a) FOMEPIZOLE vs ETHANOL: Fomepizole is easier to use clinically, requires less monitoring, does not cause CNS depression or hypoglycemia, and may obviate the need for dialysis in some patients. Ethanol requires continuous administration and frequent monitoring of serum ethanol and glucose levels, and may cause CNS depression and hypoglycemia (especially in children). The drug cost associated with ethanol use is generally much lower than with fomepizole; however, other costs associated with ethanol use (continuous intravenous infusion, hourly blood draws and ethanol levels, possibly greater use of hemodialysis) may make the costs more comparable.
b) FOMEPIZOLE: Fomepizole is administered as a 15 mg/kg loading dose, followed by four bolus doses of 10 mg/kg every 12 hours. If therapy is needed beyond this 48 hour period, the dose is then increased to 15 mg/kg every 12 hours for as long as necessary. Fomepizole is also effectively removed by hemodialysis; therefore, doses should be repeated following each round of hemodialysis. In selected patients (those who present early, without metabolic acidosis or renal failure) hemodialysis may be avoided by use of intravenous fomepizole. In patients with high ethylene glycol concentrations, who are treated with fomepizole alone, several days may be required before ethylene glycol is eliminated by the kidneys; hemodialysis may be indicated.
c) ETHANOL: Ethanol is given to maintain a serum ethanol concentration of 100 to 150 mg/dL. This can be accomplished by using a 5% to 10% ethanol solution administered intravenously through a central line. Intravenous therapy dosing, which is preferred, is 0.8 g/kg as a loading dose (8 mL/kg of 10% ethanol) administered over 20 to 60 minutes as tolerated, followed by an infusion rate of 80 to 150 mg/kg/hr (for 10% ethanol, 0.8 to 1.3 mL/kg/hr for a non-drinker; 1.5 mL/kg/hr for a chronic alcoholic). During hemodialysis, either add ethanol to the dialysate to achieve 100 mg/dL concentration or increase the rate of infusion during dialysis (for 10% ethanol, 2.5 to 3.5 mL/kg/hr). Oral ethanol may be used as a temporizing measure until intravenous ethanol or fomepizole can be obtained, but it is more difficult to achieve the desired stable ethanol concentration. The loading dose is 0.8 grams/kg (4 mL/kg of 20% {40 proof}) ethanol diluted in juice administered orally or via a nasogastric tube. Maintenance dose is 80 to 150 mg/kg/hour (of 20% {40 proof}) ethanol; 0.4 to 0.7 mL/kg/hour for a non-drinker; 0.8 mL/kg/hour for a chronic alcoholic). Concentrations greater than 30% (60 proof) ethanol should be diluted. For both modalities, blood ethanol levels must be monitored hourly and adjusted accordingly, and both require patient monitoring in an ICU setting.
d) THIAMINE: Administer 100 mg intravenously daily to stimulate the conversion of glyoxylate to alpha-hydroxy-beta-ketoadipate, a nontoxic metabolite.
e) PYRIDOXINE: Administer 100 mg intravenously daily, to allow adequate stores of cofactor necessary for the conversion of glyoxylate to nontoxic glycine.

a) This is usually accompanied by other cranial nerve deficits (deafness, ophthalmoplegia, dysphagia) and occurs 6 to 18 days after ingestion (Berger & Ayyar, 1981; Mallya et al, 1986; Anderson, 1990; Spillane et al, 1991; Lewis et al, 1997).

a) Inhalation of ethylene glycol vapor was associated with episodes of nystagmus, loss of consciousness, and lymphocytosis in 9 workers (Troisi, 1950).

a) Cardiogenic pulmonary edema may occur with severe poisoning (Friedman et al, 1962; Berman et al, 1957; Parry & Wallach, 1974; Denning et al, 1988).

a) Cardiomegaly has been reported (Friedman et al, 1962; Berman et al, 1957; Parry & Wallach, 1974).

a) Cardiorespiratory arrest is most commonly associated with severe metabolic and fluid electrolyte abnormalities (Friedman et al, 1962; Berman et al, 1957; Parry & Wallach, 1974).

a) CASE REPORT: Myocarditis was reported in a 42-year-old man with an ethylene glycol level of 40 mg/dL on admission. Metabolic acidosis, cardiogenic shock, and renal failure were present, without neurologic findings (Denning et al, 1988).

a) In two fatal cases of ethylene glycol ingestion, fragmentation of the normal striation in heart cells was found (Karlson-Stiber & Persson, 1992).

a) Hypertension (186/110 mmHg) has been reported following ingestion of antifreeze (Walder & Tyler, 1994) and in other ethylene glycol poisonings (Kralova et al, 2006; Eder et al, 1998).

a) Hypotension, which may progress to cardiogenic shock, may occur following ingestion (Jobard et al, 1996).
b) CASE REPORT: A 54-year-old chronic alcoholic man developed shock, hypotonic coma, seizures, hypothermia, and anuria following accidental ingestion of 200 to 300 grams ethylene glycol. In spite of symptomatic therapy, hemodynamic instability persisted and the patient died 48 hours after admission (Jobard et al, 1996).
c) CASE REPORT: A 57-year-old man, admitted to the emergency department after an ethylene glycol ingestion, was acidotic and hypotensive, resistant to multiple doses of sodium bicarbonate. Cardiogenic shock ensued and the patient died 24 hours after admission (Donovan et al, 1997).

a) CASE REPORT: A 54-year-old chronic alcoholic presented with large QRS complexes recorded on ECG and a flat EEG after being found (approximate time of exposure could not be determined) following accidental ingestion of 200 to 300 grams ethylene glycol (Jobard et al, 1996).

a) Delayed onset of adult respiratory distress syndrome (ARDS) was described 6 days after ingestion of ethylene glycol (Haupt et al, 1988) and in other cases (Piagnerelli et al, 1999; Catchings et al, 1985).
b) Adult respiratory distress syndrome was described on the first hospital day following an ingestion of ethylene glycol. Chest x-ray revealed bilateral pulmonary infiltrates; the PaO2/FIO2 ratio was below 200, and a pulmonary artery occlusive pressure (PAOP) was 10 mmHg with a high cardiac index (6.87 L/min/m(2)). Treatment included 100% FIO2 ventilation for 2 days and PEEP for 7 days (Piagnerelli et al, 1999; Piagnerelli et al, 1999a). The patient made a complete recovery with no apparent sequelae.

a) Hyperventilation may occur 12 to 24 hours post-ingestion as a response to the development of metabolic acidosis (Friedman et al, 1962; Berman et al, 1957; Parry & Wallach, 1974; Kralova et al, 2006).

a) Twenty prisoners were exposed to mean daily concentrations of ethylene glycol between 3 and 67 mg/m(3) for 20 to 22 hours/day for 1 month. The most frequently reported complaint was irritation of the upper respiratory tract, including an intolerable strong irritation of the upper respiratory tract (Wills et al, 1974).

a) A burning sensation along the trachea associated with a burning cough was reported when the concentration of ethylene glycol was momentarily increased to 200 mg/m(3) (Wills et al, 1974).

a) INEBRIATION: Slurred speech, ataxia, and somnolence are frequent early findings (Parry & Wallach, 1974). CNS effects are similar to ethanol intoxication.

a) CASE REPORTS: There are multiple case reports of cranial nerve deficit development 6 to 18 days following apparent recovery from ethylene glycol poisoning (Berger & Ayyar, 1981; Fellman, 1982; Mallya et al, 1986; Factor & Lava, 1987; Palmer et al, 1989; Anderson, 1990; Spillane et al, 1991; Zhou et al, 2002).
b) Deficits observed include dysarthria, dysphagia, facial weakness, anisocoria, ataxia, facial diplegia, hearing loss, absent gag reflex, or defects of cranial nerves II, V, VII, VIII, IX, X, and XII.
c) The amount of ethylene glycol ingested was more than 100 mL in patients for whom ingestion histories were obtained.
d) At least 7 patients were dialyzed (Berger & Ayyar, 1981; Fellman, 1982; Spillane et al, 1991; Zhou et al, 2002) and at least 3 of these received intravenous ethanol and bicarbonate. Treatment was not reported for 4 patients (Mallya et al, 1986; Palmer et al, 1989). One patient who presented three days after ingestion was not treated (Factor & Lava, 1987).

