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) MONITORING OF PATIENT 1) Obtain hourly blood glucose; monitor blood glucose for 8 to 12 hours.
2) Monitor vital signs.
3) Monitor fluid and electrolyte balance in symptomatic patients.
4) Plasma levels are not clinically useful for managing overdose.
B) HYPOGLYCEMIA 1) SUMMARY a) There is little clinical experience with repaglinide in overdose. Most of the following recommendations are based on experience with sulfonylurea in overdose. Because repaglinide is more rapid- and short-acting, there is a reduced risk of long-lasting hypoglycemia as compared to sulfonylureas.
2) DEXTROSE a) Treat patients who develop laboratory evidence of hypoglycemia (blood glucose less than 60 mg/dL) or significant clinical effects (altered mental status, seizures) with IV dextrose. b) DOSE 1) ADULT a) BOLUS: Symptomatic patients require immediate treatment with 0.5 to 1 g/kg of D50W (50% dextrose) IV push (Bosse, 2006). Patients with profound hypoglycemia may require a second dose. b) INFUSION: Initiation of a continuous 10% to 20% dextrose intravenous infusion is recommended in any patient who becomes hypoglycemic, as recurrent prolonged episodes of hypoglycemia may occur after overdose (Sonnenblick & Shilo, 1986; Palatnick et al, 1991). 1) Do not stop IV dextrose infusion abruptly. Intravenous dextrose may need to be prolonged or repeated, depending upon the amount ingested.
2) Slowly decrease the rate of dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
3) Prophylactic dextrose administration is not recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner (Spiller et al, 1995) .
2) PEDIATRIC a) NEONATE: BOLUS: 0.2 g/kg IV (2 mL/kg) of D10W (10% dextrose) (Committee on Fetus and Newborn & Adamkin, 2011; Jain et al, 2008; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008). b) INFANTS AND CHILDREN: BOLUS: 0.5 to 1 g/kg IV (usually given as 2 to 4 mL/kg/dose) D25W (25% dextrose) (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008). c) ADOLESCENTS: BOLUS: 0.5 to 1 g/kg IV (usually give as 1 to 2 mL/kg/dose) D50W (50% dextrose) (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008). d) INFUSION: Initiation of a continuous 10% to 20% dextrose in 0.2% normal saline intravenous infusion is recommended in any patient who becomes hypoglycemic, as recurrent prolonged episodes of hypoglycemia may occur after overdose (Sonnenblick & Shilo, 1986; Palatnick et al, 1991). Titrate to maintain blood glucose above 100 mg/dL. 1) Do not stop the IV dextrose infusion abruptly. Intravenous dextrose may need to be prolonged or repeated, depending upon the amount of ingested.
2) Slowly decrease the rate of dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
3) Prophylactic dextrose administration is not recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner (Spiller et al, 1995).
c) PRECAUTIONS 1) Avoid subcutaneous administration.
2) Avoid fluid overload with intravenous infusion.
3) Be cautious in using an IV infusion in patients with congestive heart failure.
4) Hyperosmolar coma may occur in diabetics receiving an intravenous infusion.
5) Do not stop the intravenous glucose abruptly.
3) OCTREOTIDE a) Octreotide has been used in sulfonylurea-induced hypoglycemia and may be of use in the treatment of repaglinide-induced hypoglycemia. This is a long acting analogue of somatostatin which antagonizes insulin release. In overdose, it is expected to act on closing of the ATP-sensitive potassium channel in beta-islet cells similar to sulfonylureas and would be expected to produce a similar hyperinsulinemia state as a sulfonylurea. It may reduce or obviate the need for a dextrose continuous infusion (Spiller, 1998).
b) DOSE: ADULT: 50 micrograms SubQ (usual route) or IV; may repeat every 6 to 12 hours as needed (Bosse, 2006; Spiller, 1998). CHILD: 1 microgram/kilogram SubQ (usual route) or IV; may repeat every 12 hours as needed (Spiller, 1998).
