CLINICAL APPROACH TO TOXIN-INDUCED METABOLIC ACIDOSIS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Acidosis
2) Acute metabolic acidosis
3) Acidosis, metabolic
4) High anion gap metabolic acidosis
5) Hyperchloremic metabolic acidosis
6) Increased anionic gap metabolic acidosis
7) Normal anion gap metabolic acidosis
8) METABOLIC ACIDOSIS

Overview

Life Support

Clinical Effects

0.2.1)

A) WITH POISONING/EXPOSURE

1) In the setting of metabolic acidosis induced by a toxin, physical signs and symptoms may help to reveal the poison involved. Signs and symptoms are as follows:

a) VITAL SIGNS

1) Hyperthermia - Any agent that can cause hyperthermia may cause anion gap acidosis from lactic acid. Hyperthermia may indicate salicylate or isoniazid (with protracted seizures).
2) Hypothermia - Hypothermia has been reported following an accidental ingestion of ethylene glycol. Hypothermia is common in patients who develop CNS depression associated with phenformin-induced acidosis.

b) CARDIOVASCULAR

1) Bradycardia - In severe cases of cyanide poisoning, tachycardia occurs early, followed by bradycardia.
2) Dysrhythmias - Acidemia has been reported to contribute to conduction delays, dysrhythmias, and depressed myocardial contractility in patients with cocaine toxicity. Following severe salicylate intoxication, malignant dysrhythmias may occur abruptly.

a) QT prolongation - Hypocalcemia with QT prolongation may be observed following severe ethylene glycol poisoning.

3) Hypotension - Any agents that can cause hypotension may cause anion gap acidosis from lactic acid. Hypotension is characteristic with severe iron poisoning. Hypotension may also occur with methanol, salicylate, ethylene glycol, phenformin or isoniazid intoxication. Following cyanide poisoning, hypertension may occur initially followed by hypotension.
4) Hypertension - Following cyanide poisoning, hypertension may occur initially followed by hypotension.
5) Tachycardia - Tachycardia develops in virtually all patients with theophylline overdose. Tachycardia may also develop with ethylene glycol, salicylate, or iron poisoning. In severe cases of cyanide poisoning, tachycardia occurs early, followed by bradycardia.

c) DERMATOLOGIC

1) Diaphoresis may be caused by beta-receptor agonist, salicylate or stimulants. Moist skin and mucous membranes with significant fluid losses may occur following the overdose of sympathomimetic agents (cocaine).

d) ENDOCRINE

1) Hyperglycemia - Hyperglycemia is common with iron poisoning; it may also occur with salicylate, theophylline or methanol toxicity. Hypoglycemia may develop with salicylate poisoning (particularly children) and may rarely occur following biguanide overdoses.

e) FLUIDS/ELECTROLYTES

1) Hyperkalemia - Serum potassium is often elevated secondary to the metabolic acidosis following biguanide poisoning.
2) Hypokalemia - Common with beta-receptor agonist, caffeine, or theophylline poisoning; may also develop with salicylate or methanol poisoning.
3) Hypomagnesemia - May occur with methanol toxicity.
4) Hypocalcemia - Hypocalcemia (due to formation of calcium oxalate) with QT prolongation may be observed following severe ethylene glycol poisoning.

f) GASTROINTESTINAL

1) Abdominal pain - May occur with methanol, paraldehyde, cyanide, iron, or ethylene glycol toxicity.
2) Nausea and vomiting - Prominent findings with theophylline and iron poisoning. May also develop after acetaminophen, cyanide, salicylate, ethylene glycol, methanol, or paraldehyde toxicity.
3) Hematemesis - Common with severe iron poisoning; may also occur with ethylene glycol ingestion.
4) Pancreatitis - May develop with ethanol, ethylene glycol or methanol toxicity.
5) Almond odor - An odor of bitter almonds in gastric content or expired breath suggests cyanide poisoning.
6) Dry mucous membranes - May be noted in patients with metabolic acidosis and moderate to severe dehydration.

g) GENITOURINARY

1) Acute renal failure - Suggests ethylene glycol poisoning (observed 24 to 72 hours postingestion). The presence of calcium oxalate crystals in the urine highly suggests ethylene glycol poisoning. Calcium oxalate crystals commonly occur in two forms: monohydrate and dihydrate crystals. Their absence does not exclude the diagnosis.

h) HEENT

1) EYES - Visual abnormalities that develop during acute methanol intoxication may include blurred or double vision, changes in color perception, constricted visual fields, spots before the eyes, and sharply reduced visual acuity. Mydriasis may occur with cyanide intoxication. In these patients, retinal arteries and veins that appear equally red on funduscopic examination suggest cyanide intoxication. Decreased visual acuity, mydriasis, and nystagmus may also develop with ethylene glycol intoxication.
2) NOSE - Certain odors can help reveal the poison involved: cyanide (bitter almonds), hydrogen sulfide (rotten eggs) and toluene (paint or glue).
3) EARS - Tinnitus and transient hearing loss suggest salicylate overdose.

i) HEMATOLOGIC

1) Prolonged prothrombin time/partial thromboplastin time - may develop with severe salicylate or iron toxicity. Leukocytosis is common after theophylline, iron and isoniazid overdose; it has also been reported with methanol toxicity.

j) HEPATIC

1) Hepatic dysfunction - Liver damage may be observed following acetaminophen, iron, or salicylate intoxications.

k) MUSCULOSKELETAL

1) Rhabdomyolysis - May be caused by beta-receptor agonists or salicylates (rarely following severe intoxication). Myalgia with elevated creatine kinase may be observed following ethylene glycol intoxication. Paralysis may also occur.

l) NEUROLOGIC

1) Transient lactic acidosis may be due to toxicant-induced severe agitation or seizure (eg; cocaine, methamphetamines). Many patients with toxic ingestions (eg; salicylate, methanol, ethylene glycol) will present with an altered sensorium that may progress to coma.
2) CNS depression - Development of CNS depression and metabolic acidosis in the absence of liver failure has been reported early after (very large) acetaminophen overdose. Following ethylene glycol or methanol intoxication, CNS depression, ataxia, and slurred speech may be observed.
3) Coma - May develop with ethylene glycol or methanol poisoning. Euphoria followed by deepening coma may be caused by ethylene glycol intoxication. Coma commonly develops, particularly after or between seizures episodes following isoniazid overdose. Coma and metabolic acidosis in the absence of hepatotoxicity have been reported following severe acetaminophen overdose.
4) Seizures - Common after INH overdose, often recurrent and resistent to anticonvulsants. Seizures may also develop with severe salicylate, cocaine, ethylene glycol or methanol toxicity. Significant metabolic acidosis may develop in patients with prolonged seizures following tricyclic antidepressants overdose. Severe anion gap metabolic acidosis is common in patients who develop seizures after isoniazid overdose. Following hydrogen sulfide intoxication, transient lactic acidosis may be noted following significant exposure, secondary to cellular hypoxia and seizures.

m) RESPIRATORY

1) In the setting of metabolic acidosis induced by a toxin, hyperventilation (tachypnea, hyperpnea) is usually observed.

a) RESPIRATIONS, INCREASED - Hyperventilation is a compensatory response to metabolic acidosis. Alveolar ventilation is increased, with a resulting decrease in PCO2. Tachypnea also may result from direct stimulation of the respiratory center in acute salicylate ingestions.
b) RESPIRATIONS, DECREASED - In the setting of a significant toxic ingestion (eg; methanol, ethylene glycol, paraldehyde), progressive CNS depression may result in respiratory depression, which could cause superimposed respiratory acidosis.
c) RESPIRATIONS, KUSSMAUL - In severe metabolic acidosis, Kussmaul respirations (hyperpnea and tachypnea) are prominent and represent the respiratory response to the severe metabolic acidosis.

2) Acute Lung Injury - May occur rarely following ethylene glycol or metformin/phenformin intoxications. In severe salicylate intoxication, acute lung injury and respiratory failure may occur. Respiratory tract irritation, acute lung injury, and cyanosis may indicate cyanide poisoning.

2) INDIVIDUAL AGENTS

a) ETHYLENE GLYCOL

1) Classic features of ethylene glycol intoxication occur in three stages. Initially, neurologic changes occur between 1 and 12 hours postingestion. These include hallucinations, decreased visual acuity, nystagmus, cranial nerve abnormalities, CNS depression ranging from somnolence to coma and gastrointestinal ileus. Cardiovascular and pulmonary toxicity may occur 12 to 24 hours after ingestion and is characterized by congestive heart failure, pulmonary edema, and dysrhythmias. Acute renal failure may be seen approximately 24 to 48 hours postingestion. Increased anion gap metabolic acidosis results from the metabolism of ethylene glycol to acidic metabolites, predominantly glycolic acid (NOTE: Within the first few hours post-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) IBUPROFEN

1) Elevated anion gap metabolic acidosis has been reported in children and adults after overdoses of greater than 400 mg/kg. Most patients with acute ibuprofen poisoning remain asymptomatic or develop mild gastrointestinal or neurologic symptoms. Abdominal pain, nausea, vomiting, headache, confusion, lethargy, diplopia, nystagmus may occur after very large ingestions. Life-threatening manifestations are rare but may include coma, seizures, apnea, bradycardia, hypotension, gastrointestinal bleeding, renal failure, and hepatic dysfunction. The minimal toxic dose appears to be at least 100 mg/kg.

c) IRON

1) Anion gap metabolic acidosis is a common early finding in significant ingestions. Severe metabolic acidosis may persist for days in severe overdoses. Toxicity is likely following ingestion of 60 mg/kg or more of elemental iron. Presenting symptoms within the first 6 hours of ingestion consist of nausea, vomiting, hematemesis, abdominal pain, and lethargy. These initial complaints are followed by a period of apparent recovery 6 to 12 hours post ingestion. The onset of shock and severe metabolic acidosis occurs 12 to 48 hours post ingestion. In severe intoxication, there is a rapid progression of drowsiness, coma, metabolic acidosis, and shock.

