6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) ACTIVATED CHARCOAL 1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002). 1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
2) 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).
6.5.2) PREVENTION OF ABSORPTION
A) ACTIVATED CHARCOAL 1) 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.
2) 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) TREATMENT
A) SUPPORT 1) MANAGEMENT OF MILD TO MODERATE TOXICITY a) Treatment is symptomatic and supportive.
2) MANAGEMENT OF SEVERE TOXICITY a) Treatment is symptomatic and supportive. Methanol toxicity may occur in patients with significant exposure to methoxy derivatives. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe metabolic acidosis (pH less than 7.1) with IV sodium bicarbonate. Ethanol or fomepizole may be give in patients where there is a concern for significant methanol toxicity. In addition, folic acid or leucovorin can be given to help encourage metabolism of formic acid to carbon dioxide and water.
B) MONITORING OF PATIENT 1) Monitor electrolytes, renal function, blood gases, ECG, vital signs, and mental status in patients with significant exposure to methoxy alkoxysilanes.
2) Obtain chest X-ray in patients with significant respiratory symptoms.
3) Obtain both methanol and ethanol blood levels. Determine plasma osmolarity (using freezing point depression) if methanol level is not readily available. Methanol, like ethanol, will cause an osmolar gap.
C) SEIZURE 1) 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).
2) 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 .
3) 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).
4) 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, 2009; Chin et al, 2008).
5) 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).
6) 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).
D) ACIDOSIS 1) Significant acidosis may not develop until 18 to 48 hours following ingestion and should be treated with sodium bicarbonate with close monitoring of arterial blood gases. Severe acidosis may initially be treated with 1 to 2 mEq/kg bicarbonate. Bicarbonate should be titrated to normalize arterial pH.
2) Monitor arterial blood gas as a guide to assess the severity of intoxication. Severe anion gap metabolic acidosis is common. A pH of less than 7.0 and bicarbonate less than 10 mEq/L are not uncommon following severe intoxication. The onset of acidosis may be delayed for 18 to 48 hours, especially if ethanol has also been ingested. Therefore, THE ABSENCE OF ACIDOSIS DOES NOT RULE OUT A SIGNIFICANT METHANOL INGESTION.
3) Acidosis may be refractory to treatment, especially if the absorption of methanol is ongoing or if ethanol, fomepizole, or both has not been administered.
4) Sodium bicarbonate should be administered to correct acidosis (ADULT: 1 to 2 mEq/kg; CHILDREN: 1 to 2 mEq/kg) titrated to correct arterial pH.
5) In a retrospective series of 32 patients who survived severe methanol intoxication, Liu et al (1998) reported no difference in initial pH and time to dialysis between patients with permanent visual sequelae and those with complete recovery. However, the time to correction of acidosis (initially with intravenous sodium bicarbonate boluses) tended to be longer (mean 5.4 hours) in patients with visual loss than in patients with complete recovery (mean 3.0 hours, p=0.06). When corrected for initial pH, the statistical significance of this finding was reduced (p=0.08). The authors suggest that early correction of pH with intravenous bicarbonate may improve visual outcome, but further studies are needed.
E) ALCOHOL DEHYDROGENASE INHIBITOR 1) The decision as to which antidote to use depends on a number of factors. Fomepizole is easier to use clinically, requires less monitoring, does not cause CNS depression or hypoglycemia, and may obviate the need for dialysis in some patients. Ethanol requires continuous administration and frequent monitoring of serum ethanol and glucose levels, and may cause CNS depression and hypoglycemia (especially in children). The drug cost associated with ethanol use is generally much lower than with fomepizole; however, other costs associated with ethanol use (eg, continuous intravenous infusion, hourly blood draws and ethanol levels, possible greater use of hemodialysis) may make the costs more comparable. a) One study recommended that critically ill patients with severe metabolic acidosis (base deficit greater than 15 mmol/L) or visual disturbances should receive sodium bicarbonate, fomepizole, and hemodialysis as soon as possible. Stable patients, with little to moderate metabolic acidosis (base deficit less than 15 mmol/L) and no visual disturbances should receive sodium bicarbonate and fomepizole. In these patients, the use of hemodialysis should be discussed with an experienced nephrologist or clinical toxicologist (Hovda & Jacobsen, 2008).
