6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) Induction of emesis is not recommended. B) 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) Activated charcoal has been shown to effectively adsorb theophylline in vitro and to decrease theophylline absorption in human volunteer studies (Cooney, 1995; Minton et al, 1995; Minton et al, 1995). 2) EPHEDRINE: Activated charcoal may decrease absorption from the gastrointestinal tract (USPDI , 2001). 3) 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.
4) 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).
B) GASTRIC LAVAGE 1) Gastric lavage should be considered in substantial recent ingestions. It may be indicated after ingestion of sustained release formulations even if delayed, as these products may form bezoars. 2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes). a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
3) PRECAUTIONS: a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
4) LAVAGE FLUID: a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
5) COMPLICATIONS: a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
6) CONTRAINDICATIONS: a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
C) MULTIPLE DOSE ACTIVATED CHARCOAL 1) Multiple-dose activated charcoal should be considered after potentially severe or life threatening overdoses. It has been shown effective in enhancing the elimination of theophylline in the following settings: a) Therapeutic intravenous theophylline doses in healthy volunteers (Berlinger et al, 1983; Park et al, 1983; Park et al, 1984; Mahutte et al, 1983; Radomski et al, 1984; Chyka et al, 1995) and in patients with cirrhosis (Radomski et al, 1984).
b) Therapeutic oral SR theophylline tablets in healthy children ages 8 to 18 (Lim et al, 1986).
c) Intravenous overdoses in experimental animals (Brashear et al, 1985; Arimori & Nakano, 1985; Kulig et al, 1987; Huang, 1987).
d) In case reports of patients with either a deliberate (Radomski et al, 1984; Hendeles & Weinberger, 1980; Sessler et al, 1987; Gal et al, 1984; Corser et al, 1985) or iatrogenic (Radomski et al, 1984; Hendeles & Weinberger, 1980; Sessler et al, 1987; True et al, 1984) overdose; treatment with multiple dose activated charcoal was associated with reduced theophylline half life.
e) MDC therapy has been used successfully in a pregnant patient (Davis et al, 1985), a premature newborn (Strauss et al, 1985), in infants (Bronstein et al, 1984; Ginoza et al, 1987; Shannon et al, 1987), and in children (Lim et al, 1986).
2) ADVERSE EFFECTS a) Longdon & Henderson (1992) reported two cases (one fatal) of intestinal pseudo-obstruction following the use of enteral charcoal, sorbitol and mechanical ventilation with papaveretum sedation and neuromuscular blockade. Sympathomimetic stimulation by theophylline and reduced intestinal peristalsis from opioids probably contributed to this effect.
b) A 45-year-old man with acute theophylline overdose developed intestinal pseudo-obstruction after treatment including 1000 grams of charcoal without cathartic, haloperidol, and mechanical ventilation (Brubacher et al, 1995).
c) A 64-year-old woman developed small bowel obstruction after treatment with multiple dose activated charcoal for theophylline overdose (Goulbourne & Cisek, 1994). The presence of adhesions probably contributed.
3) MULTIPLE DOSE ACTIVATED CHARCOAL a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).
D) VOMITING 1) Persistent vomiting may interfere with attempts to administer activated charcoal. In one series of 33 patients, 22% of activated charcoal doses were vomited; acutely toxic patients vomited all doses (Sessler et al, 1987).
2) Ranitidine may be useful in controlling excess gastric secretions that may lead to the persistent vomiting (Amitai et al, 1986). Cimetidine may interfere with theophylline clearance.
3) Several case reports suggest that ondansetron may be effective in intractable nausea and vomiting associated with theophylline toxicity (Sage et al, 1993; Brown & Prentice, 1992; Daly & Taylor, 1993; Roberts et al, 1993). Usual adult dose is 8 milligrams intravenously.
4) Another effective antiemetic can include metoclopramide (0.4 to 1 milligram/kilogram). Phenothiazines should be avoided.
