DESCRIPTION
USES
Predominantly used as a deicer or antifreeze in cooling systems. Ethylene glycol is also used in hydraulic brake fluids, as a solvent, and as an industrial humectant. Large amounts are used as a chemical intermediate. It may also be used as a glycerin substitute in commercial products including paints, detergents and cosmetics.
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PHYSICOCHEMICAL PROPERTIES
Colorless, odorless, sweet-tasting, hygroscopic liquid. Molecular Weight | 62.07 62.07 |
Boiling Point | 197 degrees C197 degrees C |
Melting Point | -13 degrees C-13 degrees C |
Specific Gravity (water = 1) | 1.1274 1.1274 |
Vapor Pressure | 0.07 mmHg at 20 degrees C 0.07 mmHg at 20 degrees C |
Flash Point | 111 degrees C111 degrees C |
Flammability Limits | 3.2 to 5 %3.2 to 5% |
Solubility | Chlorinated hydrocarbons: insoluble Petroleum ether: insoluble Oils: insoluble |
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INTERVENTION CRITERIA
Appropriate medical management and observation in an emergency department is recommended for: Any ingestion more than a witnessed lick or exploratory taste (e.g. a small sip) Ingestions where the dose is unknown Symptomatic patients All eye exposures Any patient showing signs or symptoms following skin or inhalational exposure should be assessed at a medical facility. |
Appropriate medical management and observation in an emergency department is recommended for: Ingestions of more than 10 mL of ethylene glycol Ingestions where the dose is unknown Ingestions with intent to harm Symptomatic patients All eye exposures Any patient showing signs or symptoms following skin or inhalational exposure should be assessed at a medical facility. |
If the patient does not require medical observation they can be monitored at home for 8 hours in the care of a reliable observer. |
The patient should be medically assessed if any symptoms develop, including: Nausea Vomiting Drowsiness Slurred speech Stumbling or difficulty in moving Confusion Inebriation |
Patients accidentally ingesting ethylene glycol should be monitored for 4 hours and may then be discharged into the care of a reliable observer provided: They are asymptomatic Venous bicarbonate level is greater or equal to 20 mmol/L (mEq/L) Serum (or breath) ethanol level is zero in adults |
A serum ethylene glycol is the preferred investigation, but is commonly not readily available at most institutions. An ethylene glycol ingestion may be inferred from an increased osmolal gap (in the early stages of intoxication) indicating a solute (glycol) load. However, this test cannot rule out ethylene glycol exposure in the presence of a normal osmolar gap. Once the glycol is metabolized this level will drop and may be replaced by an increased anion gap, indicating an increased organic acid (glycol metabolite) load, with an accompanying metabolic acidosis. Investigation should therefore include: Serum ethylene glycol level (where available in a practical time frame ie: 1 to 2 hours) Serum ethanol level (required for osmolal gap calculation) Serum electrolytes including: Calcium Chloride (required for anion gap calculation) Anion gap (elevated in later stages of poisoning) Arterial pH Serum bicarbonate Urinalysis including: Proteinuria Hematuria Examination under UV light (Wood’s lamp) for fluorescence (Fluorescein contained in many antifreeze solutions and eliminated in the urine will fluoresce when expose to UV light). A negative result does not rule out ethylene glycol exposure (fluoroscein is rapidly eliminated by the kidneys and may have already been excreted prior to presentation. Also, the ingested ethylene glycol may not contain fluoroscein). Care must be exercised when performing this test as plastic containers may exhibit some degree of fluorescence under a UV light. A glass container is preferable and previous experience with visualizing fluoroscein containing urine is useful. Microscopic examination for crystalluria (In the later stages of intoxication calcium oxalate crystals may form in the urine) Presence in the urine of either fluorescein or calcium oxalate crystals indicates ethylene glycol exposure, but their absence does not exclude this poisoning. If a serum ethylene glycol level measurement is not available a presumptive diagnosis of poisoning may be based on: either A history or suspicion of ethylene glycol ingestion plus any 2 of the following; Arterial pH < 7.3 Serum bicarbonate < 20 mmol/L (20 mEq/L) Osmolal gap > 10 mOsm/L Presence of urinary oxalate crystals or A history or suspicion of ethylene glycol ingestion within the last 1 hour and osmolal gap > 10 mOsm/L NOTE: Patients, particularly children, presenting within an hour of suspected ethylene glycol ingestion may not have any abnormal surrogate markers of ingestion. In these instances, close observation and serial monitoring of acid-base and renal function status should be performed. Any development of early metabolic acidosis would be highly suggestive of recent ethylene glycol exposure. |
Hospital admission is recommended: - For any patient with abnormal biochemistry - In all symptomatic cases Ensure the receiving hospital is able to provide: Advanced care/ICU facilities, and |
TREATMENT
TREATMENT SUMMARY