a) Coma may occur if large amounts have been ingested or treatment is delayed or inadequate (Bey et al, 2002; Berman et al, 1957; Bobbitt et al, 1986; Jobard et al, 1996). Coma is most common within hours of the ingestion but can occur at any time. Onset of coma was reported four days after ingestion in one case (Haupt et al, 1988). A 37-year old man remained comatose for 10 weeks after inadvertently ingesting food and beverages laced with a large amount of antifreeze containing ethylene glycol. He sustained permanent renal failure and hearing and vision loss but no cognitive deficits (Dezso et al, 2011).
b) CASE REPORTS

a) Seizures, which may quickly develop, and death may occur if large amounts have been ingested (Froberg et al, 2006; Dy-Liacco et al, 2003; Berman et al, 1957; Jobard et al, 1996; Faessel et al, 1995a).
b) CASE REPORT: Grand mal seizures occurred in a 28-year-old man after ingestion of 500 mL antifreeze, 60 Co-Proxamol tablets, and a bottle of whiskey. Despite treatment with anticonvulsants, veno-venous hemodiafiltration, and supportive measures, the patient expired after 24 hours. Another patient was reported to have recurrent grand mal seizures following ingestion of 500 to 2000 mL (Walder & Tyler, 1994).
c) CASE REPORT: A 28-year-old pregnant woman (26 weeks gestation) presented with speech difficulties, seizures, and hyperventilation, progressively deteriorating into a coma. Suspecting eclampsia and possible fetal asphyxia, a cesarean section was performed. Blood gas analysis obtained postoperatively revealed severe metabolic acidosis. A serum tox screen indicated ethylene glycol poisoning, with a serum ethylene glycol level of 2480 mg/L. The patient admitted drinking approximately 400 mL of ethylene glycol. The patient gradually recovered following hemodialysis and administration of ethanol (Kralova et al, 2006).

a) Cerebral edema has been reported (Bobbitt et al, 1986; Haupt et al, 1988; Maier, 1983).
b) CASE REPORT: A 39-year-old man who experienced diffuse brain stem and cerebellum swelling with no focal lesions on CT of the brain after ingestion of 500 to 2000 mL antifreeze. Brainstem death was confirmed on the 7th day (Walder & Tyler, 1994).
c) CASE REPORT: A 25-year-old man was found unresponsive after intentional ingestion of antifreeze and presented to the emergency department approximately 16 hours later with hyperventilation, tachycardia, a metabolic acidosis (pH 7.059) and high anion gap (36 mmol/L). A few hours after admission, the patient developed generalized seizures which were refractory to therapy, and a head CT revealed generalized cerebral edema. The patient expired within 24 hours of admission. Autopsy results showed oxalate crystals in the renal tubules and in small vessels of the brain, and the authors speculated that endothelial damage from the oxalate crystals may have been the cause of this patient's cerebral edema (Froberg et al, 2006).

a) Delayed or inadequately treated ethylene glycol ingestions have resulted in cerebral edema, basal ganglia and thalamic lesions, and partial or total herniation syndromes (Ford et al, 1998).
b) CRANIAL CT FINDINGS: A broad area of decreased attenuation in the mediobasilar portions of the brain and diffuse cerebral edema were associated with acute ethylene glycol intoxication (Zeiss et al, 1989). This pattern is neither believed to be diagnostic of ethylene glycol poisoning nor a barometer of clinical course or prognosis.
c) CASE REPORT: A case of brainstem and midbrain dysfunction verified by head CT results (obtained 3 days after ingestion) occurred in a 26-year-old man following an ingestion of 2 L of antifreeze. Bilateral putamen necrosis was reported on MRI of the brain 24 days after ingestion. Over the next 4 months, neurologic sequelae, including sixth nerve palsies, resolved (Morgan et al, 2000).
d) CASE REPORT/OSMOTIC DEMYELINATION SYNDROME: A 64-year-old woman presented with depressed mental status (Glasgow Coma Scale score of 7). Laboratory data revealed metabolic acidosis with an anion gap of 39 (reference range less than 17), a plasma sodium concentration of 150 mEq/L (reference range 135 to 145 mEq/L), a whole blood lactate concentration of 32 mEq/L (reference range 0.5 to 2.2 mEq/L), a plasma osmolality of 536 mOsm/kg (reference range 275 to 295 mOsm/kg) with a osmolal gap of 218 mOsm/kg (reference range less than 16 mOsm/kg), and a negative elevated blood alcohol level (less than 10 mg/dL). Suspecting a toxic alcohol ingestion, based on the patient's neurological status, her elevated lactate and osmolality concentrations, and a negative blood alcohol result, gas chromatographic analysis was conducted, demonstrating a plasma ethylene glycol concentration of 1055.5 mg/dL. Following fomepizole therapy, 750 mg IV every 12 hours, as well as thiamine administration and intermittent hemodialysis, the patient's mental status improved slightly with resolution of the metabolic acidosis and the osmolal gap. However, she experienced alternating agitation and somnolence, and hyperreflexia with bilateral weakness. An MRI of the brain revealed abnormal T2 prolongation in the thalamus, posterior hippocampus, and central pons. Based on the patient's MRI results and her history, a diagnosis of osmotic demyelination syndrome (ODS) was made. With supportive care, the patient made a full neurologic and physiologic recovery with no permanent sequelae (Ahmed et al, 2014).

a) CASE REPORT: Brainstem infarction and quadriplegia following intentional ingestion of ethylene glycol was reported in a 17-year-old man. Bilateral basal ganglia and brainstem infarcts were seen on head and cervical spine MR scan. A repeat MR scan the following day revealed absent cerebral blood flow, diffuse cortical ischemia, and bilateral uncal herniation (Dribben et al, 1999).

a) PARKINSON'S SYNDROME

a) Depressed reflexes have been reported (Pons & Custer, 1946; Vale et al, 1976; Friedman et al, 1962). Flaccid paresis has been reported (Ford et al, 1998).

a) Myoclonic jerks and tetanic contractions may occur (Pons & Custer, 1946; Vale et al, 1976; Friedman et al, 1962; Faessel et al, 1995a).

a) PERMANENT NEUROLOGIC INJURY: Central nervous system damage and associated circulatory disturbances have caused death in several cases (Rzepecki & Fabicka, 1992). Cerebral damage may be permanent, and persistent cognitive and motor deficits have been reported.

a) A 50-year-old alcoholic man developed bipallidal hemorrhage associated with an episode of ethylene glycol intoxication (ethylene glycol concentration 6.06 mmol/L; toxic greater than 1.6 mmol/L) (Caparros-Lefebvre et al, 2005). He presented with loss of consciousness, then drowsiness and inability to speak.
b) CASE REPORT: A 59-year-old man presented as comatose (Glasgow Coma Scale of 4) after inadvertently ingesting antifreeze containing ethylene glycol. CT and MR scans of the brain demonstrated bilateral hemorrhagic infarctions of the basal ganglia with restricted diffusion within the external capsule. In addition to the neurologic findings, the patient also developed acute renal failure with lactic acidosis, aspiration bronchopneumonia, and hypocalcemia. With supportive care, the patient's condition gradually improved; however, he died approximately 4 weeks after admission due to severe upper gastrointestinal bleeding (Corr & Szolics, 2012).

a) CASE REPORTS: Two patients (a 24-year-old and a 35-year-old) presented to the emergency department after subcutaneously injecting 40 mL and 60 mL, respectively, of ethylene glycol-containing antifreeze. The patients became confused, combative, and, in the case of patient #2, subsequently unresponsive, approximately 1 hour after presentation. With fomepizole administration and supportive care, both patients gradually recovered without sequelae (Murphy et al, 2013).

a) CASE REPORT: A 58-year-old man presented to the emergency department with acute left-sided weakness and left visual field defect indicative of a stroke. His medical history included hypertension, seizures, chronic kidney disease, depression and a previous suicide attempt. Physical examination revealed confusion, an odor of acetone, tachycardia, and tachypnea. Arterial blood gas analysis indicated metabolic acidosis, and a brain MRI revealed several acute infarctions with cerebral edema. The patient rapidly deteriorated, becoming comatose and necessitating intubation. Following a report that a bottle of antifreeze was found near him at his home, therapy was initiated and included fomepizole, IV sodium bicarbonate and emergent hemodialysis. Laboratory data revealed a serum ethylene glycol level of 24 mg/dL and urinalysis was positive for calcium oxalate crystals. Over the next three days, there was no neurological improvement and the patient died following a family decision to withdraw life support (Garg et al, 2015).

a) Nausea, vomiting, hematemesis, and abdominal pain are frequent early findings following ingestions (Moossavi et al, 2003; Parry & Wallach, 1974).

