studies of patients treated with fomepizole have shown that those who present without acidosis or a high glycolate level will do well.

What is the evidence?

Abramson, S, Singh, AK. "Treatment of the alcohol intoxications: ethylene glycol, methanol and isopropanol". Current Opinion in Nephrology & Hypertension. vol. 9. 2000. pp. 695-701.

Brent, J. "Fomepizole for ethylene glycol and methanol poisoning". New England Journal of Medicine. vol. 360. 2009. pp. 2216-2223.

Kraut, JA, Kurtz, I. "Toxic alcohol ingestions: clinical features, diagnosis, and management". Clinical Journal of The American Society of Nephrology:CJASN. vol. 3. 2008. pp. 208-225.

Keiran, S, Bhimani, B, Dixit, A. "Ethylene glycol toxicity". American Journal of Kidney Diseases,. vol. 46. 2005. pp. e31-33.

Guo, C, McMartin, KE. "The cytotoxicity of oxalate, metabolite of ethylene glycol, is due to calcium oxalate monohydrate formation". Toxicology. vol. 208. 2005. pp. 347-355.

Bronstein, AC, Spyker, DA, Cantilena, LR, Green, JL, Rumack, BH, Giffin, SL. "2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th Annual Report". Clinical Toxicology: The Official Journal of the American Academy of Clinical Toxicology & European Association of Poisons Centres & Clinical Toxicologists. vol. 48. 2010. pp. 979-1178.

Takayesu, JK, Bazari, H, Linshaw, M. "Case records of the Massachusetts General Hospital. Case 7-2006. A 47-year-old man with altered mental status and acute renal failure". N Engl J Med. vol. 54. 1996. pp. 1065-1072.

Oostvogels, R, Kemperman, H, Hubeek, I, ter Braak, EW. "The importance of the osmolality gap in ethylene glycol intoxication". BMJ. vol. 347. 2013. pp. 6904.

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