E) WHOLE BOWEL IRRIGATION 1) INDICATIONS - Based on limited clinical data, whole bowel irrigation with polyethylene glycol electrolyte balanced solution (e.g., Golytely(R)) may be considered in cases of extremely large amounts of a SR theophylline preparation with rising serum levels (Tenenbein, 1987). 2) ACTIVATED CHARCOAL INTERACTION - Hoffman et al (1989) and (1991) reported that polyethylene glycol electrolyte lavage solution is able to displace aminophylline (theophylline) from activated charcoal in-vitro. 3) Burkhart et al (1991) reported no additional benefit of whole bowel irrigation over activated charcoal alone in the treatment of sustained-release theophylline poisoning. a) 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. 1) 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.
b) 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). c) 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. d) 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. 6.5.3) TREATMENT
A) SEIZURE 1) SEIZURE PROPHYLAXIS a) SUMMARY: Several studies have demonstrated that prophylaxis with phenobarbital prior to the onset of seizures in theophylline-toxic animals delays or prevents seizures and improves survival. b) Prospective clinical studies are not available. Consider phenobarbital prophylaxis in patients at high risk for developing seizures, where the potential benefits exceed the risks of therapy. Patients at high risk include: 1) Those with serum theophylline level of 40 to 60 micrograms/milliliter and age greater than 60 or less than 3 years following chronic overdose (Olson et al, 1985; Shannon & Lovejoy, 1992; Shannon, 1993).
2) Those with serum level greater than 80 to 100 micrograms/milliliter following acute overdose (Olson et al, 1983; Gaudreault et al, 1983; Goldberg et al, 1986).
c) Monitor carefully for respiratory depression and hypotension; be prepared to intubate and provide mechanical ventilation (Shaner et al, 1988). Use of a propylene glycol-free preparation may lessen the risk of hypotension (i.e., sodium phenobarbital, Lilly). 2) TREATMENT a) SUMMARY: Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbital. Based on animal and limited human data, phenytoin does not appear to be effective in theophylline-induced seizures. 1) Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
2) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or treat with intravenous dextrose ADULT: 100 milligrams IV, CHILD: 2 milliliters/kilogram 25% dextrose).
b) EPHEDRINE - Seizures may occur following overdose; treat with diazepam, or phenobarbital (USPDI , 2001). c) DIAZEPAM 1) 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).
2) 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).
3) 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 .
d) NO INTRAVENOUS ACCESS 1) 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).
2) 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).
e) LORAZEPAM 1) 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).
2) 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).
3) 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).
f) PHENOBARBITAL 1) 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).
2) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
3) 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).
4) 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).
5) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
6) 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).
g) OTHER AGENTS 1) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012): a) 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).
b) 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).
c) 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).
d) 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).
h) RECURRING SEIZURES 1) 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: a) 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).
b) 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).
c) 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).
d) 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)
2) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised. 3) 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). 3) STUDIES a) HUMAN 1) In a retrospective review of 100 cases of theophylline-induced seizures, phenytoin was ineffective in 21 of 22 cases. In the patient who responded, diazepam was also given (Jacobs & Senior, 1974).
b) ANIMAL 1) RABBITS - Treatment with intravenous phenobarbital 20 milligrams/kilogram immediately following administration of 115 milligrams/kilogram of theophylline resulted in 50 percent mortality, compared to 80 percent in controls and 77 percent treated with phenytoin (Goldberg et al, 1986a). 2) MICE - Czuczwar et al (1987) demonstrated that phenobarbital antagonized tonic-clonic seizures induced by theophylline, while phenytoin was totally ineffective against clonic seizures and did not prevent lethality. 3) MICE - Pretreatment with phenobarbital (producing a mean serum level of 24.4 micrograms/milliliter) protected against seizures and delayed onset of seizures from 23.5 minutes to 44 minutes. a) A higher dose (mean serum level 44 micrograms/milliliter) further delayed onset to 64 minutes. Survival was improved in both phenobarbital dosage groups.
b) In contrast, pretreatment with phenytoin actually shortened the time to onset of seizures (5.7 minutes with a mean serum level of 9 micrograms/milliliter) (Blake et al, 1988).
4) Phenytoin was demonstrated to worsen the outcome compared to controls in some studies (Stone & Javid, 1980; Blake et al, 1988). B) HYPOTENSIVE EPISODE 1) Patients with severe theophylline overdose generally have excessive beta adrenergic stimulation. In theory, agents with predominantly alpha agonist effects may be more effective for hypotension unresponsive to fluids. If hypotension is secondary to severe tachycardia, a short acting cardioselective beta antagonist such as esmolol may be indicated. 2) EPHEDRINE - Marked hypotension may occur following overdose, use of intravenous fluids and inotropic vasopressors is indicated (USPDI , 2001). 3) 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.