d) METHANOL

1) Patients intoxicated with methanol appear drunk and may complain of abdominal pain, visual blurring, scotomata, or blindness. Eye findings include dilated pupils, nystagmus, retinal edema, and hyperemia or atrophy of the optic disc. Headache, dizziness, nausea, vomiting, bradycardia, seizures, and coma may also occur. Metabolic acidosis is classic, but may be delayed for 18 to 24 hours, or longer with concurrent ethanol ingestion. Severely poisoned patients may develop cerebral edema and brain death.

e) SALICYLATES

1) Respiratory alkalosis with compensatory metabolic acidosis develops in most adults with moderate intoxication. Other common features include fever, tachycardia, nausea and vomiting, and tinnitus. Metabolic acidosis with acidemia and compensatory respiratory alkalosis develops in severe overdose and is associated with a higher rate of complications and death. In infants respiratory alkalosis may be short lived or not occur at all; metabolic acidosis with acidemia predominates.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Hyperthermia - Any agent that can cause severe hyperthermia may cause anion gap acidosis from lactic acid. Hyperthermia is common with salicylate or isoniazid (with protracted seizures) toxicity (Dart et al, 2000; Shah et al, 1995; Dananberg, 1992; Pec et al, 1992; Leatherman & Schmitz, 1991).
2) Hypothermia - Hypothermia (33 degrees C) was reported following an accidental ingestion of 200 to 300 grams of ethylene glycol (Jobard et al, 1996). Hypothermia is common in patients who develop CNS depression associated with phenformin induced acidosis (McGuinness & Talbert, 1993; Gan et al, 1992).

Laboratory Monitoring

1) Anion gap greater than 19 mEq/L, if a cause seems likely (eg, seizures), repeat measurement in 1 to 2 hours, if the cause is unknown or osmolal gap does not improve, obtain serum lactate, methanol, ethylene glycol, salicylate and iron levels. Cyanide levels may be considered.
2) Anion gap between 16 to 19 mEq/L, repeat measurement in 2 hours.
3) Toxic causes of a high anion gap metabolic acidosis: Alcoholic ketoacidosis, carbon monoxide, cyanide, ethylene glycol, hydrogen sulfide, isoniazid, iron, metformin, methanol, paraldehyde, phenformin, salicylates, sulfur (inorganic), theophylline and toluene.
4) Toxic causes of a normal anion gap metabolic acidosis: Acetazolamide, acids (ammonium chloride; arginine hydrochloride, calcium chloride, hydrochloric acid, lysine hydrochloride), carbonic anhydrase inhibitors, cholestyramine, magnesium chloride, sulfamylon, toluene and topiramate.

Treatment Overview

0.4.2)

A) The life-threatening consequences of metabolic acidosis (cardiovascular collapse) are a function of both the severity of the resulting acidemia and the specific pathophysiologic cause of the acidosis. Treatment of metabolic acidosis requires precise identification of the etiology, with subsequent therapy aimed at correcting or controlling the cause.
B) In patients with severe metabolic acidosis (pH less than 7.2) administration of sodium bicarbonate is reasonable.
C) AIRWAY MANAGEMENT: Endotracheal intubation may be required in patients with severe acidosis, especially if there is concomitant CNS depression or hemodynamic instability. Extreme care must be taken to prevent worsening of acidemia by underventilation of the patient.
D) IV FLUIDS: For moderate to severe volume depletion:

1) ADULTS: 1 to 2 L NS over 30 to 45 minutes; repeat a bolus of 0.5 to 1 L over 30 to 45 minutes if response is poor.
2) CHILDREN: 20 mL/kg IV over 30 to 45 minutes; repeat a bolus of 10 mL/kg over 30 to 45 minutes if response is poor.

E) Administer activated charcoal if the acidosis is suspected to be secondary to a toxic ingestion.
F) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
G) HYPOTENSION: Any agents that can cause hypotension may cause anion gap acidosis from lactic acid. Adequate resuscitation and blood pressure support is essential to avoid worsening acidosis.
H) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
I) SEIZURES: Significant metabolic acidosis may develop in patients with prolonged seizures of any etiology. Control seizures aggressively to prevent worsening acidosis.
J) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).

1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

K) In patients with recurrent seizures and metabolic acidosis, presumptive treatment for INH intoxication with pyridoxine should be strongly considered. Initial dose is 5 g IV in an adult.
L) REFRACTORY SEIZURES: Consider continuous infusion of midazolam, propofol, and/or pentobarbital. Hyperthermia, lactic acidosis and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.
M) SODIUM BICARBONATE - CAUTION: Should only be used if the acidemia is purely or primarily metabolic (respiratory acidosis should be treated by hyperventilation) or if the acidemia is not readily reversible (eg, not post-seizure).

1) LIFE-THREATENING METABOLIC ACIDOSIS (eg, prolonged cardiac arrest, pH less than 7.0, HCO3 less than 5 mEq/L): ADULTS: 1 to 2 mEq/kg IV bolus (typically 1 to 2 ampules in adults); monitor blood pH (arterial or mixed venous) every 10 minutes to guide further therapy.
2) SEVERE METABOLIC ACIDOSIS (eg, pH less than 7.2, HCO3 less than 8 mEq/L):

a) NOTE: No universally appropriate dose exists.
b) SODIUM BICARBONATE DOSING FORMULA: Desired change in HCO3 (mEq/L) X patient weight (kg) X volume of distribution (assume 0.5 L/kg) = mEq NaHCO3 required. Infuse over minutes to hours. Check pH 30 minutes after infusion. Target HCO3 of 8 mEq/L to avoid overshoot alkalosis.
c) ALCOHOL DEHYDROGENASE BLOCKERS: In any patient with severe or worsening anion gap metabolic acidosis without a clear cause, institution of alcohol dehydrogenase blockers (IV fomepizole or ethanol) should be strongly considered until methanol and ethylene glycol poisoning can be ruled out.

3) INDIVIDUAL AGENTS: For more information on the treatment refer to the individual agents below.

N) INDIVIDUAL AGENTS

1) CYANIDE

a) Cyanide Antidote Kit for severe exposures: SODIUM NITRITE: Administer IV (ADULT: 10 mL of a 3% solution administered IV at rate of 2.5 to 5 mL/minute; CHILD (with normal Hgb concentration) 0.2 mL/kg of a 3% solution (6 mg/kg) administered IV at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg). SODIUM THIOSULFATE: Follow sodium nitrite with sodium thiosulfate. Administer IV immediately following sodium nitrite (ADULT: 12.5 g (50 mL of 25% solution); CHILD: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose). A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear.
b) Hydroxocobalamin (vitamin B12): ADULT: Administer 5 g IV over 15 minutes. A second dose may be given (infused over 15 to 120 minutes) in patients with severe toxicity. PEDIATRIC: A dose of 70 mg/kg has been used. Hydroxocobalamin forms cyanocobalamin which is a nontoxic, water soluble metabolite that is eliminated in the urine. It is generally safer and easier to use than other antidotes (i.e., nitrite and thiosulfate kits). Sodium thiosulfate may also be administered with hydroxocobalamin, but it is not part of the kit.
c) Acidosis: Na bicarb 1-2 mEq/kg IV if pH < 7.2.
d) Seizures: IV benzodiazepines, or barbiturates.
e) Hypotension - 0.9% NaCl, dopamine, norepinephrine

2) ETHYLENE GLYCOL

a) Acidosis: NaHCO3 1-2 meq/kg every 1-2 hrs if pH < 7.2.

1) Intravenous sodium bicarbonate should NOT routinely be administered. Sodium bicarbonate should NOT be administered prophylactically or for the treatment of mild to moderate acidosis or acidemia. The treatment of acidosis and acidemia should be directed at preventing further metabolism of ethylene glycol by administering ethanol and when indicated by revolving both the ethylene glycol and it's toxic metabolites by hemodialysis. Sodium bicarbonate administration may be useful as a temporizing measure in managing cases of severe and life-threatening acidosis and acidemia prior to hemodialysis.

b) Treat patients with either fomepizole or ethanol to block production of the toxic metabolites of ethylene glycol. Indications include: a serum ethylene glycol concentration greater than 20 mg/dL; history of ethylene glycol ingestion with an osmolar gap greater than 10 mOsm/L (not accounted by ethanol or other alcohols); or a history or strong clinical suspicion of ethylene glycol ingestion and 2 of the following: serum bicarbonate less than 20 mEq/L, an arterial pH less than 7.3, or presence of oxalate crystals in the urine.

1) 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.
2) 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.
3) Thiamine: Administer 100 mg intravenously daily to stimulate the conversion of glyoxylate to alpha-hydroxy-beta-ketoadipate, a nontoxic metabolite.
4) Pyridoxine: Administer 100 mg intravenously daily, to allow adequate stores of cofactor necessary for the conversion of glyoxylate to nontoxic glycine.

c) Hemodialysis: If metabolic acidosis or EG > 50 mg/dL.

3) IBUPROFEN

a) Acidosis: NaHCO3 1-2 meq/kg every 1-2 hrs if pH < 7.2.
b) Hypotension: IV 0.9% NaCl 10-20 ml/kg, dopamine, norepinephrine.