a) CASE REPORT: An unusual case of ischemic hemorrhagic bowel necrosis with abdominal pain and lactic acidosis has been reported in a 60-year-old chronic alcoholic man with a serum EG level greater than 20 mg/dL. Following fomepizole therapy and surgery for bowel resection and anastomosis, the patient improved. Relationship between the bowel necrosis and ethylene glycol ingestion is unclear (Singh et al, 2001).

a) CASE REPORT: A 54-year-old man presented to the hospital with hypotension and was unresponsive following acute ethylene glycol intoxication. His initial plasma ethylene glycol concentration was 2860 mg/L. During hospitalization, the patient developed mild ischemic colitis. He gradually recovered following hemodialysis and intravenous administration of ethanol and dopamine. Approximately 4 weeks later, the patient presented to the emergency department with dyspnea and decreased consciousness. Naloxone administration improved his mental status. A chest radiograph showed right lower lobe consolidation indicating aspiration pneumonia, possibly due to a narcotic overdose. Six days after hospital admission, the patient experienced intermittent lower abdominal pain. Stool was guaiac positive. An abdominal CT scan demonstrated a colonic stricture and a colonoscopy revealed a stenosis with an edematous transverse colon and the lumen filled with blood. Microscopic examination of the colon, following a subtotal colectomy, showed translucent, polyhedral crystals within the inflamed tissue, consistent with oxalate deposition.

a) OXALATE CRYSTALS

a) Calcium oxaluria, hematuria, and proteinuria are frequently reported (Friedman et al, 1962; Berman et al, 1957; Parry & Wallach, 1974). Fluorescent urine is often seen when viewed with a Wood's lamp following antifreeze ingestion. However, fluorescent urine is not a reliable indicator of ethylene glycol ingestion, due to variations in interpretation of urine fluorescence among observers and the fact that most normal urine specimens exhibit some degree of fluorescence (Casavant et al, 2001).
b) Microscopic hematuria, proteinuria, but no formation of calcium oxalate crystals were reported in 3 of 3 cases following ingestion of brake oil containing a mixture of glycols (Sharma & Jain, 2002).

a) Flank pain, costovertebral angle tenderness with oliguria, proteinuria, and anuria are common (Friedman et al, 1962). A spectrum of renal injury has been reported and may vary from acute tubular necrosis to proteinuria, hematuria, calcium oxaluria with mild increase in BUN, to prolonged and permanent anuria and azotemia (Nzerue et al, 1999; Buell et al, 1998; Berman et al, 1957). Complete recovery of renal function may follow anuria and oliguria.
b) One study looked at the in vitro activity of EG metabolites (oxalate, glycolate, glyoxylate, and glycolaldehyde) in human proximal tubule cells and resulting cytotoxicity of these metabolites to the cells. The results showed that calcium oxalate dose-dependently caused toxicity in renal tissue, while the other metabolites did not have harmful activity. The authors concluded that calcium oxalate is the toxic metabolite responsible for the renal failure observed in EG ingestions (Guo et al, 2007).
c) PREDICTIVE FACTORS: A retrospective, observational study from the California Poison Control System over a period of 10 years (1999 to 2008) was conducted to determine if there were predictive indicators associated with the outcomes of prolonged renal insufficiency (defined as kidney injury in which dialysis was required for more than 3 days after presentation) and death in patients with ethylene glycol poisoning. A total of 121 patients were identified with confirmed ethylene glycol poisoning and were divided into 2 groups: 59 patients (D/RI) who had either died (9 patients) or who had prolonged renal insufficiency (50 patients) and 62 patients (RECOV) who had an uncomplicated recovery. Analysis of the 2 groups showed that the D/RI group, compared to the RECOV group, were significantly more likely to present with somnolence or coma (98.3% vs 66.1%; odds ratio (OR) 29.71 (3.8 to 229.7) p < 0.01), develop seizures (40.7% vs 0%; p < 0.01), and require intubation (81.4% vs 17.7%; OR 20.23 (8.03 to 51) p < 0.01). Also, compared to the RECOV group, the D/RI group had a lower mean pH (7.03 vs 7.27; p < 0.01), a higher mean initial serum creatinine (1.7 mg/dL vs 1 mg/dL; p < 0.01), and a higher mean peak serum creatinine 24 hours later (2.4 mg/dL vs 1.1 mg/dL; p < 0.01), all of which suggest that clinical signs of coma, seizures, and acidosis may be predictive factors in determining the outcomes of prolonged renal insufficiency and death in patients with ethylene glycol poisoning (Lung et al, 2015).
d) CASE SERIES
e) CASE REPORTS

a) CASE REPORT: A 50-year-old woman presented 3 hours following a witnessed ingestion of EG-containing antifreeze. Initial labs revealed a metabolic acidosis (serum pH 7.3), high anion gap (29 mEq/L), and osmol gap (344.5 mOsm/L). Fomepizole therapy was initiated, along with sodium bicarbonate. Twelve hours later, the patient had a urine output greater than 11.5 liters. This osmotic diuresis resulted in the patient's serum sodium rising to 174 mEq/L, despite massive fluid replacement efforts. Hemodialysis was initiated, and the patient's recovery was not complicated by renal or CNS sequelae (Pizon & Brooks, 2006).

a) Dogs administered sublethal doses of ethylene glycol developed renal cortex ultrastructural lesions which were most common in the proximal convoluted tubules. Dilation of the distal convoluted tubules was also present and/or the tubules were packed with cellular debris (Smith et al, 1990).

a) Increased anion gap metabolic acidosis results from the metabolism of ethylene glycol to acidic metabolites, predominantly glycolic acid. (Remember: Within the first few hours after ingestion, the absence of an increased anion gap metabolic acidosis does NOT rule out ethylene glycol poisoning). Diagnosis may be suggested by a normochloremic anion gap metabolic acidosis combined with a high osmolar gap.
b) CASE REPORT: A 45-year-old woman was reported to have severe metabolic acidosis (pH 6.77), with high anion gap (25 mEq/L) and osmolal gap (60 mOsm/kg), two hours after ingestion of a product containing ethylene glycol. Ethanol therapy was initiated. Renal failure necessitated 2 weeks of hemodialysis. The patient recovered without sequelae (Piagnerelli et al, 1999).
c) CASE REPORT: A 61-year-old woman was reported to have metabolic acidosis (arterial blood pH of 7.17), with high anion gap (25 mmol/L) and osmolal gap (61 mOsm/kg) after admitting to ingesting ethylene glycol. Measured ethylene glycol level was 202 mg/dL. Following aggressive hydration and fomepizole therapy, renal function remained normal, and acidosis resolved with 24 hours (Najafi et al, 2001).
d) CASE REPORT: A 47-year-old man was admitted to the hospital 10 hours after ingestion of approximately 100 mL of antifreeze solution. Laboratory tests revealed severe metabolic acidosis (arterial blood pH of 7.05) with serum osmolality of 333 mOsm/L and calculated serum osmolarity of 317 mOsm/L. Sodium bicarbonate and ethanol infusions were maintained until resolution of anion gap. The patient made a complete recovery (Jeong et al, 2000).
e) CASE REPORT: A 44-year-old woman developed profound acidemia (arterial blood pH of 6.46) following ingestion of 720 mL of antifreeze(Blakeley et al, 1993). Therapy with ethanol and hemodialysis was initiated. Renal failure did not occur, and the patient completely recovered.
f) CASE REPORT: A 77-year-old man developed an arterial pH of 6.58 14 hours following an ingestion of radiator fluid containing ethylene glycol. The patient presented to the emergency department in a comatose state with a blood ethylene glycol concentration of 242 mg/dL, lactate level of 5.7 mmol/L, and a core temperature of 30.9 degrees Celsius. After an intravenous infusion of 10% ethanol in 5% dextrose and 8 hemodialysis treatments, the patient was discharged approximately 23 days after ingestion (Bey et al, 2002).
g) CASE REPORT: Two patients, with delayed hospital admission, presented with metabolic acidosis, arterial pH of 7.10 and 6.96, respectively, and without an elevated serum osmol gap. Subsequent laboratory tests revealed significant levels of ethylene glycol. Both patients were treated (hemodialysis and fomepizole) and recovered. The diagnosis of EG poisoning should not be ruled out due to a finding of non-elevated osmol gap (Darchy et al, 1999).
h) CASE REPORT: Severe metabolic acidosis occurred in a 28-year-old woman and her newborn infant following maternal ingestion of ethylene glycol (400 mL) prior to delivery. The woman, 26 weeks pregnant, presented with speech difficulties, seizures, and hyperventilation, subsequently becoming comatose. She was also hypertensive. Suspecting eclampsia and possible fetal asphyxia, a cesarean section was performed. A serum tox screen revealed ethylene glycol levels of 2480 mg/L and 2206 mg/L for mother and child, respectively. Blood gas analysis of the mother revealed a pH of 6.53 and an umbilical cord examination of the infant showed a pH of 6.63. Both patients gradually recovered with supportive care (Kralova et al, 2006).
i) CASE REPORT: A 38-year-old woman presented to the emergency department with severe vomiting after a 5-day history of ingesting only vodka and energy drinks. Initial blood gas analysis revealed severe metabolic acidosis (pH 7.02, base excess of -24.4 mmol/L, lactate 22 to 25.9 mmol/L). Suspecting ethylene glycol poisoning due to the high lactate concentration, toxicological analysis of the patient's blood was performed, revealing a serum ethylene glycol concentration of 280 mg/L. Following a 12-hour ethanol infusion, the patient completely recovered (Marwick et al, 2012).
j) NORMAL ANION GAP