Initial management includes airway protection and administration of IV fluids. Gastric decontamination may be performed within 1 to 2 hours of ingestion via nasogastric aspiration provided the airways are protected. Late presenters may exhibit severe acidosis with compensatory tachypnea, treat with: sodium bicarbonate, intubation with hyperventilation (hyperventilate as acidosis will otherwise worsen and may prove fatal), and hemodialysis. Seizures require a benzodiazepine - closely monitor breathing. Administer glucose in those with CNS depression and suspected hypoglycemia (unless rapid glucose screen indicates otherwise); concurrently administer thiamine and multivitamins if alcoholism is suspected. Effective antidotes exist in the form of either ethanol or fomepizole. Any patient with an elevated osmolal gap and an anion gap acidosis requires aggressive treatment including the administration of an antidote. It is recommended that patients receiving ethanol therapy be monitored in an intensive care setting. Other indications for intensive care include: coma, seizures, renal failure, hypotension, or ethylene glycol level > 8.1 mmol/L (50 mg/dL). Those with significant acidosis or a high serum ethylene glycol level should be hemodialyzed to reverse acidosis and/or reduce glycol and toxic metabolite levels. Supportive care includes management of acidosis with generous sodium bicarbonate; administration to return base excess to normal within 12 to 24 hours is recommended. Large quantities may be required, and iatrogenic hypernatremia may occur. Hemodialysis will be required in severe cases of acidosis. Calcium administration is only indicated if cardiac dsyrhythmia occurs (particularly QT prolongation), or seizures prove unresponsive to management. Correct hypoglycemia, hyperkalemia and hypomagnesemia. Calcium oxalate crystals may form in any organ with resultant multiorgan dysfunction/failure. The kidneys are often afflicted, and close monitoring and support of renal function is required due to the risk of acute renal failure. Should this occur hemodialysis is required until recovery. There is also risk of ARDS, and fluid balance will require careful (possibly invasive) monitoring. Stupor or coma indicates metabolic encephalopathy or cerebral edema. Cranial nerve palsies may occur some 4 to 18 days following ingestion and usually spontaneously resolve over weeks to months without specific therapy. Co-factor replenishment with thiamine and pyridoxine is not necessary unless the patient is considered vitamin deficient (e.g. history of alcoholism). |
EMERGENCY STABILIZATION
Ensure Adequate Cardiopulmonary Function |
Emergency stabilization includes appropriate airway management, ensuring intravenous access, cardiac monitoring, and obtaining initial laboratory values. |
Ensure the airway is protected (intubation may be required), and administer oxygen. Establish secure intra-venous access. |
Hypotension may be significant due to GIT fluid loss, and in such cases fluid replacement should be aggressive where possible, having regard to renal function. |
Immediately establish secure intravenous access. |
CHILD Where the systolic blood pressure is below normal blood pressure ranges for the age group: Age (years) | Normal Systolic Blood Pressure (mmHg) | <1 | 70 to 90 | 1 to 2 | 80 to 95 | 2 to 5 | 80 to 100 | 5 to 12 | 90 to 110 | >12 | 100 to 120 |
Administer normal (0.9%) saline 10 mL/kg IV over 5 to 10 minutes If the systolic blood pressure does not return to the normal range, give a further 10 mL/kg body weight normal saline over 5 to 10 minutes. If intravenous access cannot be obtained consider intra-osseus access ADULT Administer a bolus of normal saline if systolic blood pressure is less than 100 mmHg. Normal (0.9%) saline dose: 10 mL/kg IV over 5 to 10 minutes If the systolic blood pressure does not return to the normal range, give a further 10 mL/kg body weight normal saline over 5 to 10 minutes. |
Most toxic seizures are short-lived and often do not require intervention. Administer a benzodiazepine as first-line treatment to patients with seizure activity. Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, 50% dextrose should be administered IV (preceded by thiamine in adults). |
Seizures due to ethylene glycol intoxication may prove unresponsive to standard management unless hypocalcemia is corrected.
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IV dextrose is indicated (even if blood glucose cannot be quickly measured) in patients with altered mental status, unusual behavior, coma or seizures. Hypoglycemic patients may present with focal neurological deficits. However, these may also be due to cerebral ischemia. As administration of dextrose may exacerbate ischemic injury, it is important to verify hypoglycemia with blood glucose measurement prior to use - unless this would lead to unacceptable delay in administration. |
Must be administered to adult patients considered alcoholic or malnourished.
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Thiamine dose ADULT 100 mg IV |
Electrocardiograph Electrolytes including: Calcium Magnesium Chloride (for calculation of anion gap) Anion gap (elevated later in poisoning) Serum ethanol concentration (used in calculation of osmolal gap) Osmolal gap (elevated early in poisoning) Arterial blood gases including: Arterial pH Bicarbonate Serum ethylene glycol concentration |
DECONTAMINATION
Nasogastric aspiration is recommended if the quantity of liquid ingested is both systemically toxic and in sufficient volume to aspirate. As this procedure may increase the risk of vomiting and pulmonary aspiration, the airway must be protected in all patients. Accurate placement of the nasogastric tube must also be ensured in all patients. |
Nasogastric aspiration is recommended if the patient has presented early (within 1 to 2 hours) following ingestion of ethylene glycol.
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Single Dose Activated Charcoal |
Activated charcoal is not considered an effective decontaminant for this ingestion as ethylene glycol is rapidly absorbed from the gastrointestinal tract and has poor binding affinity for activated charcoal. Unless there is concern for coingestants, there is little benefit from activated charcoal administration in ethylene glycol ingestions.