4) IRON

a) Deferoxamine: Indicated for systemic signs of iron toxicity (acidosis, hypotension; usually associated with serum Fe>350 mcg/dL) 15 mg/kg/hr IV infusion. IM Dose - 90 mg/kg every 8 hrs as needed; maximum of 1 gram/dose. Total Daily Dose - (IM or IV) should not exceed 6 g. Duration of therapy variable; usually 8-12 hrs for moderate, and up to 24 hrs for severe toxicity.
b) Seizures: IV benzodiazepines, barbiturates.
c) Hypotension: IV 0.9% NaCl, dopamine, norepinephrine

5) ISONIAZID

a) Pyridoxine: Administer an amount equivalent to the estimated amount of INH ingested (maximum dose unknown) or 5 grams (adults) if unknown ingestion. Give IV over 30-60 min. Doses over 10 grams may cause peripheral neuropathy.
b) Seizures: IV pyridoxine, benzodiazepines, barbiturates.
c) Acidosis: NaHCO3 1-2 mEq/kg if pH <7.2.
d) Hypotension: IV 0.9% NaCl, dopamine, norepinephrine.

6) METFORMIN AND RELATED AGENTS

a) Acidosis: Untreated lactic acidosis may result in confusion, hypotension, coma and circulatory collapse. Severe metabolic acidosis (arterial pH less than 7.2) should be corrected with IV sodium bicarbonate (a reasonable starting dose is 1 to 2 mEq/kg). Monitor blood gases to guide bicarbonate therapy.
b) Hypoglycemia: Not routinely caused by biguanides. Should be treated with IV dextrose. (ADULT: Administer 50 mL of 50% dextrose solution; CHILD: Administer 0.5 gm/kg/dose).
c) Hemodialysis may be useful in restoring acid/base, fluid and electrolyte balance and should be considered in those patients with a severe metabolic acidosis who continue to deteriorate despite conventional therapy, or in patients with severe renal impairment or failure.
d) Insulin/dextrose: Therapy with intravenous insulin and glucose has been associated with a lower mortality rate than therapy with bicarbonate or dialysis in one case series.

7) METHANOL

a) Acidosis: IV NaHCO3 1-2 mEq/kg starting dose if pH < 7.2.
b) Treat patients with either fomepizole (4-methylpyrazole) or ethanol to prevent the production of formate. Indications include documented plasma methanol concentration greater than 20 mg/dL (greater than 200 mg/L) OR documented recent history of ingesting toxic amounts of methanol and osmolal gap greater than 10 mOsm/L OR history or strong clinical suspicion of methanol poisoning with at least 2 of the following criterion: arterial pH less than 7.3; serum bicarbonate less than 20 mEq/L; osmolol gap greater than 10 mOsm/L.

1) Fomepizole: Fomepizole is administered as a 15 mg/kg loading dose, followed by 4 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.
2) Ethanol: Ethanol is given to maintain a serum ethanol concentration of 100 to 150 mg/dL. This can be accomplished by using a 5% or 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 nondrinker; 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 (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 g/kg (4 mL/kg) of 20% {40 proof}) ethanol diluted in juice administered orally or via nasogastric tube. Maintenance dose is 80 to 150 mg/kg/hr (20% {40 proof}) ethanol; 0.4 to 0.7 mL/kg/hr for a nondrinker; 0.8 mL/kg/hr 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.
3) FOLATE: Folate increases clearance of formate. Administer 50 mg every 4 hours to any patient requiring ADH inhibition.

c) Hemodialysis: If acidosis, visual changes or methanol >20-50 mg/dL. Increase ETOH infusion during dialysis; and increase fomepizole dosing to every 4 hours during hemodialysis.

8) SALICYLATES

a) Alkaline diuresis: Rehydrate with 0.9% NaCl. Alkalinize urine in patients with clinical or laboratory evidence of toxicity. Infuse solution of 132 mEq/L NaHCO3/L D5W at 1.5-2 times maintenance to achieve urine pH>7.5. Additional KCl may be required.
b) Acidosis: Administer IV NaHCO3. Correct pH to 7.40; even mild acidemia can facilitate movement of salicylate into the brain. Monitor ABGs.
c) Hemodialysis: Consider if salicylate levels > 100 mg/dL, refractory acidosis, persistent CNS symptoms, ongoing deterioration despite therapy, pulmonary edema, renal failure. It removes salicylate and corrects acid base derangements, and is the procedure of choice to treat SEVERE salicylate intoxication.

Range Of Toxicity

Clinical Effects

Hepatic

3.9.2)

A) LIVER FINDING

1) WITH POISONING/EXPOSURE

a) Liver damage may be observed following acetaminophen, iron, salicylate, or isoniazid intoxication (Singhi et al, 2003; Dart et al, 2000; Panganiban et al, 2001; Manchon et al, 1990; Starko & Mullick, 1983).

Genitourinary

3.10.2)

A) RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure - Suggests ethylene glycol poisoning (observed 24 to 72 hours postingestion). The presence of calcium oxalate crystals in the urine highly suggests ethylene glycol poisoning. Calcium oxalate crystals commonly occur in two forms: monohydrate and dihydrate crystals (Huhn & Rosenberg, 1995; Olivero, 1993). Their absence does not exclude the diagnosis.
b) In methanol intoxication, hematuria and acute renal insufficiency have been reported. Proteinuria and acute renal insufficiency may occur with salicylate overdose. Renal damage may also occasionally occur following acetaminophen intoxication (develops after hepatotoxicity) (Dart et al, 2000; Harchelroad, 1993a).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) COCAINE - Severe metabolic acidosis has been reported due to seizures, agitation, and hypotension (Jonsson et al, 1983a; Stevens et al, 1994).
b) ETHYLENE GLYCOL - Increased anion gap metabolic acidosis results from the metabolism of ethylene glycol to acidic metabolites, predominantly glycolic acid (NOTE: Within the first 8 hours post-ingestion the absence of an increased anion gap metabolic acidosis does NOT rule out ethylene glycol poisoning (Leon & Graeber, 1994; Heckering, 1987). Diagnosis may be suggested by a normochloremic anion gap metabolic acidosis combined with a high osmolar gap.
c) HYDROGEN SULFIDE - Transient lactic acidosis may be noted following significant exposure, secondary to cellular hypoxia and seizures (Nelson & Robinson, 2002; ATSDR, 1998; Tanaka et al, 1999).
d) IBUPROFEN - Elevated anion gap metabolic acidosis has been reported in children and adults after severe overdose (>400 mg/kg). The minimal toxic dose appears to be at least 100 mg/kg (Wolfe, 1995; Le et al, 1994; Menzies et al, 1989; Hall & Rumack, 1988; Linden & Townsend, 1987; Lee & Finkler, 1986; Chelluri & Jastremski, 1986) .
e) IRON - Anion gap metabolic acidosis is a common early finding in significant ingestions. Severe metabolic acidosis may persist for days in severe overdoses (Schonfeld & Haftel, 1989; Wu et al, 1998). Toxicity is likely following ingestion of 60 mg/kg or more of elemental iron. Presenting symptoms within the first 6 hours of ingestion consist of nausea, vomiting, hematemesis, abdominal pain, and lethargy. These initial complaints are followed by a period of apparent recovery 6 to 12 hours post ingestion. The onset of shock and severe metabolic acidosis occurs 12 to 48 hours post ingestion. In severe intoxication, there is a rapid progression of drowsiness, coma, metabolic acidosis, and shock (Cheney et al, 1995; Proudfoot et al, 1986).
f) METHANOL - Patients intoxicated with methanol appear drunk and complain of abdominal pain, visual blurring, scotomata, or blindness. Eye findings include dilated pupils, nystagmus, retinal edema, and hyperemia or atrophy of the optic disc. Headache, dizziness, nausea, vomiting, bradycardia, seizures, and coma may also occur. Metabolic acidosis is classic, but may be delayed for 18 to 24 hours, or longer with concurrent ethanol ingestion. Severe intoxication may cause cerebral edema and brain death (Hantson et al, 2002; Radam et al, 2002; Polak et al, 2002; Girault et al, 1999; Jacobsen et al, 1982).
g) TRICYCLIC ANTIDEPRESSANTS - Significant metabolic acidosis may develop in patients with prolonged seizures or hypotension (Frommer et al, 1987).

Summary Of Exposure

1) In the setting of metabolic acidosis induced by a toxin, physical signs and symptoms may help to reveal the poison involved. Signs and symptoms are as follows:

a) VITAL SIGNS

b) CARDIOVASCULAR

a) QT prolongation - Hypocalcemia with QT prolongation may be observed following severe ethylene glycol poisoning.

c) DERMATOLOGIC

d) ENDOCRINE

e) FLUIDS/ELECTROLYTES

f) GASTROINTESTINAL

g) GENITOURINARY

h) HEENT

i) HEMATOLOGIC

j) HEPATIC

1) Hepatic dysfunction - Liver damage may be observed following acetaminophen, iron, or salicylate intoxications.

k) MUSCULOSKELETAL

l) NEUROLOGIC

m) RESPIRATORY

1) In the setting of metabolic acidosis induced by a toxin, hyperventilation (tachypnea, hyperpnea) is usually observed.

2) INDIVIDUAL AGENTS

a) ETHYLENE GLYCOL

b) IBUPROFEN

c) IRON

d) METHANOL

e) SALICYLATES

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) Visual abnormalities that develop during acute methanol intoxication may include blurred or double vision, changes in color perception, constricted visual fields, spots before the eyes, and sharply reduced visual acuity (Ingemansson, 1984; Kinney & Nauss, 1988). Mydriasis may indicate cyanide intoxication. In these patients, retinal arteries and veins that appear equally red on funduscopic examination suggest cyanide intoxication (Buchanan et al, 1976; Vogel et al, 1981). Blindness is possible with cyanide-induced damage to optic nerves and retina (Grant, 1986). Decreased visual acuity, mydriasis, and nystagmus may also indicate ethylene glycol intoxication (Vasavada et al, 2003; Buell et al, 1998).