4) 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).
5) 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).
6) PHENYLEPHRINE a) Add 10 milligrams phenylephrine to 500 milliliters of normal saline and infuse at a rate of 100 to 180 micrograms/minute initially, then lower infusion to 40 to 60 micrograms/minute as tolerated (Prod Info Neo-Synephrine(R), phenylephrine, 1996).
C) PROPRANOLOL 1) Although propranolol has been used to treat theophylline-induced hypotension (Biberstein et al, 1984), its use cannot be routinely recommended. a) It may be hazardous in asthmatic patients.
2) ANIMAL STUDIES a) Administration of propranolol 0.6 milligram/kilogram intravenously following infusion of aminophylline delayed the onset of seizures (from 46 to 55 minutes) and increased the total dose of aminophylline tolerated in rats (from 385 to 473 milligrams/kilogram) (Schneider et al, 1987).
b) In another study in mice, propranolol, in doses up to 20 milligrams/kilogram intraperitoneally, prevented tonic, but not clonic seizure activity (Czuczwar et al, 1987). Propranolol may be hazardous in asthmatic and COPD patients.
D) VENTRICULAR ARRHYTHMIA 1) MONITOR CARDIAC FUNCTION closely. Use standard anti-arrhythmic therapy as needed.
2) VERAPAMIL: 3 milligrams of intravenous verapamil was associated with prolongation of the cycle length and termination of ventricular tachycardia following a ventricular premature beat that was unresponsive to lidocaine therapy in a patient treated with theophylline (58 micrograms/milliliter in plasma) (Taniguchi et al, 1989).
E) ESMOLOL 1) CASE REPORTS a) UNSTABLE SUPRAVENTRICULAR TACHYCARDIA - Was successfully treated in a theophylline toxic patient (107.4 micrograms/milliliter) with a continuous esmolol infusion, 50 micrograms/kilogram/minute, after a 500 microgram/kilogram bolus. 1) Initial treatment with carotid massage, valsalva, adenosine, verapamil, digoxin, and cardioversion was unsuccessful (Vanden Hoek et al, 1991).
b) Tachycardia and hypotension, thought to be secondary to theophylline toxicity, responded immediately to administration of esmolol in a 28-year-old male who ingested 5,400 milligrams anhydrous theophylline 8 hours prior to admission (Seneff et al, 1990). 1) OTHER DRUGS INGESTED - 12.5 milligrams flurazepam, 750 milligrams desipramine, 750 milligrams doxepin, and 60 milligrams lorazepam were ingested 24 hours prior to admission.
2) ADULT DOSE/ADMINISTRATION - Prepare a solution containing 10 milligrams esmolol per milliliter of a compatible intravenous solution (Prod Info Brevibloc(R), esmolol hydrochloride, 1996). a) CAUTION - Esmolol is a short-acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol may be hazardous in patients with bronchospastic disease (asthmatics, COPD) (Prod Info Brevibloc(R), esmolol hydrochloride, 1996) or myocardial depression (Gomez et al, 1992). b) LOADING DOSE - Infuse 500 micrograms/kilogram of body weight for 1 minute (Prod Info Brevibloc(R), esmolol hydrochloride, 1996). c) MAINTENANCE DOSE - Follow loading dose with infusion of 50 micrograms/kilogram/minute for 4 minutes (Prod Info Brevibloc(R), esmolol hydrochloride, 1996). d) EVALUATION OF RESPONSE - If inadequate response to initial loading dose and 4-minute maintenance dose, repeat loading dose (infuse 500 micrograms/kilogram for 1 minute) followed by a maintenance infusion of 100 micrograms/kilogram/minute for 4 minutes. Reevaluate therapeutic effect. 1) If response is inadequate, repeat loading dose and increase the maintenance dose by increments of 50 micrograms/kilogram/minute, administered as above (Prod Info Brevibloc(R), esmolol hydrochloride, 1996).