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Remove contact lenses. Irrigate immediately with water or saline for at least 15 minutes. If the eye is contaminated with solid particles, the eyelid should be completely everted and any solid material removed as quickly as possible whilst continuing to irrigate. A topical anesthetic may be necessary in some patients, especially children, to enable the patient to open the lids sufficiently for effective irrigation. |
If, following irrigation, any of the following are apparent: Ocular pain (other than mild and resolving) Erythema (other than mild and resolving) Decreased visual acuity Ocular discharge/crusting The patient should receive a full ophthalmologic examination, including slit lamp examination and fluorescein staining. If there is evidence of injury an ophthalmologist should be consulted. |
Remove the patient from the exposure. If respiratory symptoms such as shortness of breath are present, administer oxygen and provide additional support if necessary. |
Remove any contaminated clothing or jewellery. Wash the affected area thoroughly with soap and water until all of the contaminant is removed. |
ANTIDOTE(S)
Appropriate use of antidotes in glycol poisoning is essential. Ethanol has long been regarded as an effective intervention, though objective data is lacking, and is cheap and available. Fomepizole has proven efficacy, but suffers the disadvantage of expense. Both act by inhibiting alcohol dehydrogenase, thus reducing the metabolic conversion of glycol to toxic metabolites (acids). Thiamine and pyridoxine may be indicated as therapeutic adjuncts. Theoretically, they act as cofactors in the formation of non-toxic metabolites of ethylene glycol. No data exists to support this assumption, but they may benefit those with a history of ethanol abuse or inadequate nutrition (e.g. those vitamin deficient). |
Ethanol is indicated if: - Plasma ethylene glycol concentration is greater than 3.2 mmol/L (20 mg/dL) or; - Recent ingestion of greater than 0.2 mL/kg ethylene glycol and presence of osmolal gap of greater than 10 mosm/L or; - History or clinical suspicion of ethylene glycol poisoning and at least two of the following: Arterial pH < 7.3 Serum bicarbonate < 20 mmol/L (20 mEq/L) Osmolal gap > 10 mosm/L Presence of urinary oxalate crystals |
For acceptable efficacy, the blood ethanol concentration should be maintained between 22 and 33 mmol/L (100 to 150 mg/dL). To achieve this both a loading dose and maintenance infusion are required. Either 100% ethanol diluted for intravenous use may be infused, or liquor (e.g. vodka, gin) may be administered orally. Prior to use of ethanol therapy a blood ethanol determination should be made to identify if the patient has an existing ethanol level requiring a modification of the loading dose. Monitoring in an intensive care setting is required during administration. Oral ethanol loading dose To calculate the loading dose of oral ethanol the following equation may be applied: Dose = (BEC x wt x Vd) / (C x SpG) Where: BEC | desired blood ethanol concentration (mg/dL) | Dose | amount of beverage (mL) | wt | patient’s weight (kg) | Vd | volume of distribution (0.6 L/kg) | C | concentration of alcohol (% v/v) | SpG | specific gravity (0.8) [converts % v/v to % w/v] |
Note: The term "proof" describing alcohol content of beverages should be halved to obtain the proper % v/v value (e.g. 60 proof = 30% v/v ethanol). Example: To obtain a therapeutic blood ethanol level of 125 mg/dL in a 70 kg patient using whisky (80 proof and therefore 40% v/v ethanol), the loading dose will be: Loading Dose = (125 x 70 x 0.6) / (40 x 0.8) = 164 mL whiskey Intravenous ethanol loading dose To prevent vascular damage when administering intra-venous ethanol the 100% alcohol must first be diluted to either a 5 or 10% solution in 5% dextrose and water (some solutions are ready made). To reach the desired blood ethanol level of 22 to 33 mmol/L (100 to 150 mg/dL) administer: - 12 to 18 mL/kg of 5% w/v ethanol, over 30 minutes, or; - 6 to 9 mL/kg of 10% w/v ethanol, over 30 minutes. (Alternatively, the above equation may be used, using 5 or 10% for concentration (C). Multiply by 0.8 (SpG) ONLY if formulation is % v/v not % w/v). When diluting 100% alcohol, it’s specific gravity of 0.8 must be taken into account. Therefore, to produce a: 10% w/v solution Dilute 100% ethanol 8 fold (e.g. one 20 mL vial of 100% alcohol to 140 mL 5% dextrose [making total volume of 160 mL]). This solution may be preferable to reduce fluid load in pediatric patients, or those suffering cerebral edema. 5% w/v solution Dilute 100% ethanol 16 fold (e.g. one 20 mL vial of 100% alcohol to 300 mL 5% dextrose [making total volume of 320 mL]). |
The rate of maintenance infusion will vary due to individual differences in ethanol metabolism. Different rates of metabolism: Non-alcoholic adult 3.3 to 4.3 mmol/L/h (15 to 20 mg/dL/h) Alcoholic adult 6.5 to 8.7 mmol/L/h (30 to 40 mg/dL/h) Child 6.5 mmol/L/h (30 mg/dL/h) The Loading Dose Equation can be used to calculate both oral and IV maintenance doses. Replace BEC with metabolism rate from the equation. Remember NOT to multiply by 0.8 (SpG) if formulation is already % w/v. Oral ethanol maintenance dose The Loading Dose Equation can be used to calculate both oral and IV maintenance doses. Replace BEC with metabolism rate from the equation. Remember NOT to multiply by 0.8 (SpG) if formulation is already % w/v. E.g. In a non-alcoholic 70 kg adult patient (e.g. elimination rate estimated as 20 mg/dL/h) the maintenance dose using 40% v/v ethanol and the above equation will be: Maintenance Dose = (20 x 70 x 0.6) / (40 x 0.8) = 26 mL/h whiskey Intravenous ethanol maintenance dose 5% w/v solution: CHILD 3.6 mL/kg/h ADULT Non-alcoholic: 1.8 to 2.4 mL/kg/h Alcoholic: 3.6 to 4.8 mL/kg/h 10 % w/v solution: CHILD 1.8 mL/kg/h ADULT Non-alcoholic: 0.9 to 1.2 mL/kg/h Alcoholic: 1.8 to 2.4 mL/kg/h |