3.4.4)

A) WITH POISONING/EXPOSURE

1) Tinnitus and hearing loss suggest salicylate overdose. It is often the first symptom reported and described as a continuous high pitch sound or mild loudness (Dart et al, 2000; Cazals, 2000; Dananberg, 1992; Anderson et al, 1976).

3.4.5)

A) WITH POISONING/EXPOSURE

1) Certain odors can help reveal the poison involved: cyanide (bitter almonds), hydrogen sulfide (rotten eggs) and toluene (paint or glue) (Dart et al, 2000).

Cardiovascular

3.5.2)

A) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) In severe cases of cyanide poisoning, tachycardia occurs early, followed by bradycardia (Dart et al, 2000; Vogel et al, 1981; Hall & Rumack, 1986a; Stewart, 1974).

B) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia develops in the majority of patients with theophylline poisoning. Tachycardia may also develop after ethylene glycol, salicylate, or iron poisoning. In severe cases of cyanide poisoning, tachycardia occurs early, followed by bradycardia (Dart et al, 2000; Dananberg, 1992; Vogel et al, 1981; Hall & Rumack, 1986a; Stewart, 1974). Sinus tachycardia has been reported in patients with hypotension or recurrent vomiting from biguanide toxicity (Larcan et al, 1979).

C) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Any agents that can cause hypotension may cause anion gap acidosis from lactic acid. Hypotension is common with severe iron overdose. Hypotension may occur with methanol, salicylate, or ethylene glycol intoxications. Severe metabolic acidosis may develop in patients with hypotension following tricyclic antidepressants or cocaine overdose. Following cyanide poisoning, hypertension may occur initially followed by hypotension (Dart et al, 2000; Frommer et al, 1987; Jonsson et al, 1983a; Stevens et al, 1994; Vogel et al, 1981; Hall & Rumack, 1986a; Stewart, 1974). Hypotension has been reported with severe phenformin poisoning (McGuinness & Talbert, 1993).

D) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Mild, transient hypertension is fairly common after theophylline overdose (Powell et al, 1993).
b) Hypertension - Following cyanide poisoning, hypertension may occur initially followed by hypotension (Dart et al, 2000; Vogel et al, 1981; Hall & Rumack, 1986a; Stewart, 1974).

1) Hypertension has been reported following ingestion of ethylene glycol (Eder et al, 1998; Walder & Tyler, 1994).

E) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Acidemia has been reported to contribute to conduction delays, dysrhythmias, and depressed myocardial contractility in patients with cocaine toxicity (Wang, 1999). Following severe salicylate intoxication, malignant dysrhythmias may occur abruptly (Dart et al, 2000).
b) Hypocalcemia with QT prolongation may be observed following severe ethylene glycol poisoning (Dart et al, 2000).

F) MYOCARDITIS

1) WITH POISONING/EXPOSURE

a) Myocarditis may occur rarely following severe ethylene glycol poisoning (Dart et al, 2000; Denning et al, 1988).

1) 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).

G) ACUTE CARDIAC PULMONARY EDEMA

1) WITH POISONING/EXPOSURE

a) Cardiogenic pulmonary edema may occur with severe ethylene glycol poisoning (Kaiser et al, 1997; Denning et al, 1988).

Respiratory

3.6.2)

A) RESPIRATORY FINDING

1) WITH POISONING/EXPOSURE

a) In the setting of metabolic acidosis induced by a toxin, hyperventilation (tachypnea, hyperpnea) is usually observed (Hoffman, 2002; Kilroy, 1997; Dananberg, 1992).
b) RESPIRATIONS, INCREASED - Hyperventilation is a compensatory response to metabolic acidosis. Alveolar ventilation is increased, with a resulting decrease in PCO2. Tachypnea also may result from direct stimulation of the respiratory center in acute salicylate ingestions (Kilroy, 1997; Hanna et al, 1995).
c) RESPIRATIONS, DECREASED - In the setting of a significant toxic ingestion (eg; methanol, ethylene glycol, paraldehyde), progressive CNS depression may result in respiratory depression, which could cause superimposed respiratory acidosis (Kilroy, 1997; Hanna et al, 1995).
d) RESPIRATIONS, KUSSMAUL - In severe metabolic acidosis, Kussmaul respirations (hyperpnea and tachypnea) are prominent and represent the respiratory response to the severe metabolic acidosis (Kilroy, 1997; Hanna et al, 1995).
e) Acute lung injury - Pulmonary edema may occur rarely following ethylene glycol or metformin/phenformin intoxications. In severe salicylate intoxication, acute lung injury and respiratory failure may occur (Dart et al, 2000; Leatherman & Schmitz, 1991; Chapman & Proudfoot, 1989). Respiratory tract irritation, acute lung injury, and cyanosis may occur with cyanide poisoning (Dart et al, 2000; Proctor et al, 1988; Finkel, 1983; Graham & Lamand, 1977).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) Transient lactic acidosis may be due to toxicant-induced severe agitation or seizure. Many patients with toxic ingestions (eg; salicylate, methanol, ethylene glycol) will present with an altered sensorium that may progress to coma (Dart et al, 2000).
b) CNS depression - Development of CNS depression and metabolic acidosis in the absence of liver failure has been reported early after severe acetaminophen overdose. Following ethylene glycol intoxication, CNS depression, ataxia, and slurred speech may be observed (Dart et al, 2000; Roth et al, 1999).
c) Coma - may be caused by ethylene glycol or methanol. Euphoria followed by deepening coma may be caused by ethylene glycol intoxication (Dart et al, 2000). Coma commonly develops, particularly after or between seizures episodes following isoniazid overdose (Panganiban et al, 2001; Martinjak-Dvorsek et al, 2000). Coma and metabolic acidosis in the absence of hepatotoxicity have been reported following a severe acetaminophen overdose (Steelman et al, 2004; Koulouris et al, 1999).
d) Seizures - Seizures are common with severe INH or theophylline overdose. Seizures may develop with salicylate, cocaine or methanol toxicity. Significant metabolic acidosis may develop in patients with prolonged seizures following tricyclic antidepressants overdose. Severe anion gap metabolic acidosis is common in patients who develop seizures after isoniazid overdose (Dart et al, 2000; Panganiban et al, 2001; Temmerman et al, 1999). Following hydrogen sulfide intoxication, transient lactic acidosis may be noted following significant exposure, secondary to cellular hypoxia and seizures (Dart et al, 2000).
e) CNS EFFECTS BY INDIVIDUAL AGENTS

1) CYANIDE - Following cyanide inhalation, headache, fatigue, confusion, seizures, and coma may be observed (Dart et al, 2000).
2) ETHANOL - Lactic or ketoacidosis may occur. Acidosis may occur due to metabolic disturbances, such as NADH overproduction, oxidation of ethanol, decreased lactate utilization, and inhibition of hepatic gluconeogenesis.

a) Acute lactic acidosis can produce a number of non-specific effects, including - fatigue, confusion, stupor, respiratory collapse, shock, and coma (Myerson & Rubin, 1992).

3) IRON - Following iron overdose, lethargy, seizures, encephalopathy and coma may be observed (Singhi et al, 2003; Dart et al, 2000).
4) ISONIAZID - Following isoniazid overdose, dizziness, slurred speech, stupor, hyperreflexia or areflexia, positive Babinski sign may be noted prior to seizures and coma. Seizures are often prolonged, recurrent and resistant to anticonvulsants (Dart et al, 2000; Orlowski et al, 1988; Siefkin et al, 1987).
5) METHANOL - Signs and symptoms of acute methanol intoxication may include lethargy, intoxication, confusion, muscular weakness, abdominal cramps with pain and tenderness, changes in the sensorium, lethargy and stupor. Hyperactivity of the deep tendon reflexes may also appear. Neurologic sighs symptoms of methanol intoxication may include general malaise, headache, dizziness, vertigo, neuritis, lethargy and weakness (Proctor & Hughes, 1978).
6) SALICYLATES - Lethargy, agitation, confusion, coma, seizures, cerebral edema, encephalopathy, asterixis, and focal neurologic findings may be observed following severe salicylate poisoning (Dart et al, 2000; Krause et al, 1992; Gittelman, 1993; McGuigan, 1987; Abdel-Magid & Ahmed, 1993; Anderson, 1981).

Gastrointestinal

3.8.2)

A) GASTROINTESTINAL SYMPTOM

1) WITH POISONING/EXPOSURE

a) Abdominal pain - Common with iron or salicylate overdose. May occur with methanol , paraldehyde, cyanide, or ethylene glycol toxicity.
b) Nausea and vomiting - Prominent with iron or theophylline poisoning. May develop with acetaminophen, cyanide salicylate, ethylene glycol, methanol, or paraldehyde toxicity.
c) Hematemesis - Common with severe iron poisoning; may also occur with ethylene glycol ingestion.
d) Pancreatitis - May occur with ethanol, ethylene glycol or methanol toxicity.
e) Almond odor - An odor of bitter almonds in gastric content or expired breath suggests cyanide poisoning.
f) Dry mucous membranes - May be noted in patients with metabolic acidosis and moderate to severe dehydration .
g) REFERENCES: (Singhi et al, 2003; Dart et al, 2000; Hantson & Mahieu, 2000; Cheney et al, 1995; Kruse, 1992; Proudfoot et al, 1986; Becker, 1983; Proudfoot, 1983; McGuigan, 1987; Parry & Wallach, 1974; Bonnischen & Maehly, 1966)

Hematologic

3.13.2)

A) HEMATOLOGY FINDING

1) WITH POISONING/EXPOSURE

a) Following salicylate poisoning, prolonged prothrombin and partial thromboplastin time, DIC, and inhibition of platelet aggregation may be observed. Increased prothrombin time or international normalized ratio may be observed following severe iron overdose (Singhi et al, 2003; Dart et al, 2000; Pond et al, 1993; Dananberg, 1992; Sainsbury, 1991).
b) Persistent coagulopathy, with increased prothrombin and partial thromboplastin times, has also been reported after severe methanol intoxications (Foster & Schoenhals, 1995).
c) Leukocytosis is common after isoniazid or iron overdose (Panganiban et al, 2001); it has also been reported less often following methanol intoxication (Singhi et al, 2003; Yu et al, 1995; Foster & Schoenhals, 1995).