a) CASE REPORT: Pancytopenia was reported in a 36-year-old man who ingested an unknown amount of ethylene glycol and was not treated until 12 hours post-ingestion (Bobbitt et al, 1986).
b) CASE REPORT: Medullary examination in a 45-year-old woman who ingested ethylene glycol revealed hematopoiesis arrest. Anemia (Hb=7 g/dL) and thrombocytopenia (38,000/mm(3)) were reported on the 5th day after ingestion. Complete recovery occurred without sequelae following intensive therapy (Piagnerelli et al, 1999; Piagnerelli et al, 1999a).

a) Moderate leukocytosis (10,000 to 40,000 cells/mm(3)), with predominantly neutrophils, may be present (Verrilli et al, 1987).

a) Chronic exposure to the vapors are reported to cause lymphocytosis (Dreisbach & Robertson, 1987).

a) CASE REPORT: A 54-year-old chronic alcoholic died within 48 hours of presentation to the emergency department with multiorgan failure and disseminated intravascular coagulation after an accidental ingestion of 200 to 300 g ethylene glycol (Jobard et al, 1996).

a) Methemoglobinemia has rarely been reported in conjunction with ethylene glycol ingestion (Rasic et al, 1999), however, antifreeze does not contain a methemoglobinemia-inducing agent. In one case, methemoglobinemia of 23% was treated with methylene blue (Siddiqi et al, 1998), and in another case methemoglobinemia of 7.1% (Hantson et al, 1998) was reported. The cause of methemoglobinemia in these cases was not established.

a) CASE REPORT: A 33-year-old man was found unconscious and was brought to the emergency room with symptoms of EG toxicity. A complete blood count revealed 55,000/mm(3) white blood cells (WBC) (49% segmented neutrophils, 39% bands) and leukocyte alkaline phosphatase (LAP) was 174 (normal 20-100). Both the elevated WBC and LAP were consistent with a leukemoid reaction. With supportive care, the patient recovered within 24 hours of admission, and confessed to an intentional ingestion of EG 5 days prior to presentation. The patient's WBC normalized in 3 days (Mycyk et al, 2002).

a) Dose-related intravascular hemolytic anemia was observed in rabbits exposed orally to ethylene glycol phenyl ether. Dermal exposures did not produce a hemolytic response (Breslin et al, 1991).

a) Ethylene glycol does not significantly irritate the skin (Rowe & Wolf, 1982; Clayton & Clayton, 1994).
b) Slight maceration of the skin may result from very severe, prolonged exposures (Rowe & Wolf, 1982; Clayton & Clayton, 1994).

a) Cyanosis may occur 12 hours or longer after ingestion (Friedman et al, 1962; Berman et al, 1957; Parry & Wallach, 1974).

a) Myalgia, muscle tenderness, and elevated CPK levels have been described (Friedman et al, 1962; Parry & Wallach, 1974; Scully et al, 1979; Verrilli et al, 1987).

a) Ethylene glycol in animals is teratogenic and causes other reproductive effects. Human mutation data have been reported (Lewis, 1996).
b) Craniofacial and neural tube closure defects and skeletal dysplasia were reported in rats and mice at doses (1250 mg/kg/day and 750 mg/kg/day, respectively) administered during organogenesis. Depressed maternal weight gain during pregnancy was present and was considered by the investigators as possibly due to fetal effects (e.g., lower body weight) rather than a manifestation of maternal toxicity (Price et al, 1985).
c) Marr et al (1992) found in rat studies that the incidence of skeletal alterations observed prenatally and through postnatal day 21 were not apparent by postnatal day 63. This suggests that perinatal skeletal alterations may not always be permanent.
d) Continuous administration of ethylene glycol in drinking water to pregnant mice resulted in facial anomalies in the 1 percent dose group (Lamb et al, 1985).
e) Administration of 11.1 g/kg of ethylene glycol to pregnant mice resulted in 10 percent maternal fatality and 60 percent neonatal fatality (Schuler et al, 1984).
f) In an attempt to determine the contribution of ingested EG to teratogenicity in whole-body exposures, fetal CD-1 mice were exposed to EG by nose-only inhalation at concentrations as high as 2,500 mg/m(3) on days 6 to 15 of gestation, and also to whole-body exposure at 2,100 mg/m(3). The nose-only exposed animals had increased incidences of fused ribs and skeletal variations but no malformations, whereas the whole-body exposed animals showed both skeletal variations and malformations. This result confirms that malformations were due mainly to ingested EG (Tyl et al, 1995b).
g) Skeletal and body weight variations seen in EG-exposed fetuses were reversible by postnatal day 63 (Marr et al, 1992).
h) Developmental studies in the rabbit via gavage were negative (Tyl et al, 1993).

a) When EG was given at lower doses of 0.04 to 1 g/kg/day to pregnant rats, no teratogenic effects were found (Maronpot, 1983), and neither male nor female fertility were affected over three generations (Depass, 1986b).
b) Multiple malformations including hydrocephaly, gastroschisis, umbilical hernia, skeletal defects, poor ossification and reduced body weights were seen in rat fetuses exposed to 2,500 mg/kg/day from days 6 to 15 of gestation. In mice exposed to 1,500 mg/kg/day, skeletal and ossification defects and reduced body weights were seen. The NOELs for developmental toxicity of ethylene glycol were 150 mg/kg/day in mice and 500 mg/kg/day in rats (Neeper-Bradley et al, 1995).
c) These results indicate that mice are more sensitive than rats to the developmental effects of EG, but rats show a broader spectrum of developmental defects (Neeper-Bradley et al, 1995).
d) Rats and mice exposed by whole-body inhalation to EG at levels up to 2,500 mg/m(3) on days 6 through 15 of gestation for 6 hours/day had increased incidence of external, visceral and skeletal malformations (Tyl et al, 1995a).

a) Ethylene glycol is used to cryopreserve embryos of many mammalian species, including pigs, goats, cows and horses (Otoi et al, 1995; Fieni et al, 1995; Hochi et al, 1994). This makes it unlikely that ethylene glycol itself is the active teratogen in whole-animal studies. The EG metabolite glycolic acid was active in contrast to EG itself for inducing developmental defects in whole-rat embryos in culture (Carney et al, 1996).
b) To distinguish between the contributions of the toxic EG metabolite glycolic acid (GA) and metabolic acidosis in producing developmental toxicity in rats, either EG, GA or the sodium salt of GA were administered to pregnant animals on gestation days 6 to 15. The sodium salt was previously shown not to produce metabolic acidosis. All agents produced decreased body weights and structural malformations, but EG and GA produced more severe effects. These results indicate that metabolic acidosis interacts with EG toxicity to enhance reproductive effects at high doses (Carney et al, 1999).
c) Rat cultivated embryo experiments suggest that glyoxalate may be the proximate teratogen in this species (Liberacki et al, 1996).

a) Normal anion gap is 12 to 16 using the formula AG = (Na + K) - (Cl + HCO3), but may vary from laboratory to laboratory.
b) Using the formula: Anion Gap = (Na - (Cl + HCO(3))): Normal values have been reported as 12 +/- 4 mEq/L, but vary depending on the laboratory used. The range for a normal anion gap reported in some laboratories is 7 +/- 4 mEq/L (Hoffman et al, 1993).

a) Patients ingesting large quantities of ethanol subsequent to ethylene glycol ingestion may develop clinical manifestations of ethylene glycol poisoning (high anion-gap metabolic acidosis, hypocalcemia, renal insufficiency). Thus, ethylene glycol toxicity should NOT be excluded based on a therapeutic ethanol level or a non-toxic but detectable EG level (Hoffman et al, 2001).