Ethanol administration may be discontinued if ethylene glycol levels can no longer be detected or are less than 2.4 mmol/L (15 mg/dL) with a normalized arterial pH - this is likely to take 2 to 3 days given ethylene glycol's half-life of elimination of 17 hours. |
Hypoglycemia may occur, especially in children. Once an infusion has been commenced blood glucose levels must be determined on a frequent basis (every 20 to 60 minutes). It may be necessary to add dextrose to intravenous solutions, or give glucose if ethanol is being administered orally. |
While availability is limited by purchase price, fomepizole appears preferable to ethanol. It is more particularly indicated in those with altered mental status, patients suffering hepatic disease, or those critically ill but lacking confirmation of poisoning. Its administration to pediatric patients avoids the disadvantages of ethanol (e.g. inebriation, hypoglycemia). |
Fomepizole is indicated if: - Plasma ethylene glycol concentration greater than 3.2 mmol/L (20 mg/dL) or; - Recent ingestion of greater than 0.2 mL/kg ethylene glycol and presence of osmolal gap greater than 10 mosm/L or; - History or clinical suspicion of ethylene glycol poisoning and at least two of the following Arterial pH < 7.3 Serum bicarbonate < 20 mmol/L (20 mEq/L) Osmolal gap > 10 mosm/L Presence of urinary oxalate crystals Particular indications: - Altered mental status - Hepatic disease - Critically ill patients lacking confirmation of ethylene glycol toxicity - Pediatric patients (avoids the inebriation and hypoglycemia that may occur with ethanol administration) |
Loading dose - 15 mg/kg diluted in 100 mL of normal saline or 5% dextrose in water and administered by IV infusion over 30 minutes Maintenance doses - 10 mg/kg should be administered every 12 hours for 4 doses, then; - 15 mg/kg every 12 hours thereafter if indicated Maintenance fomepizole should be administered in the same fashion as the loading dose. Dosing requirements will change if hemodialysis is required – as outlined in the enhanced elimination section. |
Fomepizole may be discontinued when ethylene glycol plasma concentrations are either undetectable, or below 3.2 mmol/L (20 mg/dL) in an asymptomatic patient with a normal pH. |
Abdominal pain, skin rash, nausea, headache and pain at site of injection have been reported following fomepizole use. |
Pyridoxine acts as a co-factor in the conversion of glyoxylic acid to the non-toxic metabolite glycine. While the clinical benefit of pyridoxine administration for the treatment of ethylene glycol poisoning has not been demonstrated in healthy individuals, it is recommended for use in malnourished or alcoholic patients who may have vitamin deficiencies. |
The formulation should be diluted at least 1 to 5. ADULT - 50 to 100 mg pyridoxine given as an IV infusion over 15 to 30 minutes every six hours - Continue for two days |
Profound peripheral neuropathy may occur after very large single doses or a series of doses (for example a total of > 2 g/kg pyridoxine over a three day period). The sensory (if not motor) disturbances are potentially irreversible. |
Thiamine acts as a co-factor in the conversion of glyoxylic acid to the non-toxic metabolite alpha-hydroxy-beta-ketoadipate. While the clinical benefit of thiamine administration for the treatment of ethylene glycol poisoning has not been demonstrated in healthy individuals, it is recommended for use in malnourished or alcoholic patients who may have vitamin deficiencies. |
ADULT - Administer 100 mg IV or IM thiamine every six hours - Continue for two days |
ENHANCED ELIMINATION
Hemodialysis is a highly effective method to enhance excretion of glycols and their toxic metabolites, reducing duration of antidote use and enhancing patient outcome. The 6-hour half-life of elimination of ethylene glycol may be reduced to 2.5 to 3.5 hours. In severe poisonings it can be life-saving. If dialysis is prolonged monitor for and treat hypophosphatemia. Hemodialysis is indicated where: Clinical signs are deteriorating despite intensive supportive care or; Metabolic acidosis with pH < 7.25 or; Acute renal failure or; Serum ethylene glycol level > 8.1 mmol/L (50 mg/dL) in those not receiving fomepizole therapy. Ethanol Maintenance This therapy should continue during hemodialysis. As ethanol is dialysed, infusions must be increased (approximately doubled, possibly tripled) or ethanol added to the dialysate. Further infusion rates must be guided by regular measurement of serum ethanol concentration. Hemodialysis should be continued in those receiving ethanol until: Measured serum ethylene glycol concentration is < 1.6 mmol/L (< 10 mg/dL) and renal function is restored and acidosis resolved, or Osmolal gap, anion gap, electrolyte concentrations, acid-base, and renal function have normalized. To reduce risk of recurrence of toxicity (due to redistribution or continued absorption) consideration should be given to continuation of ethanol treatment for 24 hours after completion of hemodialysis. Fomepizole Maintenance The dose of fomepizole must be increased during hemodialysis to compensate losses from the procedure. If the dialysis is started six or more hours after the last administration, the next scheduled dose should be given at the commencement of the procedure. All patients should then receive four hourly administrations for the duration of the treatment. Hemodialysis should be continued in those receiving fomepizole until: Acid-base and renal function have normalized; Signs of systemic toxicity have disappeared, and; Serum ethylene glycol levels are 3.2 mmol/L (20 mg/dL) or less. While the procedure is preferably terminated under