F) FOMEPIZOLE 1) 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) AVAILABILITY a) 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).
3) ADVERSE EFFECTS a) Studies in healthy human volunteers have shown fewer adverse effects and a slower elimination rate compared with ethanol (McMartin et al, 1987).
b) The most frequent adverse effects reported in 78 patients and 63 volunteers receiving fomepizole were headache (14%), nausea (11%), and dizziness, increased drowsiness, and dysgeusia (6% each) (Prod Info ANTIZOL(R) IV injection, 2006).
c) Another study reported transient adverse effects including nausea, headache, eosinophilia, lymphangitis, and fever following therapeutic doses of fomepizole in acute methanol intoxication (Megarbane et al, 2001). Brent et al (2001) reported only minor transient adverse effects in 6 methanol-intoxicated patients treated with fomepizole (Brent et al, 2001).
d) A placebo-controlled, double-blind study among HEALTHY volunteers showed mild, transient increase in liver function tests and slower elimination rate of fomepizole (4-methylpyrazole). The mild, sporadic, and transient elevations in blood pressure were not dose-related (Jacobsen et al, 1990).
4) DOSE a) 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). 1) 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).
2) 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).
b) DOSING WITH HEMODIALYSIS 1) Consider hemodialysis in addition to fomepizole therapy in cases of renal failure, severe metabolic acidosis, or a measured methanol concentration of greater than 50 mg/dL. Fomepizole is dialyzable; the frequency of dosing should be increased to every 4 hours during hemodialysis (Prod Info ANTIZOL(R) IV injection, 2006). a) DOSE AT THE BEGINNING OF HEMODIALYSIS: If less than 6 hours have elapsed since last dose, do not give a dose; if 6 hours or more have elapsed since the last fomepizole dose, give the next scheduled dose (Prod Info ANTIZOL(R) IV injection, 2006).
b) DURING HEMODIALYSIS: 15 mg/kg IV loading dose, followed by 10 mg/kg IV every 4 hours for 4 doses, then 15 mg/kg IV every 4 hours until ethylene glycol or methanol concentrations are below 20 mg/dL (Prod Info ANTIZOL(R) IV injection, 2006).
c) DOSING AT THE TIME HEMODIALYSIS IS COMPLETED: If the time between the last dose and the end of hemodialysis is less than 1 hour, do not give a dose; if the time between the last dose and the end of hemodialysis is 1 to 3 hours, give 50% of the next scheduled dose; if the time between the last dose and the end of hemodialysis is greater than 3 hours, give the next scheduled dose (Prod Info ANTIZOL(R) IV injection, 2006).
c) One study recommended that critically ill patients with severe metabolic acidosis (base deficit greater than 15 mmol/L), visual disturbances, or both should receive sodium bicarbonate, fomepizole, and hemodialysis as soon as possible. Stable patients, with little to moderate metabolic acidosis (base deficit less than 15 mmol/L) and no visual disturbances should receive sodium bicarbonate and fomepizole. In these patients, the use of hemodialysis should be discussed with an experienced nephrologist or clinical toxicologist (Hovda & Jacobsen, 2008; Hovda et al, 2005). 5) ADMINISTRATION a) Fomepizole solidifies at temperatures below 25 degrees C (77 degrees F); thus, the vial should be liquefied by running warm water over it or holding it in the hand. Solidification does NOT affect efficacy, safety, or stability. Draw appropriate fomepizole dose from vial and inject into at least 100 mL of sterile 0.9% sodium chloride injection or dextrose 5% injection. Infuse over 30 minutes (Prod Info ANTIZOL(R) IV injection, 2006).
6) CONCURRENT FOMEPIZOLE AND ETHANOL a) A combination of fomepizole and ethanol does not appear to reliably decrease ethanol clearance antidotally during the treatment of methanol toxicity. Wax et al (1998) measured mean ethanol t1/2 and elimination rate after fomepizole (4-MP) dosing in 6 patients who had serum ethanol levels prior and during fomepizole (4-MP). Ethanol half-life and elimination rate were 4.3 hr (+/-2.6) and 25.1 mg/dL/hr (+/-32.6) before fomepizole (4-MP) and 2.6 hr (+/-0.8) and 14.6 mg/dL/hr (+/-7.4) after fomepizole (4-MP) (Wax et al, 1998).