a) NORMAL OSMOLAL GAP: There are wide variations in "normal" osmolal gaps depending on the formula used. An individual's osmolal gap may fall within the "normal" range and still be distinctly elevated for that individual. Thus a "normal" osmolal gap cannot be reliably used to exclude the possibility of ethylene glycol ingestion (Hoffman et al, 1993; Glaser, 1996; Kruse & Cadnapaphornchai, 1994; Aabakken et al, 1994). An increased osmolal gap would be suggestive of intoxication with an osmotically active substance such as ethylene glycol (Glaser, 1996).
b) CASE REPORT: Steinhart (1990) reports a 23-year-old man with a normal osmolal gap (measured by freezing point depression) and an ethylene glycol concentration of 21.7 mg%(Steinhart, 1990).
c) CASE REPORT: Two patients, with delayed hospital admission, presented with metabolic acidosis, arterial pH of 7.10 and 6.96, respectively, and without an elevated serum osmolal gap. Subsequent laboratory tests revealed significant levels of ethylene glycol. Both patients were treated (hemodialysis and fomepizole) and recovered. The diagnosis of ethylene glycol poisoning should not be ruled out due to a finding of non-elevated osmolal gap (Darchy et al, 1999).

a) Determine the calculated serum osmolality (Osm-Cal):

             TRADITIONAL UNITS
Osm-Cal = 1.86 Na + Glucose + BUN
                    -------   ---
                       18     2.8
          -----------------------
                     0.93
where:
   1.86 = osmotic coefficient of Na
     Na = mEq/L MEASURED sodium
Glucose = mg/dL MEASURED glucose
    BUN = mg/dL MEASURED blood urea nitrogen
     18 = molecular wt glucose/deciliter conversion
    2.8 = molecular wt BUN/deciliter conversion
   0.93 = correct for serum water
                    SI UNITS
Osm-Cal = 1.86 Na + Glucose + BUN
          -----------------------
                    0.93
where:
   1.86 = osmotic coefficient of Na
     Na = mmol/L MEASURED sodium
Glucose = mmol/L MEASURED glucose
    BUN = mmol/L MEASURED blood urea nitrogen
   0.93 = correct for serum water

b) Correct for co-ingested ethanol by dividing the measured blood ethanol concentration (in mg/dL) by 4.6 and adding the result to the calculated osmolality before determining the osmolal gap.
c) Subtract the calculated serum osmolality from the measured serum osmolality to determine the osmolal gap. This difference can be accounted for by the presence of osmotically active substances (including ethylene glycol).
d) The osmolal gap may be used to estimate the serum ethylene glycol level (in mg/dL) by simply multiplying the gap by 6.2 (the molecular weight of ethylene glycol/10). This method assumes that the patient's serum contains only ethylene glycol (and no other osmotically active substances such as ethanol).
e) HYPERTONIC HYPONATREMIA: In patients with hyperglycemia, free water moves into the extracellular space, and measured serum sodium concentrations are lower. This must be corrected for in the calculation of the serum osmolality, or the osmolal gap will be falsely elevated. The serum sodium concentration must be corrected by about 1.6 mEq/L for every increase of 100 mg/dL in serum glucose above 100 mg/dL(Sztajnkrycer & Scaglione, 2005).
f) OTHER LIMITATIONS: Isopropyl alcohol, methanol, ethanol, and acetone can cause an osmolal gap (Cadnapaphornchai et al, 1981). The sensitivity and accuracy of this method of estimating blood ethylene glycol concentrations diminishes when levels fall below 50 to 100 mg/dL.

a) Wallace et al (1999) found Wood's lamp determination of urine fluorescence NOT to be accurate for detection of sodium fluorescein ingestion in an amount consistent with a toxic ingestion of antifreeze in a blinded study utilizing 28 healthy men ingesting 0.6 mg sodium fluorescein (Wallace et al, 1999).
b) A study conducted by Parsa et al involving the detection of urine fluorescence in children using a Wood lamp also found that the Wood lamp is a poor diagnostic tool in suspected ethylene glycol ingestions in children (Parsa et al, 2005).

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

a) The following criteria have been proposed by the American Academy of Clinical Toxicology as indications for treatment of ethylene glycol poisoning with an antidote (either ethanol or fomepizole) (Barceloux et al, 1999):

a) Ethanol therapy was associated with significant CNS and respiratory depression and hypotension, necessitating intubation and vasopressor support in a 50-year-old man following ingestion of 2 L of antifreeze. After metabolic acidosis with respiratory compensation was reported on ABG, the patient was given an ethanol loading dose of 70 grams of a 10% solution over 1 hour, after which he experienced a complicated course (Baumann et al, 1998). In this case, fomepizole may have been a better choice of therapy, due to the volume of ethylene glycol ingested .
b) Kowalczyk et al (1998) report a patient who experienced respiratory arrest following a bolus infusion of ethanol for EG toxicity.

1) Ingestion of multiple substances resulting in depressed level of consciousness
2) Altered consciousness
3) Lack of adequate intensive care staffing or laboratory support to monitor ethanol administration
4) Relative contraindications to ethanol
5) Critically-ill patient with anion gap-metabolic acidosis of unknown origin and potential exposure to ethylene glycol
6) Patients with active hepatic disease

a) An initial loading dose of 15 mg/kg is intravenously infused over 30 minutes followed by doses of 10 mg/kg/every 12 hours for 4 doses, then 15 mg/kg every 12 hours until ethylene glycol concentrations are below 20 mg/dL (Prod Info ANTIZOL(R) IV injection, 2006).
b) HEMODIALYSIS - The frequency of dosing should be increased during dialysis. If dialysis is begun 6 hours or more since the last fomepizole dose the next scheduled dose should be administered. Dosing during dialysis should be increased to every 4 hours (Prod Info ANTIZOL(R) IV injection, 2006).
c) Jobard et al (1996) have recommended that a loading dose of 10 to 20 mg/kg before dialysis and an infusion of fomepizole of 1 to 1.5 mg/kg/hr during hemodialysis is sufficient to maintain therapeutic fomepizole concentrations(Jobard et al, 1996a). In one patient this regimen during dialysis maintained plasma fomepizole concentrations above 14 mg/L.
d) Faessel et al (1995) found a rate of infusion for fomepizole to maintain therapeutic level at steady-state to be at least 3 to 4 times higher than the rate used without hemodialysis(Faessel et al, 1995a).
e) In patients with large ethylene glycol ingestions, several days of fomepizole administration may be required before ethylene glycol levels are below the limits of detection. Thus, even in patients who present early and do not develop metabolic acidosis or renal insufficiency, it may be more cost effective to perform a single hemodialysis session that allows a 24-hour hospitalization rather than administer fomepizole monotherapy for several days of hospitalization (Vasavada et al, 2003).
f) HEPATIC FAILURE - Wax & McMartin (1999) reported the use of fomepizole in an adult who presented with fulminant liver failure due to chronic use of acetaminophen and ethanol. One dose of fomepizole (15 mg/kg, total 1050 mg) was given intravenously. Fomepizole is normally eliminated from the body by hepatic metabolism. In this case nonlinear elimination was reported with first order kinetics, and a half-life of 17.8 hours (half-life with healthy liver is about 2 hours) (Wax et al, 1999).

a) Fomepizole (Antizole(R); 4-MP) is available in the United States for the treatment of methanol and ethylene glycol poisoning (Prod Info ANTIZOL(R) IV injection, 2006).