these conditions it has been reported as safe with ethylene glycol levels above 8.1 mmol/L (50 mg/dL) when associated with fomepizole therapy. Fomepizole treated patients should continue this therapy following hemodialysis. If a dose has been administered within the last hour a further is not required. Those not having received a dose within 1 to 3 hours should be administered half their next scheduled dose at the completion of dialysis; while those who have not received fomepizole for more than 3 hours should receive their full dose. All should maintain 12 hourly dosing thereafter during the monitoring period. Post-hemodialysis monitoring Glycols may redistribute following cessation of hemodialysis causing re-intoxication requiring repeat hemodialysis. Serum osmolal gap, anion gap, acid-base status, electrolytes and renal function should be monitored (2 to 4 hourly) for the next 24 hours. Patients may suffer acute renal failure as a result of their poisoning and require hemodialysis for some weeks. It is usual (but not inevitable) that full renal function will return. |
The renal clearance of the acidic metabolites of glycols (such as glycolic acid, a toxic metabolite of ethylene glycol), may be increased by aggressive treatment of metabolic acidosis with sodium bicarbonate due to “ion-trapping” within the kidney. |
SUPPORTIVE CARE
ECG Plasma glucose Liver function Electrolytes including: Calcium Magnesium Chloride (for calculation of anion gap) Anion gap (will be increased in later stages of poisoning) Serum ethanol level (ethanol may influence antidote dose) Osmolal gap (will be increased in early stages of poisoning) Blood urea nitrogen (urea) Creatinine Fluid output Arterial blood gas Serum ethylene glycol level Head CT (if neurological abnormality) |
Increased anion gap metabolic acidosis results from the metabolism of ethylene glycol to acidic metabolites, predominantly glycolic acid. It is widely accepted that early and aggressive treatment of acid-base abnormality (pH < 7.3) with potentially large quantities of sodium bicarbonate is life-saving following ethylene glycol intoxication (beware of the potential for hypernatremia). Bicarbonate may also enhance renal excretion of toxic metabolites by renal “ion trapping”, but may contribute to hypocalemia. It is recommended that base excess be raised to normal within 12 to 24 hours however much bicarbonate that requires. In severe acidosis, use of an antidote to halt production of acidic metabolites, and aggressive hemodialysis are necessary. |
Monitor: Arterial blood gases (pH, bicarbonate, pCO2, pO2) Plasma lactate Base excess |
Follow standard protocols for the management of metabolic acidosis. |
Early use of hemodialysis must be considered, and should be used where cardiorespiratory support and sodium bicarbonate are insufficient to control acidosis.
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Renal failure may occur due to the toxic metabolites of ethylene glycol crystallizing in the presence of calcium and being deposited in the kidneys. Acute tubular necrosis, cortical edema, and other direct toxicity is possible. Signs and symptoms of renal insufficiency predominate at 2 to 3 days post ingestion. Alkalinize the urine and ensure adequate output. Hemodialysis is indicated in the presence of renal failure. |
Patients should be monitored for the onset of renal failure: Urine output Creatinine Blood urea nitrogen (urea) Proteinuria Hematuria Loin pain may occur |
Manage following standard treatment protocols for acute renal failure. |
Prophylactic calcium or treatment of asymptomatic hypocalcemia is not recommended due to the risk of further precipitation of calcium oxalate in the tissues. Calcium is recommended for patients continuing to seize despite standard anticonvulsant management, or in the presence of cardiac dysrhythmia – particularly prolonged QT interval. (It should be noted that available ionized calcium will rise with increasing acidosis [due to release from plasma proteins] and fall with return to normal serum pH). |
Monitor for onset of hypocalcemia with: Observation for signs and symptoms of hypocalcemia Serum ionized calcium Serum electrolytes (hypomagnesemia and hyperkalemia are often also present) 12 lead ECG (prolonged QTc) |
Magnesium is a cofactor with thiamine in the metabolic detoxification of ethylene glycol metabolites. Serum magnesium levels should be monitored and hypomagnesemia corrected. |
Monitor: Serum magnesium Nausea and vomiting Lethargy, weakness, fatigue Tremor Hyperreflexia |
Manage hypomagnesemia following standard protocols. |
Seizure activity unresponsive to standard management is indicative of hypocalcemia, particularly in the presence of calcium oxalate crystalluria, or following administration of sodium bicarbonate (which can lower ionized serum calcium). Supplemental calcium should be provided in such cases. |
Observe the patient closely for onset of seizure activity. |
DISCHARGE CRITERIA
All asymptomatic patients should be observed until appropriate investigations have been carried out. If treatment is not required they may be: - Discharged into the care of a reliable observer, or - Referred for psychological assessment (if the overdose was intentional) Symptomatic patients may be considered for discharge once symptoms and toxic sequelae have resolved, and ethylene glycol serum levels have declined to below 3.2 mmol/L (20 mg/dL). In some cases, patients may exhibit transient renal failure, requiring continuing dialysis. Furthermore, ongoing cranial nerve palsies may occur, but typically resolve within weeks to months. |
FOLLOW UP
Standard protocols should be used for follow-up of patients suffering renal failure or CNS effects. Psychiatric intervention may be necessary depending on the circumstances of the exposure.