Dermatologic

3.14.2)

A) SKIN FINDING

1) WITH POISONING/EXPOSURE

a) Moist skin and mucous membranes with significant fluid losses may occur following the overdose of sympathomimetic agents (eg; cocaine) (Hoffman, 2002).
b) Diaphoresis may be caused by beta-receptor agonist, salicylates or stimulants (Dart et al, 2000; McGuigan, 1987).

Musculoskeletal

3.15.2)

A) MUSCULOSKELETAL FINDING

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis may be caused by beta-receptor agonists or salicylates (rarely following severe intoxication). Myalgia with elevated creatine kinase may be observed following ethylene glycol intoxication. Paralysis may also occur (Dart et al, 2000; Montgomery et al, 1994; Leventhal et al, 1989; Verrilli et al, 1987; Parry & Wallach, 1974).

Endocrine

3.16.2)

A) ENDOCRINE FINDING

1) WITH POISONING/EXPOSURE

a) Hyperglycemia is common with iron and theophylline poisoning. Hyperglycemia may also develop with salicylate, or methanol toxicity. Hypoglycemia may occur following salicylate or (rarely) biguanide overdoses (Singhi et al, 2003; Dart et al, 2000; Williams et al, 1997; Thisted et al, 1987; Buchanan & Rabinowitz, 1974; Larcan et al, 1979; Luft et al, 1978).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor serum electrolytes, including magnesium, potassium and calcium, glucose and renal function. Repeat serum electrolytes in 1 to 2 hours and administer intravenous fluids.
B) If acidosis is worsening or if initial acidosis is severe obtain an arterial blood gas and lactate level.
C) Monitor vital signs and neurologic function. Initiate continuous cardiac monitoring and obtain an ECG.
D) Calculate anion gap:

E) Monitor ECG, vital signs, CBC with differential, serum glucose, osmolality, BUN, creatinine and urine output. Baseline PT, PTT, CBC and LFT's should be obtained in patients with severe acidosis.
F) An elevated osmolal gap increases the suspicion for toxic alcohol poisoning. A mnemonic for common causes of increased osmolal gap (MADGAS) has been reported: M-Mannitol; A-Alcohols (ethanol, ethylene glycol, isopropanol, methanol, propylene glycol); D-Diatrizoate; G-Glycerol; A-Acetone; S-Sorbitol. The absence of an osmolal gap DOES NOT rule out toxic alcohols poisoning. For example, as methanol and ethylene glycol are metabolized, the osmolar gap decreases and the anion gap increases.
G) Obtain abdominal x-ray to evaluate for material (iron, salicylates) in the gut and need for decontamination.
H) Following ethylene glycol intoxication, urine may show fluorescence under Wood's light, and urinalysis may show characteristic envelope-shaped calcium oxalate and hippurate crystals; however the absence of these findings DOES NOT rule out ethylene glycol poisoning.

4.1.2)

A) CYANIDE

1) Elevated anion gap metabolic acidosis and elevated serum lactate levels are frequently found in cyanide poisoning (Hall & Rumack, 1986; Vogel et al, 1981; Singh et al, 1989).

B) ETHYLENE GLYCOL

1) An ethylene glycol level must be specifically requested because most alcohol screens do not include ethylene glycol. Diagnosis depends on the clinical suspicion and detection of an increased anion gap acidosis. Increased osmolal gap is often but NOT ALWAYS present (Szerlip, 1999; Buell et al, 1998).
2) Increased anion gap metabolic acidosis results from the metabolism of ethylene glycol to acidic metabolites, predominantly glycolic acid (NOTE: Within the first few hours post-ingestion the absence of an increased anion gap metabolic acidosis does NOT rule out ethylene glycol poisoning) (Fall, 2000; Leon & Graeber, 1994; Heckering, 1987) .
3) Obtain a serum ethylene glycol concentration. If the determination of a serum ethylene glycol concentration will be delayed or if a serum ethylene glycol concentration can not be obtained then determine the plasma osmolarity using the freezing point depression method (NOTE: A normal osmolar gap does NOT rule out ethylene glycol poisoning). Obtain a blood ethanol level in patients who may have also ingested ethanol. Treatment with an alcohol dehydrogenase inhibitor (ethanol or fomepizole) should be initiated prior to laboratory confirmation of ethylene glycol intoxication in the setting of an increased anion gap metabolic acidosis without another obvious cause.

C) IRON

1) Laboratory evaluation reveals an increased anion gap acidosis in severe cases, hyperglycemia and leukocytosis may be present. Severity of toxicity is assessed by the severity of presenting symptoms, serum iron level is confirmatory but severe toxicity is unlikely in patients with a peak serum iron level below 350 micrograms/deciliter. The need for deferoxamine treatment is determined primarily by clinical signs and symptoms (persistent vomiting, diarrhea, lethargy, GI bleeding, hypotension, metabolic acidosis)(Proudfoot et al, 1986; Henretig et al, 1983).

D) METHANOL

1) The diagnosis is confirmed by an elevated serum methanol level.
2) Increased anion gap acidosis are typical but may be delayed for several hours after ingestion. Increased osmolal gap is also common but its absence DOES NOT rule out significant methanol poisoning. CNS depression and visual changes are also common (Fall, 2000)

a) LACTIC ACIDOSIS

1) A serum lactate level of at least 2 mEq/L is necessary for diagnosis of this condition (Adrogue & Madias, 1998; Aduen et al, 1994; Oliva, 1970).

a) Mild elevations in serum lactate concentrations are usually self-limited, resolve without therapy, and need not be pathologic (eg; secondary to exercise). Considerable evidence is available demonstrating an inverse relationship between hyperlactatemia and survival (Abramson et al, 1993; Rashkin et al, 1985; Roumen et al, 1993).
b) In general, pH less than 7.2 identifies conditions with significant elevations of serum lactate. Persistently high or progressively rising serum lactate concentrations greater than 4 mmol/L may indicate a poor prognosis (Aduen et al, 1994).
c) An elevated anion gap acidosis occurs with build-up of lactate as an unmeasured anion. The decrement in bicarbonate is roughly equal to the increment in the anion gap. Thus, lactic acidosis results in an anion gap metabolic acidosis.
d) Elevation serum lactate levels have been reported in patients with ethylene glycol poisoning due to laboratory interference (Woo et al, 2003). An elevated serum lactate alone should NOT be used to exclude the diagnosis of ethylene glycol poisoning (Kruse, 1992).

E) SALICYLATES

1) A salicylate level will help to confirm the diagnosis, serial levels should be followed every 2 hours (Chan et al, 1995).

4.1.3)

A) ETHYLENE GLYCOL

1) Urine may show fluorescence under Wood's light, and urinalysis may show characteristic envelope-shaped calcium oxalate and hippurate crystals; however the absence of these findings DOES NOT exclude ethylene glycol poisoning (Fall, 2000; Szerlip, 1999; Buell et al, 1998; Cadnapaphornchai et al, 1981).

4.1.4)

A) OTHER

1) CALCULATIONS

a) ANION GAP - The difference between unmeasured anions and unmeasured cations (normal 12 mEq/L; range 7 to 16 mEq/L) (Fall, 2000):

Anion gap = (Na+) - (Cl-) - (HCO3-)

b) Calculate anion gap (Dart et al, 2000):

1) Anion gap greater than 19 mEq/L, if the likely cause is known (eg; seizures), repeat measurement in 1 to 2 hours, if the cause is unknown or osmolal gap is increased, obtain serum lactate, methanol, ethylene glycol, iron, salicylate levels. Cyanide levels may be useful.
2) Anion gap between 16 to 19 mEq/L, repeat measurement in 2 hours.

a) TOXIC CAUSES OF A HIGH ANION GAP METABOLIC ACIDOSIS

1) Carbon monoxide
2) Cyanide
3) Ethylene glycol
4) Hydrogen sulfide
5) Isoniazid
6) Iron
7) Metformin
8) Methanol
9) Paraldehyde
10) Phenformin
11) Propylene glycol (large doses)
12) Salicylates
13) Sulfur (inorganic)
14) Theophylline
15) Toluene (occasionally increased, usually normal)

1) REFERENCES - (Kraut & Madias, 2007; Seifert, 2004; Hoffman, 2002; Dart et al, 2000)

b) TOXIC CAUSES OF A NORMAL ANION GAP METABOLIC ACIDOSIS

1) Acetazolamide
2) Acids (ammonium chloride; arginine hydrochloride; calcium chloride; hydrochloric acid; lysine hydrochloride)
3) Carbonic anhydrase inhibitors
4) Cholestyramine
5) Magnesium chloride
6) Sulfamylon
7) Toluene
8) Topiramate

1) REFERENCES - (Kraut & Madias, 2007; Seifert, 2004; Hoffman, 2002)

c) OSMOLAL GAP - The difference between measured serum osmolarity and calculated osmolarity (normal = 10 to 20 mOsm/L). The osmolal gap shows the presence of an unmeasured solute. Agents with a low molecular weight that can achieve high serum levels (eg; methanol, ethylene glycol, ethanol, isopropyl alcohol) can increase serum osmolarity. In addition to high-anion-gap metabolic acidosis, both methanol and ethylene glycol can cause increase osmolal gap (Fall, 2000).