a) Baud et al (1986-87) treated 3 patients recently intoxicated with ethylene glycol with 20 mg/kg/day of fomepizole(Baud et al, 1986-87). Renal function remained normal in all three; reversible metabolic acidosis occurred in two. Hemodialysis was not done. Eosinophilia and skin rash were side effects noted.
b) Administration of fomepizole, beginning 9 hours and ending 61 hours postingestion, was successful in a 42-year-old man who ingested 1.5 liters of 93% ethylene glycol (EG level 320 mg/dL) (Baud et al, 1988). Hemodialysis was not done, and the patient received one dose of intravenous ethanol 4.5 hours postingestion. Normal 24-hour oxalate excretion occurred within 36 hours of the start of fomepizole therapy.
c) Fomepizole completely blocked metabolism of ethylene glycol in a case of ingestion of 100 mL. The dosage was 1200 mg IV infused over 30 minutes, followed by 600, 400, 200 and 100 mg every 12 hours until plasma ethylene glycol was below 0.1 g/L. The patient recovered with no ill effects (Harry et al, 1994).
d) Hantson et al (1998) report a 19-year-old woman admitted to the emergency department within an hour of ethylene glycol ingestion. Initial serum EG level was 1.34 g/L (21.6 mmol/L), anion gap 14.5, and osmolal gap 24. Therapy with fomepizole (9.5 mg/kg loading dose, followed by 7.0, 3.6, 1.2, 0.6, and 0.6 mg/kg at intervals of 12 hr) alone was effective in preventing EG metabolism. No ethanol therapy, hemodialysis, or sodium bicarbonate was required. An EG half-life of 11 hr was reported during fomepizole therapy .
e) CASE REPORT - A 33-year-old man presented to the emergency department approximately 1 hour after ingesting one-half gallon of ethylene glycol antifreeze and ethanol. The patient's vital signs were normal, his physical examination was unremarkable, and there was no evidence of metabolic acidosis. His initial serum ethylene glycol level was 706 mg/dL and his serum ethanol level was 84 mg/dL. After 72 hours of treatment with fomepizole (a total of 8 doses), without hemodialysis, the patient's serum ethylene glycol level was 6 mg/dL. Serial laboratory data showed normal anion gap and normal renal function throughout therapy, suggesting that early intervention with fomepizole as monotherapy may be all that is needed for a good patient outcome, although further studies are recommended (Velez et al, 2002).
f) Brent et al (1999) reported the successful use of early fomepizole in a series of 19 patients with ethylene glycol plasma levels >20 mg/dL(Brent et al, 1999a). Renal injury was prevented when fomepizole was started early in the course of poisoning, resulting in inhibition of toxic metabolite formation. Seventeen of the patients concurrently underwent hemodialysis. An average of 3.5 doses (range, 1 to 7) over an average of 17.8 hr (range, 5 to 58) were administered. All patients experienced progressive declines in plasma glycolate concentrations. Eighteen of the 19 patients survived. A patient with an arterial pH of 7.05 and a myocardial infarct prior to starting fomepizole died. Adverse fomepizole effects were minimal.
g) Donovan et al (1998) found similar good outcomes in 2 ethylene glycol poisoned patients treated with fomepizole and hemodialysis and 2 ethylene glycol poisoned patients treated with fomepizole alone. However, the length of hospital stay was longer in the fomepizole-only treated patients.
h) Fomepizole was given to two patients following ethylene glycol ingestions. One patient ingested approximately 500 mL of ethylene glycol, developed metabolic acidosis (pH 7.10, HCO3 5.4 mM, anion gap 32 mM), and was started on fomepizole therapy, 5 to 6 hours postingestion, that continued for 2 days. The patient's renal function status remained normal throughout the treatment period, and hemodialysis was not performed. The second patient presented with severe metabolic acidosis (pH 6.93, HCO3 3.6 mM, anion gap 33 mM) after ingesting an unknown amount of ethylene glycol, and was treated with fomepizole for three days. The patient's metabolic acidosis resolved, there was no evidence of renal failure, and hemodialysis was not performed. The authors speculate that fomepizole administration may help to prevent renal failure and the need for hemodialysis even in patients who present in the later stages of ethylene glycol poisoning (Moestue et al, 2002), however most authorities would recommend hemodialysis in addition to fomepizole in such patients.
i) INFANT - An 8-month-old boy (7.7 kg) was admitted to the hospital after drinking up to 120 mL ethylene glycol 95%. At 3 hr postingestion ethylene glycol serum level of 384 mg/dL was reported. Fomepizole (15 mg/kg) was started at 4 hours postingestion. Fomepizole (10 mg/kg) was repeated at 10 hours postingestion, then every 12 hours for 2 more doses. At 33 hours postingestion an ethylene glycol level of 11 mg/dL was reported. A total of 4 hours of hemodialysis was also utilized, starting at 5 hours postingestion (Baum et al, 2000).
j) PEDIATRIC - Fomepizole was effectively used to treat a potentially lethal ethylene glycol ingestion in a 4-year-old child. Treatment was started 7 hours after the ingestion. Plasma fomepizole levels remained in the range of values reported to block ethylene glycol metabolism. Rapid correction of acidosis occurred without alkalinization, and increased ethylene glycol half-life was reported. No adverse effects of fomepizole were reported (Harry et al, 1998).
k) PEDIATRIC - 30 minutes after ingestion of 4 ounces of antifreeze, a 13-year-old girl was admitted to the ED. Measured serum ethylene glycol concentration was 103 mg/dL. An ethanol bolus of 600 mg/kg was given followed by continuous infusion of 20% ethanol at 30 mL/hr. Six hours postingestion she received a fomepizole loading dose of 15 mg/kg intravenously followed by 10 mg/kg every 12 hours (requiring a total of 5 fomepizole doses). Serum ethylene glycol concentration at 36 hours postingestion was 13 mg/dL (Boyer et al, 2001).

a) Oral loading doses of fomepizole were followed by supplemental doses every 12 hours through 5 days, producing plasma levels in the therapeutic range.

a) In a placebo-controlled, single-dose, randomized, sequential, ascending-dose study, fomepizole elimination from plasma followed nonlinear kinetics with mean rates of decline of 3.66, 5.05, and 14.9 micromoles/liter/hour at 10, 20, and 100 mg/kg doses, respectively, in healthy male volunteers. Only 3% of the administered dose was excreted unchanged in the urine, with an average renal clearance of 0.016 mL/min/kg (Jacobsen et al, 1989).
b) A prolonged ethylene glycol half-life is predicted when fomepizole pretreatment creatinine is >1.2 mg/dL and the creatinine clearance is depressed (Sivilotti et al, 2000a).
c) Ethylene glycol elimination during fomepizole therapy can be predicted using serum creatinine concentration at presentation and creatinine clearance, which has correlated well with ethylene glycol elimination during fomepizole monotherapy. There is a postulated linear relationship between these 2 variables; this may help determine which patients will require hemodialysis to further ethylene glycol elimination. Absolute ethylene glycol concentration above 50 mg/dL should NOT be the sole criterion for starting hemodialysis in patients treated with fomepizole (Sivilotti et al, 2000).

a) Sivilotti et al (2000) have found a slow rate of ethylene glycol serum elimination during fomepizole monotherapy and a significant increase when fomepizole concentrations were <10 micromoles/L in a meta trial of 18 patients with ethylene glycol poisoning(Sivilotti et al, 2000a). This suggested a strong inhibition of hepatic metabolism by fomepizole.

a) A study in normal human volunteers showed that subjective side effects were not noted in the presumed therapeutic range of 10 to 20 mg/kg, while slight to moderate dizziness and nausea were noted with doses of 50 and 100 mg/kg (McMartin et al, 1987). No changes in blood or urine or objective clinical parameters were seen at any dosing level (McMartin et al, 1987).
b) Other reported side effects have included unpleasant taste after ingestion, a mild, transient increase in serum transaminases and increased serum triglycerides. Increased serum triglycerides were also present in placebo-treated controls (Jacobsen et al, 1990).
c) Headache has been reported in approximately 10% of subjects (Personal Communication, 1997).

a) Ethanol competitively inhibits alcohol dehydrogenase (ADH) and prevents the formation of toxic metabolites (Wacker, 1965). The affinity of ethylene glycol for ADH appears to be similar to ethanol.
b) CASE REPORT - A 16-year-old girl was treated with ethanol and sodium bicarbonate following unknown amounts of ethylene glycol ingestion. Arterial blood pH was 7.26, anion gap 25 mmol/L and osmolal gap 26 mOsm/kg H2O. Peak ethylene glycol plasma concentration was 14 mmol/L. Blood ethanol concentrations were maintained between 130-140 mg/dL (28-30 mmol/L) and were reached within 3 hours after starting therapy and maintained for 22 hours. 77% of the total body clearance was calculated to be due to renal clearance in the urine collection period. Hemodialysis was not performed. The patient recovered (Kowalczyk et al, 1998).

a) INDICATIONS FOR USING ETHANOL - The following guidelines were developed by the American Academy of Clinical Toxicology (Barceloux et al, 1999):

a) CONCENTRATIONS AVAILABLE (V/V)
b) PREPARATION OF 10% V/V ETHANOL IN A 5% DEXTROSE SOLUTION

a) HYPOGLYCEMIA
b) CONCURRENT ETHANOL
c) DISULFIRAM

a) INTRAVENOUS LOADING DOSE
b) ORAL LOADING DOSE

a) MAINTENANCE DOSE
b) MAINTENANCE DOSE/ETHANOL DIALYSATE
c) MAINTENANCE DOSE/ETHANOL-FREE DIALYSATE

a) There is very little information on ethanol dosing in the pediatric patient (Barceloux et al, 2002). The loading dose and maintenance infusion should be the same as for an adult non-drinker. Loading dose is 0.8 g/kg (8 mL/kg) of 10% ethanol infused over 1 hour, maintenance dose is 80 mg/kg/hr (0.8 mL/kg/hr) of 10% ethanol (Howland, 2011).
b) Blood ethanol concentration should be initially monitored hourly and the infusion rate should be adjusted to obtain an ethanol concentration of 100 to 150 mg/dL (Howland, 2011; Barceloux et al, 2002).