7) ETHANOL VERSUS FOMEPIZOLE a) In a cohort study of 172 cases of suspected methanol and ethylene glycol poisoning, fomepizole was associated with a lower adverse drug events rate than ethanol. At least 1 adverse drug event was identified in 74 of 130 (57%) ethanol-treated and 5 of 42 (12%) fomepizole-treated cases. The most frequent adverse effect was CNS depression (48% ethanol, 2% fomepizole). Severe adverse drug events occurred in 26 of 130 (20%) ethanol-treated patients (coma, extreme agitation, cardiovascular) and 2 of 42 (5%) fomepizole-treated patients (coma, cardiovascular). Serious (life-threatening) adverse events occurred in 11 of 130 (8%) ethanol-treated patients (respiratory depression, hypotension), and 1 of 42 (2%) fomepizole-treated patients (hypotension, bradycardia) (Lepik et al, 2009).
8) CASE REPORTS/FOMEPIZOLE AND BICARBONATE: Four patients with methanol poisoning (the mean serum methanol level was 14.4 mmol/L {45 mg/dL} range 9.4 to 18.8) with moderate metabolic acidosis (mean pH was 7.23 {range 7.12 and 7.33}) and no visual disturbances were successfully treated with fomepizole and bicarbonate; hemodialysis was not required. Frequent acid/base monitoring was found to be normal throughout therapy, indicating that formic acid did not accumulate in any patient. The mean plasma half-life of methanol was 25 hours during treatment. The authors concluded that patients with serum methanol levels up to 19 mmol/L (60 mg/L), moderate metabolic acidosis, and no visual disturbances can be safely treated with fomepizole and bicarbonate without dialysis (Spillum et al, 2003). Because of the prolonged half-life of methanol in patients receiving fomepizole (25 hours or more), patients treated with fomepizole alone may require prolonged hospitalization. 9) CASE REPORT (MIXED INGESTION): A 35-year-old man ingested a glass cleaner solution containing approximately 100 g methanol and 36 g isopropanol over a 24-hour period. Fomepizole was started about 5 hours after his most recent ingestion, with a starting dose of 10 mg/kg. This was given twice daily for 8 days, in a tapering dose schedule until methanol and isopropanol levels were undetectable. No adverse effects due to fomepizole were noted. The patient was discharged with no toxic-related sequelae (Bekka et al, 2001). 10) PREGNANCY a) CASE REPORT (PREGNANCY): A 21-year-old woman with a long history of inhalant abuse and in the first trimester of pregnancy developed methanol poisoning (serum level, 24 mg/dL) after inhaling a carburetor cleaner. She received 1 dose of fomepizole (15 mg/kg) and vitamins. Her methanol level was then undetectable. The patient was discharged and returned again (now at gestational age of 16 to 17 weeks) when she was found inhaling the methanol product. She recovered following 1 dose of fomepizole and hemodialysis. No gross fetal anomalies were seen on ultrasound. The outcome of the pregnancy is unknown since the patient did not return for follow-up (Kulstad et al, 2001).
11) ETHANOL INTERFERENCE a) A study in RATS demonstrated that the rate of fomepizole (4-methylpyrazole) elimination was decreased about 50% by concomitant administration of ethanol. In this study, fomepizole (4-MP) was dosed orally at 5, 10, or 20 mg/kg and ethanol was dosed orally at 1 g/kg/hr for 3 hours (McMartin & Collins, 1988).
G) ETHANOL 1) EFFICACY a) Dosing the patient with ethanol effectively inhibits oxidation of methanol into its far more toxic products. Ethanol has about 20 times the affinity for alcohol dehydrogenase compared with methanol. This competitive effect of ethanol gains more time for excretion of unchanged methanol from the body, and it also inhibits the formation of methanol metabolites that produce severe acidosis. Formic acid is metabolized to carbon dioxide and water via a folate-dependent system.
b) A rebound in blood formate levels was observed in 4 methanol-intoxicated patients after ethanol infusion was discontinued. In 2 well-documented cases, the formate levels rose from 2.4 to 2.5 mg/L during ethanol therapy to 43 and 100 mg/L after discontinuation. Methanol blood levels were 22 and 32 mg/dL, respectively (Mahieu et al, 1989).