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PROGNOSIS
Those patients surviving an initial severe acidosis may face oliguric renal failure and require regular hemodialysis for weeks to months. Fortunately, recovery is expected and very few cases lead to permanent renal failure. The return of renal function is usually signified by an increase in urine output and concomitant decrease in serum creatinine. Those who develop severe CNS manifestations, including seizures and coma, can recover full neurologic function. Cranial nerve palsies may occur in nerves II, V, VII, VIII, IX and XII, typically resolving over weeks to months. |
SIGNS AND SYMPTOMS
Symptoms following ethylene glycol ingestion can be divided into three acute stages and one sub-chronic phase. Initial symptoms of ethylene glycol ingestion are due to the direct toxicity of ethylene glycol. CNS effects predominate and include inebriation (without the alcohol odor on the breath), gastrointestinal upset, and drowsiness. In severe cases, coma, and seizures may develop. In subsequent phases of intoxication, the various metabolites of ethylene glycol are responsible for the presenting symptoms, which in the second phase of poisoning include, metabolic acidosis and cardiopulmonary symptoms 12 to 24 hours post ingestion. In significant poisonings, severe metabolic acidosis with compensatory hyperventilation can develop with multiple organ failure. Tachycardia, mild hypertension, pulmonary edema, and congestive heart failure are all believed to be due to the deposition of calcium oxalate crystals within the vascular tree, myocardium and the lung parenchyma. Most deaths occur in this second phase. The renal phase of intoxication, beginning 24 to 48 hours after ingestion, is marked by the predominance of oliguria, acute tubular necrosis, renal failure, and occasionally bone marrow suppression. Hematuria and proteinuria are common. In severe poisonings, renal failure may appear early and progress to anuria. Calcium oxalate crystals may be detected in the urine of some patients. Renal symptoms may last up to 45 days or more. In addition, cranial nerve palsies that develop in some patients may persist for weeks to months. Convulsions and coma are considered ominous signs. Following inhalation, irritation of the nose and throat can occur. Its low evaporation rate (and vapor pressure) at ambient temperatures make it unlikely to present an acute inhalation hazard in most situations; systemic effects would not typically be expected following inhalation. Eye exposure to vapors or direct contact with the liquid may lead to eye irritation; significant eye injury would not be expected. Skin contact is unlikely to cause harm to the skin on brief or occasional contact but prolonged or repeated exposure may lead to irritation. It is possible absorption through the skin could lead to systemic effects following large prolonged exposures. |
Symptoms predominantly occur following ingestion of ethylene glycol. However, toxicity is also possible via dermal, intravenous and intramuscular routes.
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Onset/Duration of Symptoms |
Stage I: Neurological Phase 0.5 to 12 hours post-ingestion Inebriation Euphoria Nausea Vomiting Metabolic acidosis CNS depression Stage II: Cardiopulmonary Phase 12 to 24 hours post-ingestion Hypertension Tachycardia Severe metabolic acidosis Hyperventilation Hypoxia Adult respiratory distress syndrome (ARDS) Congestive heart failure Stage III: Renal Phase 24 to 72 hours post-ingestion Oliguria Acute tubular necrosis Renal failure Hematuria Proteinuria Subacute Stage Onset several (5 to 20) days after ingestion Cranial nerve neuropathies Most deaths are reported in Stage II. The severity of these stages and their progression from one to the other often depends on the amount ingested. |
| Mild Ethylene Glycol Toxicity | Moderate Ethylene Glycol Toxicity | Severe Ethylene Glycol Toxicity | Nausea Vomiting Inebriation Drowsiness | Mild metabolic acidosis Tachycardia Hypertension Hematuria Proteinuria | Pulmonary edema Congestive cardiac failure Anuria Hyperventilation Severe metabolic acidosis Seizures Multiple organ failure Coma Death |
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ACUTE EFFECTS (ROUTE OF EXPOSURE)
Exposures via this route are rare due to the low vapor pressure of ethylene glycol at normal temperatures. However, when heated or aerosolized, exposures may occur. Upper respiratory tract irritation, cough and lymphocytosis have been reported. |
Ethylene glycol does not significantly irritate the skin. Following severe, prolonged exposures, slight maceration of the skin may result and dermal absorption could occur. Repeated skin exposures may result in sensitivity.
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Direct eye contact with ethylene glycol may result in immediate eye irritation with temporary conjunctival inflammation. No significant corneal damage would be expected.
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ACUTE EFFECTS (ORGAN SYSTEM)
Nausea Vomiting Hematemesis Abdominal pain Abdominal cramping |
Inebriation without the smell of alcohol on the breath (unless concomitant exposure) occurs early after ingestion. Coma may occur in the first 12 hours, as may seizures and death. Permanent cranial nerve deficits may occur following large ingestions (>100 mL) and usually occur several days after the development of the features of acute toxicity. Early CNS Toxicity Confusion Dizziness Somnolence Ataxia Slurred speech Hallucinations Dysarthria Coma Delayed CNS Toxicity Slurred speech Facial weakness Anisocoria (unequal pupil diameters) Facial diplegia Hearing loss Absent gag reflex Permanent deficit in gross and fine motor skill Cerebral edema Hyporeflexia Myoclonus Ataxia Seizures Encephalopathy Coma |
Hyperventilation and tachypnea Adult respiratory distress syndrome Non-cardiogenic pulmonary edema |
Pancytopenia Thrombocytopenia Anemia Leukocytosis Lymphocytosis Disseminated intravascular coagulation Methemoglobinemia (rare) |
Increased anion gap metabolic acidosis Increased osmolal gap NB. A normal anion or osmolal gap does not rule out ethylene glycol ingestion. |
Hypocalcemia may occur following the combination of ethylene glycol’s oxalate metabolite with serum calcium to form calcium oxalate. Hypokalemia Hypocalcemia |
Hypotension Hypertension Cardiogenic pulmonary edema Cardiomegaly Cardiorespiratory arrest Myocarditis However, cardiac involvement is generally relatively uncommon. |
Myalgia (muscle pain) Rhabdomyolysis Increased creatine kinase (CK) |
Hematuria Proteinuria Oliguria Anuria |
Dilated or poorly reactive pupils Blurred or edematous optic discs Reduced vision Strabismus (involuntary squint) Oculomotor nerve palsies Nystagmus |
CHRONIC EFFECTS
Chronic exposures to ethylene glycol vapor may result in CNS abnormalities and lymphocytosis.