a) Determine blood ethanol concentrations at the end of the loading dose and hourly thereafter until stable levels of 100 to 120 mg/dL have been achieved. Monitor blood ethanol concentrations at least three times daily once a stable ethanol infusion has been achieved. Monitor concentrations more frequently during dialysis.

a) SERUM CONCENTRATIONS AVAILABLE - Ethanol therapy should be continued until the following criteria are met:
b) NO SERUM CONCENTRATIONS AVAILABLE - Following a significant ingestion or when clinical and laboratory data suggest ethylene glycol poisoning, ethanol therapy should be initiated immediately. In the rare instance when an ethylene glycol level would be unobtainable, ethanol therapy should be continued for a minimum of three days in the absence of dialysis or one day with dialysis, or until clinical findings resolve, whichever is longer.

a) Patients who have concurrently ingested ethanol and ethylene glycol may have a normal acid-base profile and urinalysis despite a dangerously elevated blood ethylene glycol concentration. Consider implementing the ethanol treatment regimen in these patients until an ethylene glycol concentration can be determined. Determine blood ETOH concentration before beginning ETOH therapy and modify the loading dose accordingly.
b) To modify the ethanol loading dose for the patients who have concurrently ingested ethanol, use the following equation to calculate the loading dose:
c) Note the loading dose obtained by this method is the amount of pure ethanol in mg/kg. It must be converted for intravenous and oral use to mL/kg. This can be accomplished by using the following relationship:

                   LD (mg/kg)
LD (ml/kg) =  --------------------------------
             (specific gravity  (concentration
                of ethanol)       as a fraction)

d) 10% (V/V) ethanol for intravenous infusion:

                 LD (mg/kg)
LD(mL/kg) = --------------------------
              (790 mg/mL) (10/100)

e) 95% (V/V) ethanol for oral use:

               LD (mg/kg)
LD(mL/kg) = --------------------------
              (790 mg/mL) (95/100)

f) Calculation of loading dose assumes instantaneous absorption.

a) In a retrospective study, the hospital records of 49 adults treated with ethanol for methanol (n=15) or ethylene glycol (n=32) ingestion were evaluated. Two patients ingested both methanol and ethylene glycol. Adverse effects developed in 45 (92%) patients, including tachycardia (heart rate greater than 100 beats/min; n=16; 33%), hypotension (n=9; 18%), decreased level of consciousness (necessitating intubation; n=10; 20%), agitation (necessitating chemical or physical restraints; n=35; 71%), seizures (n=3; 6%), vomiting (n=11; 22%), and phlebitis (n=5; 10%). It is unclear if the adverse effects were related to the ethanol, underlying poisoning or other therapies. Hypoglycemia (blood glucose less than 4 mmol/L) did not develop in any patients. Four patients died; 38% were admitted to an ICU unit and 92% of patients (n=45) were treated with hemodialysis. Serum ethanol concentrations were obtained a median of 6 times per case (range, 0 to 24). Patients were treated with ethanol for 0.5 to 119 hours (median, 21 hours). Serum ethanol concentration was within target range (22 to 30 mmol/L) in only 27% of measurements; 47% were below the target range and 25% were above the target range. Inappropriate change in ethanol dosing was reported in 59% of the cases when a serum ethanol concentration was outside the target. Inappropriate dosing changes were also reported during 69% of the hemodialysis sessions. Overall, 92% of patients survived and were discharged home (Wedge et al, 2012).

1) Faessel et al (1995) reported, in 2 cases of ethylene glycol poisoning with anuric renal failure, the mean dialysance following administration of fomepizole (10 mg/kg and 18 mg/kg, respectively) was 117 mL/min and 137 mL/min, respectively. This clearance corresponded to removal of fomepizole of 50 mg/hr and 83 mg/hr, respectively.
2) One report describes the use of a 95% ethanol enriched, bicarbonate-based dialysate solution for the treatment of a massive ethylene glycol ingestion (40 ounces of antifreeze solution)(Nzerue et al, 1999). An intravenous ethanol infusion was concomitantly used. The authors stated that the enrichment of dialysate aided in maintaining intradialytic ethanol concentration between 98 and 130 mg/dL over the 8 hour dialysis session. The patient's renal status gradually improved over a 2-week period.

1) Twenty prisoners were exposed to mean daily concentrations of ethylene glycol between 3 and 67 mg/m(3) for 20 to 22 hours/day for 1 month.
2) Accidental inhalation over a period of several weeks of aerosolized ethylene glycol from a leaking automobile heater core resulted in complaints of headache, nausea, vomiting, malaise, and pharyngeal irritation. A serum ethylene glycol level of 28 mg/dL was measured. Treatment with oral, then IV, ethanol was successful (Wezorek et al, 1995).

1) A 36-year-old epileptic man ingested an unknown amount of ethylene glycol and presented with ataxia and nystagmus, which progressed to stage 4 coma within 6 hours. Metabolic acidosis and hematuria were noted. The serum ethylene glycol concentration 12 hours after admission was 465 mg/dL. Hemodialysis was done for 15 hours on day 1 and 8 hours on day 2. The ethylene glycol concentration rapidly decreased to 18.9 mg/dL within 36 hours. Prolonged coma (7 days), seizures, anuric renal failure (8 days), bone marrow arrest (2 weeks), and cerebral edema complicated the hospital course. The patient recovered normal renal and neurologic functions (Bobbitt et al, 1986).
2) A 30-year-old man presented approximately 24 hours after ingestion of an unknown amount of ethylene glycol. Signs and symptoms included fluctuating consciousness, blurred vision, nystagmus, diplopia, central facial weakness, and mild dysarthria. The following night he developed anuria, severe metabolic acidosis, and deep coma with flaccid tetraplegia. He was treated with hemodialysis. Coma persisted for 12 days, and renal insufficiency for 45 days. Complete recovery occurred. The admission ethylene glycol blood concentration was 40 mg/dL (Steinke et al, 1989).

1) Exposure to the vapor from the liquid heated to 100 degrees C has been reported to cause nystagmus and coma of 5 to 10 minute duration (Hathaway et al, 1996).

a) Ethylene glycol levels greater than 20 milligrams/deciliter (3.22 millimoles/liter) are frequently associated with intoxication. As a rough estimate, ingestion of 3 milliliters of 100% ethylene glycol in a child weighing 10 kilograms (assuming a volume of distribution of 0.65 L/kg) would produce a potential maximum peak plasma level of 50 milligrams/deciliter. In the same child, an average swallow (2 to 8 milliliters) would produce a potential maximum peak level of 34 to 135 milligrams/deciliter.
b) EXAMPLE: A 15 kilogram child ingests 30 milliliters of a product containing 90% ethylene glycol. Note: This example is based on a volume of distribution of 0.83 L/kg, which can vary depending on the source used (see Volume of Distribution below), and a specific gravity of 1.11 g/mL.