Osmole gap = measured serum osm - calculated osm

d) A mnemonic for common causes of increased osmolal gap (MADGAS) has been reported: M-Mannitol; A-Alcohols (ethanol, ethylene glycol, isopropanol, methanol, propylene glycol); D-Diatrizoate; G-Glycerol; A-Acetone; S-Sorbitol . The absence of an osmolal gap DOES NOT rule out toxic alcohols poisoning (Seifert, 2004).
e) CALCULATED OSMOLARITY (Fall, 2000)

1) Calculated osm (mOsm/L) = (2 x Na+) + (glucose/18) + (blood urea nitrogen/2.8) = 275 to 290 mOsm/L

f) Hypertonic hyponatremia can cause an erroneous elevation in the calculated osmolal gap. In the setting of hyperglycemia, the serum sodium concentration is reduced by 1.6 mEq/L for every 100 mg/dL increase in the serum glucose above 100 mg/dL. The serum sodium concentration should be adjusted to make up for this when calculating the osmolal gap, or the gap will be erroneously elevated by 3.2 mOsm for each 100 mg/dL increase in the serum glucose (Sztajnkrycer & Scaglione, 2005).
g) Ethanol - Elevated blood ethanol level will increase the osmolarity. To correct for the presence of ethanol, divide the blood ethanol level by 4.6 and add to the rest of the equation.

1) Calculated osm (mOsm/L) = (2 x Na+) + (glucose/18) + (blood urea nitrogen/2.8) + ethanol/4.6

Radiographic Studies

1) Obtain abdominal x-ray to evaluate for material (iron, salicylates) in the gut and need for decontamination. In iron overdose, as dissolution occurs, a diffuse density rather than discrete tablets may be seen.
2) Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981; Ng et al, 1979). A positive abdominal radiograph is more likely to be associated with significant symptoms than a negative x-ray (James, 1970).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) The decision to admit a patient with metabolic acidosis depends on the severity of the underlying condition and the ease with which the acidosis can be controlled and corrected in the ED.
B) In general, most patients with significant metabolic acidosis will require admission to the hospital.
C) Patients with ongoing metabolic acidosis associated with depressed cardiac function, circulatory collapse, or dysrhythmias require admission to the intensive care unit.

Monitoring

Oral Exposure

6.5.2)

A) ACTIVATED CHARCOAL

1) Administer activated charcoal if metabolic acidosis may be secondary to toxic ingestion.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) Treatment is symptomatic and supportive. Some causes of severe metabolic acidosis (pH less than 7.2) may require therapy with sodium bicarbonate.
2) AIRWAY MANAGEMENT: Endotracheal intubation may be required in patients with severe acidosis, particularly those with altered mentation or hemodynamic instability. Extreme care must be taken not to worsen acidemia by underventilation of the patient.
3) IV FLUID: For moderate to severe volume depletion:

a) ADULTS: 1 to 2 L NS over 30 to 45 minutes; repeat a bolus of 0.5 to 1 L over 30 to 45 minutes if response is poor.
b) CHILDREN: 20 mL/kg IV over 30 to 45 minutes; repeat a bolus of 10 mL/kg over 30 to 45 minutes if response is poor.

4) Treatment of acidosis following methanol or ethylene glycol toxicity requires blockade of alcohol dehydrogenase and dialysis as well as supportive and adjunctive measures. To treat salicylates poisoning, increasing elimination by urinary ion trapping and dialysis should be considered (Seifert, 2004).

B) SODIUM BICARBONATE

1) SODIUM BICARBONATE - CAUTION: Should only be used if the acidemia is purely or primarily metabolic (respiratory acidosis should be treated by hyperventilation) or if the acidemia is not readily reversible (eg, not post-seizure).

a) LIFE-THREATENING METABOLIC ACIDOSIS (eg; prolonged cardiac arrest, pH less than 7.0, HCO3 less than 5 mEq/L): ADULTS: 1 to 2 mEq/kg IV bolus (typically 1 to 2 ampules in adults); monitor blood pH (arterial or mixed venous) every 10 minutes to guide further therapy.
b) SEVERE METABOLIC ACIDOSIS (eg, pH less than 7.2, HCO3 less than 8 mEq/L):

1) NOTE: No universally appropriate dose exists.
2) SODIUM BICARBONATE DOSING FORMULA: Desired change in HCO3 (mEq/L) X patient weight (kg) X volume of distribution (assume 0.5 L/kg) = mEq NaHCO3 required. Infuse over minutes to hours. Check pH 30 minutes after infusion. Target HCO3 of 8 mEq/L to avoid overshoot alkalosis.

C) SEIZURE

1) Seizures - Seizures may indicate salicylates, isoniazid, cocaine or methanol toxicity. Significant metabolic acidosis may develop in patients with prolonged seizures of any etiology. Severe anion gap metabolic acidosis is common in patients who develop seizures after isoniazid overdose. Following hydrogen sulfide intoxication, transient lactic acidosis may be noted following significant exposure, secondary to cellular hypoxia and seizures. Treat seizures aggressively to avoid worsening acidemia.
2) SUMMARY

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).

3) DIAZEPAM

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 .

4) NO INTRAVENOUS ACCESS

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).

5) LORAZEPAM

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, 2010; Chin et al, 2008).

6) PHENOBARBITAL

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).

7) OTHER AGENTS

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):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

8) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

D) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

E) POISONING

1) GENERAL

a) The following is a list of potential substances that may produce acidosis along with the expected monitoring and treatment.

2) ETHYLENE GLYCOL

a) SODIUM BICARBONATE

b) FOMEPIZOLE

1) SUMMARY: Fomepizole, a specific antagonist of alcohol dehydrogenase, has been demonstrated to be highly effective in the treatment of ethylene glycol poisoning (Battistella, 2002; Druteika et al, 2002; Sivilotti et al, 2000; Borron et al, 1999; Brent et al, 1999). Fomepizole has not been approved for use in children.
2) INDICATIONS FOR USING FOMEPIZOLE: The following guidelines were developed by the American Academy of Clinical Toxicology (Barceloux et al, 1999):

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

3) AVAILABILITY

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).

4) DOSE

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).

c) ETHANOL THERAPY

1) INDICATIONS

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

1) Fomepizole unavailable
2) Hypersensitivity to fomepizole

2) PREPARATION

a) CONCENTRATIONS AVAILABLE (V/V)

1) In the United States, 5% or 10% (V/V) ethanol in 5% dextrose for intravenous infusion is no longer available commercially (Howland, 2011). Ethanol 10% (V/V) contains approximately 0.08 gram ethanol/mL.
2) ABSOLUTE ETHANOL or dehydrated ethanol, USP contains no less than 99.5% volume/volume or 99.2% weight/weight of ethanol with a specific gravity of not more than 0.7964 at 15.56 degrees C. Absolute ethanol is hygroscopic (absorbs water from the atmosphere) and when exposed to air may be less than 99.5% ethanol by volume (S Sweetman , 2002).

b) PREPARATION OF 10% V/V ETHANOL IN A 5% DEXTROSE SOLUTION

1) A 10% (V/V) solution can be prepared by the following method (Howland, 2011):

a) If available, use sterile ethanol USP (absolute ethanol). Add 55 mL of the absolute ethanol to 500 mL of 5% dextrose in water for infusion. This yields a total volume of 555 mL. This produces an approximate solution of 10% ethanol in 5% dextrose for intravenous infusion (Howland, 2011).

c) PRECAUTIONS

1) HYPOGLYCEMIA

a) Hypoglycemia may occur, especially in children. Monitor blood glucose frequently (Howland, 2011; Barceloux et al, 2002).

2) CONCURRENT ETHANOL

a) If the patient concurrently has ingested ethanol, then the ethanol loading dose must be modified so that the blood ethanol level does not exceed 100 to 150 mg/dL (Barceloux et al, 2002).

3) DISULFIRAM

a) Fomepizole is preferred as an alcohol dehydrogenase inhibitor in patients taking disulfiram. If fomepizole is not available, ethanol therapy should be initiated in those patients with signs or symptoms of severe poisoning (acidemia, toxic blood level) despite a history of recent disulfiram (Antabuse(R)) ingestion.
b) The risk of not treating these patients is excessive, especially if hemodialysis is not immediately available.
c) Administer the ethanol cautiously with special attention to the severity of the "Antabuse reaction" (flushing, sweating, severe hypotension, and cardiac dysrhythmias).
d) Be prepared to treat hypotension with fluids and pressor agents (norepinephrine or dopamine). Monitor ECG and vital signs carefully. Hemodialysis should be performed as soon as adequate vital signs are established, and every effort should be made to obtain fomepizole.

d) LOADING DOSE

1) INTRAVENOUS LOADING DOSE

a) Ethanol is given to maintain a patient’s serum ethanol concentration at 100 to 150 mg/dL. This can be accomplished by using a 5% or 10% ethanol solution administered intravenously through a central line (10% ethanol is generally preferred due to the large volumes required for 5%). 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. Begin the maintenance infusion as soon as the loading dose is infused (Howland, 2011).

2) ORAL LOADING DOSE

a) 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 concentrations. The loading dose is 0.8 g/kg (4 mL/kg) of 20% (40 proof) ethanol diluted in juice administered orally or via a nasogastric tube(Howland, 2011).

e) MAINTENANCE DOSE

1) MAINTENANCE DOSE

a) Maintain a serum ethanol concentration of 100 to 150 mg/dL. Intravenous administration is preferred, but oral ethanol may be used if intravenous is unavailable(Howland, 2011; Barceloux et al, 2002).