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TOXICITY
TOXIC MECHANISM
The major toxic agent in ethylene glycol poisoning is not the parent compound, but the metabolites produced by the action of alcohol dehydrogenase (ADH) on the parent compound. Ethylene glycol is rapidly metabolized via ADH into glycoaldehyde, which is rapidly converted into glycolic acid by aldehyde dehydrogenase. The rate-limiting step in the metabolism of ethylene glycol is the formation of glyoxylic acid from glycolic acid via lactic dehydrogenase or glycolic acid dehydrogenase. Glyoxylic acid can be either metabolized into non-toxic alpha-hydroxy-beta ketoadipate and glycine via thiamine and pyridoxine respectively, or into oxalate. The etiology and pathophysiology of the CNS, metabolic, cardiopulmonary, and renal toxicity are primarily due to the formation and accumulation of toxic intermediary metabolites, especially glycolic acid (produces profound acidemia, oxalosis, and renal interstitial edema) and to a lesser but histologically important extent, oxalate production and excretion. |
HUMAN
The toxic dose is variable in humans. However, the lethal dose for humans is reported to be about 100 mL (1.4 mL/kg) of the concentrate, although survival has occurred with ingestions much higher than this and death has occurred with just 30 mL of the concentrate in adults. The intervention criteria has been derived from a consensus opinion. It was concluded that any ingestion of pure ethylene glycol greater than a witnessed lick or taste in a child or more than a 'swallow' (10-30 mL) in an adult warrants referral to an emergency department. For ingestion of lower concentration products (<20%) it was concluded that any ingestion of greater than 0.1 mL/kg of pure substance equivalent warrants referral. |
100 ml antifreeze solution (ingested) 13 year old female: normal physical examination 30 minutes post-ingestion Became ataxic and dysarthic and urinalysis revealed calcium oxalate crystals. Serum ethylene glycol concentration was 103 mg/dL Received ethanol and fomepizole Recovered discharged after three days. 300 ml antifreeze solution (ingested) 19 year old female (62 kg): nausea, vomiting, drowsiness. Serum ethylene glycol concentration was 134 mg/dL Received fomepizole Recovered discharged after four days 2,250 ml antifreeze solution (ingested) 27 year old male: somnolence Received gastric lavage, activated charcoal and intravenous ethanol Discharged after two days 4,500 ml antifreeze solution (ingested) 58 year old male: metabolic acidosis and increased anion and osmolal gap. Serum ethylene glycol concentration was 791 mg/dL Received activated charcoal, intravenous ethanol and hemodialysis Recovered discharged after five days |
ANIMAL
Ethylene glycol poisoning in animals may be relatively common as it has a sweet taste and looks like water. Water drained from a radiator containing ethylene glycol may be consumed unwittingly and relatively low amounts may cause toxicity.
LD50 Oral, Rat | 4700 mg/kg | LD50 Oral, Mouse | 5500 mg/kg | LD50 Oral, Dog | 5000 mg/kg | LD50 Oral, Cat | 5000 mg/kg | LD50 Oral, Guinea Pig | 6000 mg/kg |
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| LD50 IP, Rat | 5010 mg/kg | LD50 IP, Mouse | 5614 mg/kg |
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| LD50 SC, Rat | 2800 mg/kg | LD50 SC, Mouse | 10000 mg/kg |
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| MLD Oral, Cat | 1 to 2.5 mL/kg | MLD Oral, Dog | 4 to 5 mL/kg | MLD Oral, Cattle | 2 to 10 mL/kg | MLD Oral, Fowl | 7 to 8 mL/kg |
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BIOLOGICAL LEVELS - TOXIC
To convert an ethylene glycol concentration expressed in mg/dL into mmol/L: Multiply the mg/dL by 0.1611 To convert an ethylene glycol concentration expressed in mmol/L into mg/dL: Multiply the mmol/L by 6.2070 Units: 1 dL = 0.1 L 1 ug/L = 0.1 ug/dL 1 ug/dL = 10 ug/L |
Plasma Ethylene Glycol Level Serum ethylene glycol concentrations at admission are not predictive of outcome. Low pH and low base excess, indicative of toxic metabolites, do predict outcome. Initial ethylene glycol concentration greater than 20 mg/dL may result in toxic effects. Initial ethylene glycol concentration greater than 30 mg/dL has the potential to be fatal. Patients presenting with established signs of acute ethylene glycol toxicity may have relatively low or undetectable serum concentrations of ethylene glycol. It is rapidly metabolized to the toxic metabolites responsible for the development of clinical and biochemical signs of poisoning. Correlation Of Toxic Concentration And Effect < 20 mg/dL Low Level Nausea Vomiting Inebriation 20 to 30 mg/dL Moderate Level Mild anion gap metabolic acidosis Elevated osmolal gap (absence does not rule out toxicity) Tachycardia Hypertension > 30 mg/dL Severe Level Severe metabolic acidosis Hyperventilation Seizure Multiple organ failure Death Ethylene Glycol Toxic Plasma Concentrations 103 mg/dL (1 hour post ingestion) After approximately 120 mL of antifreeze orally, a 13 year old female had ataxia, dysarthria, calcium oxalate crystals in urine 134 mg/dL (1 hour post-ingestion) After approximately 300 mL of antifreeze orally, a 19 year old female had nausea, vomiting and drowsiness 222.6 mg/dL (3 hours post ingestion) After an unknown amount of ethylene glycol was ingested a 35 year old male was exhibiting bizarre behavior, was somnolent and had an elevated osmolal and anion gaps 235.9 mg/dL (24 hours post ingestion) After an unknown amount of ethylene glycol was ingested a 35 year old male was comatose with calcium oxalate crystals, rhabdomyolysis and transient renal failure 888 mg/dL (3 hours post ingestion) After an unknown amount of ethylene glycol was ingested a 28 year old male was comatose with hyperventilation, calcium oxalate crystals in urine and acute renal failure |