Step 1.  Calculate dose ingested in mL -
           90 mL pure ethylene glycol
    90% = ---------------------------
          100 mL mixture
    90 mL     x
    ----- = -----   x = 27 mL pure ethylene
   100 mL   30 mL        glycol ingested
Step 2.  Convert mL to mg -
   1.11 g/mL (specific gravity) x 27 mL =
    29.97 g = 29,970 mg
Step 3.  Calculate volume of distribution in dL -
   Vd = 0.83 L/kg x 15 kg
      = 12.45 liters
      = 124.5 deciliters
Step 4.  Calculate estimated maximal plasma
         concentration (Cp) assuming instan-
         taneous absorption 
        Dose   29,970 mg
   Cp = ---- = --------- = 240.7 mg/dL
         Vd     124.5 dL

c) GLYCOLATE CONCENTRATIONS

a) INGESTION
b) INHALATION

1) Ethylene glycol

a) TWA:
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): See Appendix D

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

a) 5614 mg/kg -- caused pulmonary edema; induced changes in kidney (both tubules and glomeruli) and spleen
b) 5.8 g/kg (HSDB, 2002)

a) 5500 mg/kg
b) 8050 mg/kg (OHM/TADS, 2002)
c) 14.6 g/kg (HSDB, 2002)

a) 10.0 g/kg (HSDB, 2002)

a) 5010 mg/kg

a) 4700 mg/kg
b) 6.14 g/kg (HSDB, 2002)
c) 8540 mg/kg (OHM/TADS, 2002)
d) 13,000 mg/kg (OHM/TADS, 2002)

a) 2800 mg/kg

a) 10,000 mg/m(3) -- caused lacrimation, coughing, and additional respiratory system changes

a) Female, 1000 mg/m(3) for 6H at 6-15D of pregnancy -- fetotoxicity; affected pre- and post-implantation mortalities; changed newborn sex ratio; caused maternal effects to the uterus, cervix, and vagina
b) Female, 2100 mg/m(3) for 6H at 6-15D of pregnancy -- caused maternal effects and fetotoxicity; affected pre- and post- implantation mortalities; changed litter size; induced developmental abnormalities in musculoskeletal system

a) Female, 2500 mg/m(3) for 6H at 6-15D of pregnancy -- caused maternal effects and developmental abonormalities of the musculoskeletal system
b) 8400 mcg/m(3) for 24H/12W- continuous -- caused changes in brain weight; decreased urine volume; induced weight loss
c) 1 mg/m(3) for 32W-intermittant -- caused changes in respiratory system; affected kidney and liver, including acute renal failure and acute tubular necrosis
d) 12 mg/m(3) for 8H/90D- intermittent -- corneal damage; death

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

a) EMESIS/GASTRIC LAVAGE -
b) ACTIVATED CHARCOAL/CATHARTIC -
c) DERMAL DECONTAMINATION -
d) OCULAR DECONTAMINATION -
e) EMESIS/LAVAGE -
f) ACTIVATED CHARCOAL -
g) CATHARTIC -
h) DERMAL -

a) The following table demonstrates volume of fomepizole (4-MP) to administer based on a concentration of 50 mg/mL:
b) Adverse effects following fomepizole therapy have included an anaphylactic type reaction in approximately 1% of treated dogs following the second dose. Clinical signs/symptoms included tachypnea, gagging, salivation and tremor (Prod Info Antizol-Vet(R), 1996). Fomepizole causes no CNS depression, no additional serum hyperosmolality, or osmotic diuresis at the recommended doses. Excessive doses may result in CNS depression. Fluid treatment may be less aggressive since the dog may be able to drink on its own (Dial et al, 1989) Letter, 1989).

a) Results showed fomepizole treatment at 0 hr was most effective in preventing development of renal failure while fomepizole given 2 or 3 hr after EG ingestion was less effective than ethanol in preventing EG metabolism. The authors concluded that fomepizole should not be recommended as an alternative to ethanol for treatment of EG poisoning in cats.
b) In vitro studies suggest that higher doses of fomepizole may be required to effectively treat cats (Connally et al, 2000).

a) FOOD AND WATER may be offered throughout treatment if gag reflex and postural reflexes are normal.
b) URINE OUTPUT - Monitor urine output, since oliguria or anuria are possible.
c) PULMONARY EDEMA - Monitor patient for pulmonary edema, because fluid overload is possible, especially if oliguria or anuria is present. Decrease rate of IV fluid administration to less than 66 mL/kg/day. Monitor blood gases if possible. Maintain adequate ventilation and oxygen via face mask or continuous-positive-airway pressure in awake patients or via positive-end-expiratory pressure in intubated patients. Maintain arterial PO2 above 50 mL Hg.
d) FUROSEMIDE - Furosemide is indicated in the treatment of oliguric or anuric kidney failure and in treatment of pulmonary edema. Dosage is 2 to 4 mg/kg IV in the dog and cat.
e) DOPAMINE - Dopamine is indicated as adjunctive therapy for oliguric kidney failure, at a dose of 2 to 5 mcg/kg/min, in conjunction with the use of furosemide.
f) PERITONEAL DIALYSIS may also be necessary if animal becomes oliguric or anuric.
g) HYPOTHERMIA - Keep animal warm, preventing hypothermia.
h) VITAMINS - Thiamine (B1) and pyroxidine (B6) can be given, as these are cofactors in alternative metabolic pathways of glyoxylic acid (Beasley et al, 1989).
i) SHOCK - Fluids and corticosteroids can be helpful in treatment of shock.
j) CALCIUM - If the animal has a low blood IONIZED calcium or if severe hypocalcemia occurs, calcium may be given carefully. Calcium borogluconate may be used for seizure control at a dosage of 0.25 mL/kg of a 10% solution IV in 3 divided doses daily (Osweiler, 1985).

a) NEPHROTOXICITY - Ethylene glycol is nephrotoxic. Monitoring renal function tests and urinalysis is suggested for patients with significant exposure.
b) On hospital admission: CBC, blood chemistry panel, complete urinalysis.
c) ACID-BASE STATUS - Monitor acid-base status while treating with bicarbonate to maintain urine pH of 7.5 (Merck, 1991); monitor plasma bicarbonate every 4 to 6 hours during treatment.
d) FOLLOW-UP - Instruct the owner to return for a follow-up appointment at which time physical exam and appropriate laboratory tests will be repeated, with emphasis on renal function tests and urinalysis.

a) GENERAL - Kidney biopsy or impression smear of renal cortex will demonstrate calcium oxalate crystals in the proximal convoluted tubules. Other signs may include renal edema, lung congestion, and hemorrhagic gastroenteritis related to acute kidney failure (Mount, 1989) Merck, 1991).
b) POULTRY -
c) CAT - Renal edema, lung congestion, and hemorrhagic gastroenteritis (Merck, 1991).
d) COW - Post-mortem signs may include perirenal edema, with kidneys swollen and dark (Merck, 1991).
e) PIG - Subcutaneous edema, straw-colored fluid in abdomen and thoracic cavity, pulmonary edema, perirenal edema, pale brown kidneys with petechiae and ecchymoses. On histopathology, kidneys show tubular necrosis with basement membrane damage, and oxalate crystals (Osweiler & Eness, 1972).

a) POULTRY - 7 to 8 mL/kg body weight (Merck, 1991)
b) CAT - 1.5 mL/kg body weight (Merck, 1991)
c) COW - 2 to 10 mL/kg body weight (Merck, 1991)
d) DOG - 4.2 to 6.6 mL/kg body weight (Merck, 1991; (Grauer & Thrall, 1986)
e) MACAQUE - 1.6 mL/kg body weight (Jones & Hunt, 1983)

a) DOG
b) GOAT

1) Gastric lavage is preferred over emesis. Treatment includes ethanol administration or fomepizole (Antizol-Vet(R)) (dogs), sodium bicarbonate, and supportive measures.
2) SUMMARY
3) Treatment should always be done on the advice and with the consultation of a veterinarian.
4) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
5) ASPCA ANIMAL POISON CONTROL CENTER
6) SMALL ANIMALS: Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only.
7) In the case of a poisoning involving large animals, consult a veterinary poison control center.

1) GENERAL TREATMENT

1) Ethylene glycol - - glycoaldehyde (oxidation by alcohol dehydrogenase; rate-limiting step)
2) glycolic acid (causes acidosis and nephrosis)
3) glyoxylic acid
4)

1) SUMMARY - Prognosis worsens as time post-ingestion increases. Treatment must be begun as soon as possible after ingestion, preferably before any damage has occurred to the kidney tubules. If therapy is begun as late as 8 hours post-ingestion, prognosis is fair to guarded, even if no azotemia is present at that time (Dial et al, 1989). Dogs in severe metabolic acidosis, in comatose situations, or in acute kidney failure are less likely to respond to treatment, as they are in the terminal stages of toxicity (Beasley et al, 1989).
2) ULTRASOUND - Ultrasonic examination of the kidneys may be a helpful adjunct in determining prognosis. Increases echogenicity is seen in conjunction with anuria, and thus provides a guarded to poor prognosis (Adams, 1991).

1) Ketoacidotic diabetes mellitus, hypoglycemic shock
2) Acute gastroenteritis, Foreign body obstruction, Garbage poisoning
3) Acute pancreatitis
4) Lactic acidosis
5) Encephalitis, Rabies, Leptospirosis
6) Head injury, Trauma, Shock
7) Anaphylactic shock
8) Acute kidney failure, Nephritis, Uremia
9) Drug overdoses: antidepressants, sedatives, tranquilizers, other psychoactive drugs, ethanol, methanol, aspirin, acetaminophen
10) Mushroom toxicity (psychoactive)
11) Plant oxalate toxicosis
12) Reference: Merck, 1991; Mount, 1989; Osweiler, 1985