2) 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.
3) 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, 2011a). 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, 2011a): 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, 2011a).
c) Instead of using a micron filter when preparing the ethanol infusion, possibly a better alternative would be to use the filter between the solution and the patient. 4) PRECAUTIONS a) HYPOGLYCEMIA 1) Hypoglycemia may occur, especially in children. Monitor blood glucose frequently (Howland, 2011a; 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.
5) 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, 2011a).
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, 2011a).
6) 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, 2011a; Barceloux et al, 2002). 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, 2011a; Barceloux et al, 2002): 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
7) 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, 2011a). 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, 2011a; Barceloux et al, 2002). 1) Monitor blood glucose and mental status frequently during therapy (Howland, 2011a). 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). 8) 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, 2011a).
9) DURATION OF THERAPY a) SERUM CONCENTRATIONS AVAILABLE: Ethanol therapy should be continued until the following criteria are met: 1) Methanol blood concentration, measured by a reliable technique, is less than 10 mg/dL.
2) Formate blood concentration is less than 1.2 mg/dL (Abolin et al, 1980; Baumann & Angerer, 1979; Martin-Amat et al, 1978; Sejersted et al, 1983).
3) Methanol-induced acidosis (pH, blood gases), clinical findings (CNS), electrolyte abnormalities (bicarbonate), serum amylase, and osmolal gap have resolved.
b) NO SERUM CONCENTRATIONS AVAILABLE: When unable to obtain methanol blood levels, ethanol therapy should be initiated and the patient transported as soon as possible to a facility capable of measuring serum methanol concentrations and performing hemodialysis. 1) Ethanol therapy should be continued for a minimum of 9 days in the absence of dialysis, 1 day when dialysis has been performed, or until clinical findings resolve, whichever is longer. It is extremely difficult to maintain therapeutic ethanol levels for long periods of time. Hemodialysis is strongly recommended in patients with acidosis or serum methanol levels of greater than 25 to 50 mg/dL.
2) If the clinical findings have not resolved, it may indicate the continued presence of methanol, metabolites, both, or some other etiology.
c) Based on pharmacokinetic theory, 93.75% of methanol is eliminated over a period of 4 elimination half-lives (Winter, 1988). Assuming a prolonged methanol elimination half-life of up to 52 hours during ethanol therapy (Palatnick et al, 1995), pharmacokinetic theory would predict elimination of 93.75% of the absorbed dose of methanol over 208 hours (9 days). Therefore, ethanol therapy (in the absence of hemodialysis) should be continued for at least 9 days. d) It is possible that 5-day treatment may be inadequate in some cases. Jacobsen et al (1988) reported zero-order elimination of methanol with a rate of 8.5 mg/dL/hr prior to institution of ethanol therapy or dialysis. e) Palatnick et al (1995) found that methanol elimination in the presence of treatment levels of ethanol follows first-order kinetics. However, since hepatic metabolism is inhibited by the ethanol, the primary pathways for elimination become renal and pulmonary clearance. These 2 mechanisms are very inefficient, and thus the methanol half-life is considerably prolonged, up to 52 hours. f) In a series of 3 methanol-poisoned patients treated with only ethanol and 3 cases retrieved from a literature review, methanol half-life while on IV ethanol was 43 hours (range 30 to 52 hours) (Palatnick et al, 1995). Because of the prolonged need for ethanol therapy and the difficulty in consistently maintaining therapeutic ethanol levels, these authors suggested that dialysis be considered in all patients requiring ethanol infusion. 