Ethylene Glycol Concentrations in Human Fatal Cases (g/L or g/kg)
| Blood | Brain | Liver | Kidney | Urine | Average | 2.4 | 2.0 | 6.7 | 4.6 | 5.7 | (Range) | (0.3 to 4.3) | (0.3 to 3.9) | (0.2 to 15.1) | (0.2 to 11.3) | (0.6 to 10.8) |
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The osmolal gap represents the difference between the measured osmolality (osmoles per kilogram solvent) and calculated osmolarity (osmoles per liter of solution). When positive, it may indicate the presence of low molecular weight compounds such as alcohols and glycols. A normal osmolar gap does not reliably rule out the presence of a toxic alcohol in the blood stream. OSMOLALITY Serum osmolality is generally in the range 270 to 290 mOsm/kg H 2O, and should be measured by freezing point depression. OSMOLARITY The osmolarity may be calculated using SI units or using Mass (traditional) units. Osmolarity Calculation Using SI Units Osmolarity = 2 x sodium[mmol/L] + glucose[mmol/L] + urea[mmol/L] + ethanol[mmol/L] Urea = BUN (blood urea nitrogen) Include ethanol if found on serum measurement Osmolarity Calculation Using Mass (traditional) Units Osmolarity = (2 x sodium[mEq/L]) + (glucose[mg/dL] /18) + (BUN[mg/dL]/2.8) + (ethanol[mg/dL]/4.6) All units should be expressed as mg/L BUN = urea Include ethanol if found on serum measurement These equations should also include other compounds such as ethanol or mannitol, if present. This calculation should be undertaken in the earlier phases of intoxication prior to the metabolic removal of alcohols and glycols. OSMOLAL GAP CALCULATION Osmolar gap = Osmolality - Osmolarity The mean normal osmolal gap has been determined to be approximately < 10 or 15 mOsm/kg H 2O (though this range will vary between laboratories). However, there exists considerable variation in osmolar gaps between individuals. Hence, a ‘normal’ osmolar gap does not rule out the presence of an alcohol or glycol. The osmolar gap is most useful in suggesting the presence of suspected glycol or alcohol ingestion when it is significantly elevated (usually > 20 to 30 mOsm/kg). |
The anion gap represents the difference between the sum of measured cations and the sum of measured anions. An elevated anion gap indicates the presence of unmeasured organic acids (including products of the metabolism of alcohols or glycols). ANION GAP CALCULATION Anion gap = [([sodium]) – ([bicarbonate] + [chloride])] Potassium is normally omitted from the calculation because its range is relatively small and constant. All units should be expressed as mmol/L. A “normal” anion gap may be considered within the range 3 to 11. |
REPRODUCTION
PREGNANCY
The effects of human exposure to ethylene glycol during pregnancy are unknown. Ethylene glycol has been shown to be teratogenic in animals. Teratogenicity was observed in the absence of maternal toxicity in both rats and mice. Effects in mice given 1640 mg/kg ethylene glycol by mouth included: Reduced number of live pups Decreased pup weight Malformations including Craniofacial abnormalities Neural tube defects (anencephaly, meningomyelocele) Visceral malformations Skeletal malformations (fused ribs, abnormally-shaped or missing vertebrae, twisting of spine) Similar effects were noted in rats but at a higher dose (2500 mg/kg/day). Inhalational exposure to ethylene glycol may also result in teratogenicity. |
LACTATION
It is unknown whether this compound is excreted in human breast milk. |
KINETICS
ABSORPTION
Dermal Absorption Thought to be minimal, but a large prolonged exposure could be significant 10 to 26% transcutaneous absorption has been demonstrated in both animal and human models following prolonged exposure Onset of Action CNS effects may occur just 30 minutes after ingestion Duration of Action 1 to 4 hours |
DISTRIBUTION
Volume of Distribution - 0.5 to 0.8 L/kg
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METABOLISM
Metabolites - Glycoaldehyde, glycolic, glyoxylic acid, oxalate
- Glyoxal, formic acid, glycine, oxalomalate, 2-hydroxy-3-oxadipate, 2-oxo-4-hydroygluconate, and malate
Major Metabolic Pathways Parent: - By the enzyme alcohol dehydrogenase to glycoaldehyde
Glycoaldehyde is then metabolized to glycolic acid with subsequent conversion to glyoxylic acid and oxalate: |
ELIMINATION
Excretion Ethylene glycol initially excreted unchanged in urine (up to 80%) - Glycolic acid and its salts are also excreted in the urine
- Carbon dioxide formed by breakdown of metabolites is excreted via the lungs (up to 60% in rabbits)
Half-life Overdose - In absence of ethanol: 3 hours
- In presence of ethanol: 17 hours
- In presence of ethanol with dialysis: 2.5 hours
- In presence of 4-methylpyrazole: 11 to 14 hours
Clearance Rate - Urinary: Estimated at 3.2 mL/kg/min
Potential for Accumulation - Calcium oxalate crystals can accumulate in the kidney leading to renal damage and renal failure
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IDENTIFICATION
OTHER NAME(S)
| 1,2-Ethandiol | 1,2-Ethanediol | 2-Hydroxyethanol | | Antifreeze | Athylenglykol | Coolant | | Deicer | Dowtherm | EG | | Ethane-1,2-diol | Ethylene alcohol | Ethylene dihydrate | | Ethylene glycol | Fridex | Glycol | | Glycol alcohol | Glycolmonomer | Lutrol-9 | | M.E.G | Monoethylene glycol | Norkool | | Radiator fluid | Ramp | Tescol | | Ucar 17 | | |
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Do Not Archive. This document is current on day of issue,
NZ: 18.May.2012 |