2) Unlike propranolol, esmolol will not reverse theophylline-induced hypokalemia and other toxicities which appear to be beta-2 mediated.
e) END-POINT OF THERAPY - When desired heart rate or safety end-point (blood pressure) is reached: 1) Omit loading dose and reduce incremental dose in maintenance infusion from 25 to 50 micrograms/kilogram/minute or lower;
2) Or increase interval between titration steps from 5 to 10 minutes (Prod Info Brevibloc(R), esmolol hydrochloride, 1996).
f) USUAL ADULT DOSAGE - 25 to 200 micrograms/kilogram/minute (Prod Info Brevibloc(R), esmolol hydrochloride, 1996) 3) PEDIATRIC DOSE/ADMINISTRATION - Safety and effectiveness of esmolol has not been established in children (Prod Info Brevibloc(R), esmolol hydrochloride, 1996). 4) DISCONTINUATION - Taper dose prior to discontinuation. Follow manufacturer's recommendations for switching to oral agent if appropriate. Esmolol has been well tolerated for up to 48 hours of use (Prod Info Brevibloc(R), esmolol hydrochloride, 1996). 5) A swine study compared the use of propranolol, esmolol, and methoxamine for the treatment of the hypotension and tachycardic effects associated with acute theophylline overdose. Only methoxamine demonstrated significant ability to reverse the hypotensive and tachycardic effects (Martin et al, 1991). F) ADENOSINE 1) This short-acting agent is effective treatment for supraventricular tachycardias.
2) Because theophylline's mechanism of pharmacologic and toxic effects may involve adenosine antagonism, this agent may be useful therapy in theophylline-induced supraventricular tachycardias.
3) In a rat model of severe aminophylline intoxication, pretreatment with intracerebroventricular or intravenous adenosine increased the dose of aminophylline required to induce seizures and delayed the onset of seizures (Shannon & Maher, 1994; Shannon & Maher, 1994; Shannon & Maher, 1995).
4) In a mouse model of severe aminophylline intoxication, treatment with adenosine 5 minutes after aminophylline infusion delayed the onset of seizures and death (Wang, 1994).
G) HYPERTENSIVE EPISODE 1) EPHEDRINE - Hypertension may occur following acute overdose of ephedrine. Nitroprusside or phentolamine may be considered (USPDI , 2001). 2) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses. 3) SODIUM NITROPRUSSIDE/INDICATIONS a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
4) SODIUM NITROPRUSSIDE/DOSE a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
8) PHENTOLAMINE/INDICATIONS a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
9) PHENTOLAMINE/ADULT DOSE a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
10) PHENTOLAMINE/PEDIATRIC DOSE a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
11) PHENTOLAMINE/ADVERSE EFFECTS a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
12) CAUTION a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
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A) HEMOPERFUSION
1) Charcoal hemoperfusion increases theophylline clearance in overdose and is associated with a theophylline half life of approximately 2 hours (Burgess & Sargious, 1995). 2) INDICATIONS: Should be considered if the plasma theophylline concentration exceeds 40 to 60 micrograms/milliliter in CHRONIC overdose (222 to 333 micromoles/liter) and/or significant signs of intoxication are present (Chang et al, 1980; Hendeles & Weinberger, 1980; Sahney et al, 1983). 3) Other authors (Goldberg et al, 1986a; Shannon & Lovejoy, 1992) have suggested that hemoperfusion should be performed prophylactically if: a) The serum theophylline concentration is greater than 80 micrograms/milliliter after acute overdose.
b) The serum theophylline concentration is greater than 60 micrograms/milliliter after chronic overdose, or
c) The serum theophylline concentration is greater than 50 micrograms/milliliter and the patient is 60 years of age or older or has significant liver disease or congestive heart failure, or the patient is unable to tolerate oral activated charcoal therapy.
4) SEVERE SYMPTOMS (cardiac dysrhythmias, hemodynamic instability, seizures) generally occur at levels greater than 40 to 60 micrograms/milliliter in CHRONIC intoxications and at levels greater than 80 to 100 micrograms/milliliter in ACUTE intoxications (Olson et al, 1983) Gaudrealt et al, 1983; (Shannon, 1993). a) Hemoperfusion may alter the course of major adverse events if performed early, ie, before seizure or dysrhythmia onset (Shannon & Woolf, 1992a).