4) DIAZOXIDE a) Diazoxide has been used in sulfonylurea-induced hypoglycemia and may be of use in the treatment of repaglinide-induced hypoglycemia that does not respond to dextrose, steroids, or glucagon (Jacobs et al, 1978; Palatnick et al, 1991). Diazoxide can reduce calcium influx in the beta-cells and reduce insulin secretion, however its use is not universally recommended (Spiller, 1998).
b) DOSE: The following is a suggested dose: ADULT: 300 milligrams IV infused slowly over one hour. CHILD: 1 to 3 milligrams/kilogram IV infused slowly over one hour (Spiller, 1998).
c) MECHANISM: Diazoxide directly inhibits insulin secretion from the pancreas as evidenced by a decrease in plasma insulin concentrations following an intravenous infusion of diazoxide. Slow intravenous infusion should cause no decrease in blood pressure (Johnson et al, 1977).
d) CAUTION: Because of the potential to cause hypotension, diazoxide is only recommended if octreotide is ineffective or unavailable (Bosse, 2006).
5) GLUCAGON a) SUMMARY: Glucagon may be of limited value and is usually not recommended in the treatment of hypoglycemia caused by repaglinide. It should only be considered when the treatment with glucose or intravenous access is not available or possible (Bosse, 2006; Spiller, 1998). Because of the short half-life of glucagon, repeated hypoglycemia may occur. Oral carbohydrate or IV dextrose should be given as soon as possible. b) DOSE FOR SEVERE HYPOGLYCEMIA 1) GENERAL: Reconstituted GlucaGen is approximately 1 mg/mL glucagon and should be used immediately after reconstitution. It will provide transient elevation of glucose if there are adequate liver stores. Intravenous glucose must be administered if the patient fails to respond to glucagon. After the patient has responded to treatment, give oral carbohydrates to restore the liver glycogen and prevent recurrence of hypoglycemia. 2) ADULT: Inject 1 mL SubQ, IM or IV (Prod Info GlucaGen(R) intravenous intramuscular subcutaneous injection, 2010). 3) LESS THAN 12 YEARS OF AGE: 0.5 mg (or a dose equivalent to 10 to 30 mcg/kg) SubQ, IM, or IV push (Clarke et al, 2009; Aman & Wranne, 1988). A second dose is not recommended (Aman & Wranne, 1988), but rather additional carbohydrate or IV glucose (Clarke et al, 2009). 4) 12 YEARS OF AGE AND OLDER: 1 mg (or a dose equivalent to 10 to 30 mcg/kg) SubQ, IM, or IV push (Clarke et al, 2009; Aman & Wranne, 1988). A second dose is not recommended (Aman & Wranne, 1988), but rather additional carbohydrate or IV glucose (Clarke et al, 2009). 5) MANUFACTURER DOSING a) CHILDREN WEIGHING MORE THAN 55 LBS (25 KG) or CHILDREN 6 YEARS OR OLDER: Inject 1 mL (1 mg) SubQ, IM or IV (Prod Info GlucaGen(R) intravenous intramuscular subcutaneous injection, 2010).
b) CHILDREN WEIGHING LESS THAN 55 LBS (25 KG) or CHILDREN LESS THAN 6 YEARS: Inject 0.5 mL (0.5 mg) SubQ, IM or IV (Prod Info GlucaGen(R) intravenous intramuscular subcutaneous injection, 2010).
c) CONTRAINDICATIONS: Glucagon is contraindicated in patients with pheochromocytoma or insulinoma (Prod Info GlucaGen(R) intravenous intramuscular subcutaneous injection, 2010). d) PRECAUTIONS: Glucagon is of little benefit in presence of starvation, adrenal insufficiency, liver disease, alcoholism or chronic hypoglycemia. e) ADVERSE EFFECTS: Nausea and vomiting and stimulation of hepatic ketogenesis (Johnson et al, 1977) f) GLUCAGON FAILURE: To reverse coma may be due to irreversible CNS damage as a consequence of prolonged hypoglycemia, or due to insufficient hepatic glycogen stores (Gilman et al, 1985). Other causes should be ruled out. 6) DIET a) When the patient awakens, supplement intravenous glucose with daily carbohydrate intake of 300 grams or more.
C) FLUID/ELECTROLYTE BALANCE REGULATION 1) MONITOR FLUID AND ELECTROLYTE BALANCE: Potassium supplementation may be needed.
D) SEIZURE 1) Seizures are usually manifestations of hypoglycemia; correct with intravenous dextrose. If seizures persist despite euglycemia, anticonvulsants are indicated. 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).
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