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.8 to 1.3 mL/kg/hr)
Chronic drinker	150 mg/kg/hr (1.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL*
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.4 to 0.7 mL/kg/hr) orally or via nasogastric tube
Chronic drinker	150 mg/kg/hr (0.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

2) MAINTENANCE DOSE/ETHANOL DIALYSATE

a) During hemodialysis maintenance doses of ethanol should be increased in accordance with the recommendation given below, or ethanol should be added to the dialysate to achieve a concentration of 100 milligrams/deciliter (Pappas & Silverman, 1982).

3) MAINTENANCE DOSE/ETHANOL-FREE DIALYSATE

a) Maintain a serum ethanol concentration of 100 to 150 mg/dL(Howland, 2011; Barceloux et al, 2002):

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL - 250 to 350 mg/kg/hr (2.5 to 3.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL* - 250 to 350 mg/kg/hr (1.3 to 1.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

b) Variations in blood flow rate and the ethanol extraction efficiency of the dialyzer will affect the dialysance(McCoy et al, 1979).
c) If the ethanol dialysance ((CL)D) is calculated, the infusion rate during dialysis (Kod) can be individually adjusted using the following expression (McCoy et al, 1979):

Kod = Vmax x   Cp   + (CL)D x Cp
             -------
             Km + Cp
where Cp = desired blood ethanol level
*  Vmax = 175 mg/kg/hr in chronic ethanol drinkers 
*  Vmax = 75 mg/kg/hr in non-chronic drinkers
*  Km = 13.8 mg/dL

f) PEDIATRIC DOSE

1) 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).
2) 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) Monitor blood glucose and mental status frequently during therapy (Howland, 2011). Ethanol-induced hypoglycemia is more common in children (Barceloux et al, 2002) and children may develop more significant CNS depression.

g) MONITORING PARAMETERS

1) 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.

d) THIAMINE/PYRIDOXINE

1) ADMINISTER THIAMINE AND PYRIDOXINE: 100 mg IV daily.

3) IRON

a) Whole bowel irrigation with polyethylene glycol is of theoretical value in the management of patients who have ingested substantial amounts of iron that is confirmed radiographically because of the high morbidity and mortality of this poisoning and a lack of other options for gastrointestinal decontamination.

1) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

a) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

2) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
3) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
4) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

c) DEFEROXAMINE: Indicated for systemic signs of iron toxicity (acidosis, hypotension; usually associated with serum iron greater than 350 mcg/mL) 15 mg/kg/hour IV infusion. Duration of therapy variable; usually 8 to 12 hours for moderate, and up to 24 hours for severe toxicity.
d) Refer to IRON management for more information.

4) ISONIAZID

a) PYRIDOXINE: If INH overdose (acute ingestion in excess of 80 mg/kg) is suspected in an asymptomatic patient administer IV pyridoxine; DOSE: administer an amount of pyridoxine equivalent to the estimated amount of INH ingested. If amount INH ingested is unknown, administer 5 grams pyridoxine IV over 30 minutes. Repeat dose if needed for seizures.
b) SEIZURES: Initial treatment should consist of pyridoxine as above as well as benzodiazepines and/or barbiturates. Diazepam IV bolus (DOSE: ADULT: 5 to 10 mg initially which may be repeated every 15 minutes PRN. CHILD: 0.25 to 0.4 mg/kg dose up to 10 mg/dose) or lorazepam IV bolus (DOSE: ADULT: 2 to 4 mg; CHILD: 0.05 to 0.1 mg/kg).

1) If seizures are uncontrollable or recur, give phenobarbital.

c) ACIDOSIS: Large doses of sodium bicarbonate may be necessary to correct severe acidosis. However, since the acidosis is secondary to seizures, control of seizures with sufficient doses of IV pyridoxine and diazepam will diminish the severity of the associated acidosis.

1) Severe initial acidosis or acidosis unresolved by IV pyridoxine and diazepam administration should be treated with IV sodium bicarbonate. A reasonable initial dose of bicarbonate is 1 to 3 mEq/kg. Monitor blood gasses to guide bicarbonate therapy. Up to 100 to 200 mEq of bicarbonate in the first hour in an adult may be needed. Children have required up to 3 mEq/kg/hr during the first few hours.
2) IF LARGER DOSES ARE NEEDED, monitor serum sodium carefully to avoid hypernatremia and fluid overload.

5) METFORMIN AND RELATED AGENTS

a) Although hypoglycemia does not usually occur with metformin alone, even in overdosage, it may occur if given concomitantly with alcohol or other hypoglycemic agents.

1) HYPOGLYCEMIA should be treated with IV dextrose. (ADULT: Administer 50 mL of 50% dextrose solution; CHILD - Administer 0.5 gm/kg/dose).

b) ACIDOSIS: Untreated lactic acidosis may result in confusion, hypotension, coma and circulatory collapse. Severe metabolic acidosis (arterial pH less than 7.2) should be corrected with IV sodium bicarbonate (a reasonable starting dose is 1 to 2 mEq/kg). Monitor blood gases to guide bicarbonate therapy.
c) INSULIN/DEXTROSE: Therapy with intravenous insulin and glucose has been associated with a lower mortality rate than therapy with bicarbonate or dialysis in one case series.

6) METHANOL

a) Monitor arterial blood gases, electrolytes, acid-base status, CBC, and renal function tests. Monitor blood levels of methanol, ethanol, concomitant ingestants, and formate if available.
b) ACIDOSIS: May not develop until 18 to 48 hours post ingestion. Temporize with IV sodium bicarbonate; monitor arterial blood gases to guide dosing. Patients with metabolic acidosis need antidotal therapy (fomepizole or ethanol) and hemodialysis.
c) FOMEPIZOLE: Specific alcohol dehydrogenase antagonist. Fomepizole (Antizole(R); 4-MP) is currently approved and available in the United States for the treatment of methanol poisoning (Prod Info ANTIZOL(R) IV injection, 2006).

1) INDICATION: Fomepizole, a specific antagonist of alcohol dehydrogenase, is approved for the treatment of methanol and ethylene glycol poisoning. It had previously been used in experimental animals and in humans and showed an apparent low level of toxicity and ability to replace ethanol as treatment for methanol poisoning (Brent et al, 2001; Prod Info ANTIZOL(R) IV injection, 2006; Megarbane et al, 2001; Burns et al, 1997; Brent et al, 1997; Blomstrand et al, 1980).
2) Dosing should be started immediately on suspicion of methanol ingestion based on patient history or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, OR a documented methanol serum concentration of greater than 20 mg/dL (Prod Info ANTIZOL(R) IV injection, 2006).

a) Give fomepizole loading dose of 15 mg/kg, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until methanol concentrations are undetectable or have been reduced below 20 mg/dL and the patient is asymptomatic with normal pH. Administer all doses as a slow intravenous infusion over 30 minutes (Prod Info ANTIZOL(R) IV injection, 2006).
b) Plasma level of fomepizole necessary to inhibit alcohol dehydrogenase is approximately 0.8 mcg/mL (Brent et al, 2001). Under fomepizole treatment, the decay of methanol follows first-order kinetics, with a plasma elimination half-life of methanol reported as 48 to 54 hours (Bekka et al, 2001; Brent et al, 2001).

d) ETHANOL: Partially inhibits the formation of toxic metabolites.

1) INDICATIONS

a) Ethanol therapy must be considered in any of the following situations (Barceloux et al, 2002):

1) Documented plasma methanol concentration greater than 20 mg/dL (greater than 200 mg/L);
2) Documented recent history of ingesting toxic amounts of methanol and osmolal gap greater than 10 mOsm/L;
3) History or strong clinical suspicion of methanol poisoning and at least 2 of the following criterion: arterial pH less than 7.3; serum bicarbonate less than 20 mEq/L; osmolol gap greater than 10 mOsm/L.

2) PREPARATION

a) CONCENTRATIONS AVAILABLE (V/V)

b) PREPARATION OF 10% V/V ETHANOL IN A 5% DEXTROSE SOLUTION

1) A 10% (V/V) solution can be prepared by the following method (Howland, 2011):

3) PRECAUTIONS

a) HYPOGLYCEMIA

1) Hypoglycemia may occur, especially in children. Monitor blood glucose frequently (Howland, 2011; Barceloux et al, 2002).

b) CONCURRENT ETHANOL

1) If the patient concurrently has ingested ethanol, then the ethanol loading dose must be modified so that the blood ethanol level does not exceed 100 to 150 mg/dL (Barceloux et al, 2002).

c) DISULFIRAM

1) Fomepizole is preferred as an alcohol dehydrogenase inhibitor in patients taking disulfiram. If fomepizole is not available, ethanol therapy should be initiated in those patients with signs or symptoms of severe poisoning (acidemia, toxic blood level) despite a history of recent disulfiram (Antabuse(R)) ingestion.
2) The risk of not treating these patients is excessive, especially if hemodialysis is not immediately available.
3) Administer the ethanol cautiously with special attention to the severity of the "Antabuse reaction" (flushing, sweating, severe hypotension, and cardiac dysrhythmias).
4) Be prepared to treat hypotension with fluids and pressor agents (norepinephrine or dopamine). Monitor ECG and vital signs carefully. Hemodialysis should be performed as soon as adequate vital signs are established, and every effort should be made to obtain fomepizole.

4) LOADING DOSE

a) INTRAVENOUS LOADING DOSE

1) Ethanol is given to maintain a patient’s serum ethanol concentration at 100 to 150 mg/dL. This can be accomplished by using a 5% or 10% ethanol solution administered intravenously through a central line (10% ethanol is generally preferred due to the large volumes required for 5%). 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. Begin the maintenance infusion as soon as the loading dose is infused (Howland, 2011).

b) ORAL LOADING DOSE

1) 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 concentrations. The loading dose is 0.8 g/kg (4 mL/kg) of 20% (40 proof) ethanol diluted in juice administered orally or via a nasogastric tube(Howland, 2011).