10) METHANOL INGESTION a) Patients who concurrently ingested ethanol and methanol may have a normal acid-base profile despite a dangerously elevated blood methanol level. Consider implementing the ethanol treatment regimen in these patients until a methanol level can be determined. Determine blood ETHANOL level before beginning ETHANOL therapy and modify the loading dose accordingly. Ingestion of Sterno fuel products (which contain greater than 60% ethanol and less than 4% methanol) may result in delayed toxicity due to the high ethanol concentration in these products. b) In a series of 84 chronic alcoholics who ingested a cleaning solution containing 90% ethanol and 5% methanol, no acidosis was reported despite mean methanol levels of 64 mg/dL and absence of specific therapy (ethanol or hemodialysis). Insufficient data are presented to determine the safety of this conservative treatment. Individual or pooled blood gas data are not given, although 13 patients were stated to have a decrease in base excess. No outcome data are given, and methanol levels were measured only until less than 48 mg/dL (Martensson et al, 1988). c) To modify the loading dose for the patients who have concurrently ingested ethanol, use the following equation to calculate the loading dose: LD=(100 mg/dL-existing) apparent
ETOH plasma concentration) x vol of
(in mg/dL) distributiond) Note the loading dose obtained by this method is the amount of pure ethanol in mg/kg. It must be converted for intravenous and oral use to mL/kg. This can be accomplished by using the following relationship: LD(mg/kg)
LD(mL/kg)=----------------------------------
(spec gravity (concentration
of ETOH) as a fraction)e) Ten percent (V/V) ethanol for intravenous infusion: LD(mg/kg)
LD(mL/kg)=---------------------------
(790 mg/mL) (10/100)f) 95 percent (V/V) ethanol for oral use: LD(mg/kg)
LD(mL/kg)=--------------------------
(754 mg/mL) (95/100)g) Calculation of loading dose assumes instantaneous absorption. 11) ADVERSE EFFECTS a) In a retrospective study, the hospital records of 49 adults treated with ethanol for methanol (n=15) or ethylene glycol (n=32) ingestion were evaluated. Two patients ingested both methanol and ethylene glycol. Adverse effects developed in 45 (92%) patients, including tachycardia (heart rate greater than 100 beats/min; n=16; 33%), hypotension (n=9; 18%), decreased level of consciousness (necessitating intubation; n=10; 20%), agitation (necessitating chemical or physical restraints; n=35; 71%), seizures (n=3; 6%), vomiting (n=11; 22%), and phlebitis (n=5; 10%). It is unclear if the adverse effects were related to the ethanol, underlying poisoning or other therapies. Hypoglycemia (blood glucose less than 4 mmol/L) did not develop in any patients. Four patients died; 38% were admitted to an ICU unit and 92% of patients (n=45) were treated with hemodialysis. Serum ethanol concentrations were obtained a median of 6 times per case (range, 0 to 24). Patients were treated with ethanol for 0.5 to 119 hours (median, 21 hours). Serum ethanol concentration was within target range (22 to 30 mmol/L) in only 27% of measurements; 47% were below the target range and 25% were above the target range. Inappropriate change in ethanol dosing was reported in 59% of the cases when a serum ethanol concentration was outside the target. Inappropriate dosing changes were also reported during 69% of the hemodialysis sessions. Overall, 92% of patients survived and were discharged home (Wedge et al, 2012).
H) FOLIC ACID 1) Leucovorin and folic acid enhance the metabolism of formic acid (formate) to carbon dioxide and water (Noker et al, 1980a; Anon, 1979; Makar & Tephly, 1976). 2) Either folic acid or leucovorin (folinic acid) may be used in patients with methanol toxicity (Howland, 2011). Leucovorin (folinic acid) is the active form of folic acid and does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions using folate as a source of one-carbon moieties. It may be used for the initial dose in symptomatic patients, but it is more expensive than folic acid and there is no data that it improves outcome compared with folic acid. In symptomatic patients (anion gap acidosis, visual disturbances) and asymptomatic patients with known or suspected methanol intoxication, administer intravenous folic acid. a) DOSE: 1 to 2 mg/kg every 4 to 6 hours for the first 24 hours. It should be continued until methanol is cleared and acidosis resolved. Folate is removed by hemodialysis so in patients undergoing hemodialysis, administer one dose prior to and another at the completion of hemodialysis. In studies, the use of folic acid 50 to 70 mg IV every 4 hours for the first 24 hours did not produce any complications (Howland, 2011).
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