5) ENHANCED RECOVERY - Enhanced recovery without neurologic defects was seen in three pediatric patients with severe theophylline toxicity (theophylline levels of 60 to 180 micrograms/milliliter (333 to 999 micromoles/liter)) when hemoperfused early after seizure onset (Sahney et al, 1983). 6) PEDIATRIC - Consider in pediatric patients who deteriorate despite conventional therapy or in those patients with serum concentrations greater than 80 to 100 micrograms/milliliter (444 to 555 micromoles/liter) (Gaudreault et al, 1983). 7) SUSTAINED-RELEASE - HEMOPERFUSION (HP) may also be indicated following massive overdose with sustained-release theophylline products due to rising and sustained toxic plasma concentrations (Connell et al, 1982). 8) REBOUND - Cessation of HP may lead to small (5 micrograms/milliliter) rebound toxic theophylline levels (Connell et al, 1982). 9) ADVERSE EFFECTS - Associated with hemoperfusion utilizing a coated-charcoal cartridge included a transient decrease in platelets, calcium, and blood pressure and one case of possible hemolysis (Gallagher et al, 1987). 10) CONTINUOUS ARTERIOVENOUS HEMOPERFUSION - a) In one case of theophylline intoxication continuous arteriovenous hemoperfusion was associated with a theophylline clearance of 193 milliliters/minute (Lin & Jeng, 1995).
B) HEMODIALYSIS
1) Hemodialysis also has been reported to increase the elimination rate of theophylline with clearances of 33 milliliters/minute (Levy, 1977), 74 milliliters/minute (Snodgrass, 1980), 88 milliliters/minute (Lee, 1979), and 128 milliliters/minute (Bouffard et al, 1993) in several case reports. a) Newer dialysis membranes appear to provide theophylline clearance rates similar to those achieved with hemoperfusion (Bouffard et al, 1993; Nogue S, Munne P & Nadel P et al, 1994).
2) INDICATIONS: Should be considered if the plasma theophylline concentration exceeds 40 to 60 micrograms/milliliter in CHRONIC overdose (222 to 333 micromoles/liter) and/or significant signs of intoxication are present (Chang et al, 1980; Hendeles & Weinberger, 1980; Sahney et al, 1983). 3) Other authors (Goldberg et al, 1986a; Shannon & Lovejoy, 1992) have suggested that hemodialysis should be performed prophylactically if: a) The serum theophylline concentration is greater than 80 micrograms/milliliter after acute overdose.
b) The serum theophylline concentration is greater than 60 micrograms/milliliter after chronic overdose, or
c) The serum theophylline concentration is greater than 50 micrograms/milliliter and the patient is 60 years of age or older or has significant liver disease or congestive heart failure, or the patient is unable to tolerate oral activated charcoal therapy.
4) SEVERE SYMPTOMS (cardiac dysrhythmias, hemodynamic instability, seizures) generally occur at levels greater than 40 to 60 micrograms/milliliter in CHRONIC intoxications and at levels greater than 80 to 100 micrograms/milliliter in ACUTE intoxications (Olson et al, 1983) Gaudrealt et al, 1983; (Shannon, 1993). a) Hemodialysis may alter the course of major adverse events if performed early, i.e., before seizure or arrhythmia onset (Shannon & Woolf, 1992a).
5) PEDIATRIC - Consider in pediatric patients who deteriorate despite conventional therapy or in those patients with serum concentrations greater than 80 to 100 micrograms/milliliter (444 to 555 micromoles/liter) (Gaudreault et al, 1983). 6) SUSTAINED-RELEASE - Hemodialysis may also be indicated following massive overdose with sustained-release theophylline products due to rising and sustained toxic plasma concentrations (Connell et al, 1982). 7) EPHEDRINE - It is NOT known whether ephedrine is removable by dialysis (USPDI , 2001). C) CLEARANCE RATES TABLE 1
THEOPHYLLINE CLEARANCE WITH DIALYSIS
AND HEMOPERFUSION
1) HEMOPERFUSION CLEARANCE
2) HEMODIALYSIS
3) CONTINUOUS ARTERIOVENOUS HEMOPERFUSION
Lin & Jeng, 1995 193 mL/min
4) PERITONEAL DIALYSIS - NOT EFFECTIVE
Miceli et al, 1980 5 mL/min
Weinberger & 10 to 49 mL/min
Hendeles, 1980
5) ENDOGENOUS CLEARANCE
1) Non-smoking Adult 40 mL/kg/hr
2) Smoking Adult 65 mL/kg/hr
6) ACTIVATED CHARCOAL, MULTIPLE DOSE
95 to 145 mL/kg/hr
D) COMBINED HEMOPERFUSION/HEMODIALYSIS
1) Combined use of hemodialysis and charcoal hemoperfusion, along with oral activated charcoal, for 7 hours was successful in decreasing the serum theophylline level from 1000 micromoles/liter to about 100 micromoles/liter (from 180 micrograms/milliliter to 18 micrograms/milliliter) (Stegmayr, 1988).