5) MAINTENANCE DOSE

a) MAINTENANCE DOSE

1) Maintain a serum ethanol concentration of 100 to 150 mg/dL. Intravenous administration is preferred, but oral ethanol may be used if intravenous is unavailable(Howland, 2011; Barceloux et al, 2002).

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.8 to 1.3 mL/kg/hr)
Chronic drinker	150 mg/kg/hr (1.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL*
Non-drinker to moderate drinker	80 to 130 mg/kg/hr (0.4 to 0.7 mL/kg/hr) orally or via nasogastric tube
Chronic drinker	150 mg/kg/hr (0.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

b) MAINTENANCE DOSE/ETHANOL DIALYSATE

1) During hemodialysis maintenance doses of ethanol should be increased in accordance with the recommendation given below, or ethanol should be added to the dialysate to achieve a concentration of 100 milligrams/deciliter (Pappas & Silverman, 1982).

c) MAINTENANCE DOSE/ETHANOL-FREE DIALYSATE

1) Maintain a serum ethanol concentration of 100 to 150 mg/dL(Howland, 2011; Barceloux et al, 2002):

INTRAVENOUS ADMINISTRATION OF 10% ETHANOL - 250 to 350 mg/kg/hr (2.5 to 3.5 mL/kg/hr)
ORAL ADMINISTRATION OF 20% (40 proof) ETHANOL* - 250 to 350 mg/kg/hr (1.3 to 1.8 mL/kg/hr) orally or via nasogastric tube
*Diluted in juice

2) Variations in blood flow rate and the ethanol extraction efficiency of the dialyzer will affect the dialysance(McCoy et al, 1979).
3) If the ethanol dialysance ((CL)D) is calculated, the infusion rate during dialysis (Kod) can be individually adjusted using the following expression (McCoy et al, 1979):

Kod = Vmax x   Cp   + (CL)D x Cp
             -------
             Km + Cp
where Cp = desired blood ethanol level
*  Vmax = 175 mg/kg/hr in chronic ethanol drinkers 
*  Vmax = 75 mg/kg/hr in non-chronic drinkers
*  Km = 13.8 mg/dL

6) PEDIATRIC DOSE

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).

1) Monitor blood glucose and mental status frequently during therapy (Howland, 2011). Ethanol-induced hypoglycemia is more common in children (Barceloux et al, 2002) and children may develop more significant CNS depression.

c) PEDIATRIC ADVERSE EFFECTS: In a retrospective review of 60 pediatric patients receiving oral or IV ethanol, the rate of clinically important adverse effects due to ethanol was low. Mild glycemia, drowsiness, 3% of patients with hypotension, and 1 patient with erosive gastritis were reported. Good prognosis was reported in children treated with ethanol in spite of a wide variation in ethanol levels (Roy et al, 2001; Roy et al, 2001a).

7) MONITORING PARAMETERS

a) ETHANOL CONCENTRATION

1) Blood ethanol concentrations should be determined every 1 to 2 hours until concentrations are maintained within the therapeutic range (100 - 150 mg/dL). Thereafter concentrations should be monitored every 2 to 4 hours. Any change in infusion rate will require monitoring every 1 to 2 hours until the therapeutic range is reached and maintained (Barceloux et al, 2002).

b) ADDITIONAL MONITORING

1) Monitor serum electrolytes and blood glucose, monitor for CNS depression (Howland, 2011).

e) LEUCOVORIN/FOLIC ACID: If symptomatic - IV leucovorin 1 mg/kg once (up to 50 mg/dose) followed by IV folic acid 1 mg/kg (up to 50 mg/dose) every 4 hours for 6 doses.
f) Prognosis should be based upon the clinical presentation, severity of acidosis, blood methanol and formate levels (if available), and response to treatment.

7) SALICYLATES

a) Correct dehydration with 0.9% NaCl at a rate of 10 to 20 mL/kg/hr over 1 hour until a good urine flow is obtained. Do not overhydrate and follow pulmonary status carefully. Potassium should be added to subsequent fluid. Monitor urine output, urine pH, and serum potassium.
b) Alkalinize the urine in patients with clinical or laboratory evidence of toxicity. Infuse a solution of 132 mEq/L sodium bicarbonate (3 amps) in 1 liter D5W at 1.5 to 2 times maintenance fluid requirements to achieve a urine pH greater than 7.5. Additional KCl (20 to 40 mEq/L) may be required. Even higher concentrations of potassium may be required to achieve an alkaline urine.
c) ACIDOSIS: Administer IV NaHCO3. Correct pH to 7.40; even mild acidemia can facilitate movement of salicylate into the brain. Monitor ABGs.
d) HYPERTHERMIA: Should be treated with external cooling.

Enhanced Elimination

1) Indicated for methanol or ethylene glycol poisoning with acidosis. Also indicated for severe salicylate or theophylline poisoning.
2) ETHYLENE GLYCOL

a) The American Academy of Clinical Toxicologists have developed the following guidelines as indications for hemodialysis (Barceloux et al, 1999):

1) Severe metabolic acidosis (<7.25-7.3) unresponsive to therapy
2) Renal failure
3) Blood EG 50 mg/dL (8.06 mm/L) unless fomepizole is being given and patient is asymptomatic with normal arterial pH
4) Deteriorating vital signs despite intensive supportive therapy
5) Electrolyte imbalances unresponsive to conventional therapy

1) Porter et al (2001) recommend another criterion for initiation of hemodialysis to be serum glycolic acid level >8 mmol/L. In a retrospective review of 41 admissions for EG poisoning, they found that patients with a glycolic acid of <8 mmol/L did not develop acute renal failure regardless of EG concentration, if adequate dosing with fomepizole or ethanol is maintained. In the absence of glycolic acid concentration, an anion gap >20 mmol/L or pH <7.3 predicts acute renal failure. Some of these patients were treated with hemodialysis, which may have prevented the development of renal failure in some patients.

3) METFORMIN AND RELATED AGENTS

a) HEMODIALYSIS MAY BE USEFUL in restoring acid/base, fluid and electrolyte balance and should be considered in those patients who continue to deteriorate despite conventional therapy, or in patients with severe renal impairment or failure.

4) ISONIAZID

a) HEMODIALYSIS: Hemodialysis should be considered in those patients unresponsive to anticonvulsants, pyridoxine and bicarbonate therapy.

5) METHANOL

a) Hemodialysis is highly effective at removing methanol (McCoy et al, 1979; Girault et al, 1999) but FOMEPIZOLE or ETHANOL therapy should be continued during dialysis. Peak blood methanol concentration greater than 50 milligrams/deciliter (15 millimoles/liter), severe acidosis regardless of the blood methanol level, severe acid-base and or fluid-electrolyte disturbances despite conventional therapy, renal failure, and visual symptoms are indications for dialysis (Prod Info Antizol(R), fomepizole injection, 2000; Vogt et al, 1993). Increase ethanol infusion during dialysis; and increase fomepizole dosing to every 4 hours during hemodialysis.

1) Because chronic alcoholics who have ingested methanol may be at higher risk for severe sequelae or death despite ethanol infusion, some authors have advocated hemodialysis for these patients regardless of peak methanol levels (Roeggla et al, 1993).

6) SALICYLATES

a) HEMODIALYSIS INDICATIONS: Patients with high blood salicylate levels (>80 to 100 mg/dL after acute overdose, >50 to 60 mg/dL after chronic overdose), or refractory acidosis, inability to maintain appropriate respiratory alkalosis, acidemia, CNS toxicity (seizures, mental status depression, persistent confusion, coma, cerebral edema), progressive clinical deterioration despite appropriate therapy, pulmonary edema, or renal failure are candidates for hemodialysis. Clinical signs and symptoms are more important than serum salicylate levels in determining the need for hemodialysis. Consider dialysis at lower serum concentrations for patients with subacute on chronic or chronic salicylism.

7) A patient with high anion gap metabolic acidosis following the infusion of aminocaproic acid, improved briefly with sessions of hemodialysis. Following the discontinuation of aminocaproic acid, she improved completely (Budris et al, 1999).

Abstracts

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Death has occurred after ingestion of about 15 mL of 40 percent methanol (Bennett, 1953).

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) METHANOL

a) FATAL - A plasma methanol concentration of about 40 milligrams/100 milliliters (12 millimoles/liter) of blood (= 40 milligrams percent = 40 milligrams/deciliter) has been fatal in humans, but there is a wide variation in individual sensitivity (Kahn & Blum, 1979).

1) Thus, deaths have been reported with blood methanol levels of 19.4 (6 millimoles/liter), 27.7 (8.6 millimoles/liter), and 27.5 (8.6 millimoles/liter) milligrams/100 milliliters at 48, 50 and 50 hours, respectively, after ingestion. In most of these cases it is not known what the true peak methanol levels were.

b) PEDIATRIC - As a rough estimate, ingestion of 1.5 milliliters of 100 percent methanol by a child weighing 10 kilograms (assuming a volume of distribution of 0.6 liter/kilogram) would produce a potential maximum peak plasma level of 20 milligrams/deciliter, a level at which institution of alcohol dehydrogenase blockers would be considered.

1) In the same child, an average swallow (2 to 8 milliliters) would produce a potential maximum peak level of 26 to 105 milligrams/deciliter.

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

269)

270)

271)

272)

273)

274)

275)

276)

277)

278)

279)

280)

281)

282)

283)

284)

285)

286)

287)

288)

289)

290)

291)

292)

293)

294)

295)

296)

297)

298)

299)

300)

FeedBack

CLINICAL APPROACH TO TOXIN-INDUCED METABOLIC ACIDOSIS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Hepatic

Genitourinary

Acid-Base

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Monitoring Parameters Levels

Radiographic Studies

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

General Bibliography