2) Combined treatment cannot be expected to increase the total body clearance more than for hemoperfusion alone (Ahlmen et al, 1984).
E) EXCHANGE TRANSFUSION
1) Exchange transfusion is less effective in removing substantial amounts of drug, but may be useful in infants in whom hemodialysis and hemoperfusion is difficult. 2) Several reports suggest single and triple volume exchange transfusions are a potentially useful alternative to hemodialysis, hemoperfusion, and repetitive oral charcoal in the critically ill newborn and premature neonate suffering from the theophylline overdose (Shannon & Lovejoy, 1992; Henry et al, 1991; Barazarte et al, 1992) Osborn et al, 1993). 3) CASE REPORT a) A newborn with a serum theophylline level of 93.3 micrograms/milliliter was treated with triple volume whole blood exchange transfusion (total exchange volume 600 milliliters) successfully.
b) Pre-exchange elimination half-life of theophylline was 39 hours; postexchange was 9.2 hours. Serum theophylline concentration was decreased to 37.8 micrograms/milliliter (Shannon & Lovejoy, 1992).
F) PLASMAPHERESIS
1) Plasmapheresis should not be used instead of hemoperfusion or hemodialysis in theophylline intoxication as it offers little compared with endogenous clearance (Bania et al, 1992). 2) Laussen et al (1991) report a 14-year-old female treated with plasmapheresis (using a PF1000 plasmafilter and a veno-venous extracorporeal circuit), charcoal hemoperfusion, and multiple dose activated charcoal for severe theophylline toxicity. a) TREATMENT - The serum theophylline concentration fell from 100 to 64 milligrams/liter during the 3 hour procedure (Laussen et al, 1991). She subsequently underwent 6 hours of charcoal hemoperfusion.
b) The serum theophylline concentration at the end of the charcoal hemoperfusion procedure was 17.5 milligrams/liter.
c) Approximately 3 hours into the hemoperfusion, she was extubated and begun on 12.5 grams of activated charcoal and 7.5 grams of magnesium sulfate by nasogastric tube every hour until charcoal appeared in stool.
d) ESTIMATED HALF-LIFE - The calculated elimination half-lives during plasmapheresis and hemoperfusion were 1.4 hours and 1.7 hours, respectively.
G) DIURESIS
1) Since only small amounts of unchanged theophylline are excreted by the kidneys, forced diuresis is ineffective in enhancing elimination.
H) PERITONEAL DIALYSIS
1) Peritoneal dialysis was ineffective, with theophylline clearances of 5 milliliters/minute (Miceli, 1980) and 10 to 49 milliliters/minute (Hendeles & Weinberger, 1980) being reported.
I) PREGNANCY
1) If the fetus develops severe distress, then hemoperfusion or hemodialysis of the mother should be considered. 2) Prematurity and low birth weights in newborns, hypotension and vaginal bleeding in the mother, and premature contractions or labor during or immediately after hemodialysis have been reported. 3) Hemodialysis in pregnant patients should include the use of isolated ultrafiltration for volume removal, the support of blood pressure with albumin, the use of a dialysate containing glucose and bicarbonate, and the use of low-dose heparin regimen (Nissenson, 1981). 4) Hemodialysis performed on a 21-year-old pregnant woman resulted in mild uterine contractions immediately following dialysis which terminated spontaneously after four hours. a) Fetal heart tones were not audible during dialysis or for fourteen hours after dialysis but were heard again approximately 30 hours after admission.
b) The patient delivered a normal, full-term viable baby four months later (Kurtz et al, 1966).
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