6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) SUMMARY 1) Consider activated charcoal in the prehospital setting if the patient is awake and can protect their airway and does not show signs of significant toxicity. If the patient is displaying signs of moderate to severe toxicity do NOT administer activated charcoal because of the risk of aspiration.
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).
C) NALOXONE 1) NALOXONE/SUMMARY a) Naloxone, a pure opioid antagonist, reverses coma and respiratory depression from all opioids. It has no agonist effects and can safely be employed in a mixed or unknown overdose where it can be diagnostic and therapeutic without risk to the patient.
b) Indicated in patients with mental status and respiratory depression possibly related to opioid overdose (Hoffman et al, 1991).
c) DOSE: The initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated due to the risk of opioid withdrawal in an opioid-tolerant individual; if delay in obtaining venous access, may administer subcutaneously, intramuscularly, intranasally, via nebulizer (in a patient with spontaneous respirations) or via an endotracheal tube (Vanden Hoek,TL,et al).
d) Recurrence of opioid toxicity has been reported to occur in approximately 1 out of 3 adult ED opioid overdose cases after a response to naloxone. Recurrences are more likely with long-acting opioids (Watson et al, 1998)
2) NALOXONE DOSE/ADULT a) INITIAL BOLUS DOSE: Because naloxone can produce opioid withdrawal in an opioid-dependent individual leading to severe agitation and hypertension, the initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated (Vanden Hoek,TL,et al). 1) This dose can also be given intramuscularly or subcutaneously in the absence of intravenous access (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Maio et al, 1987; Wanger et al, 1998).
b) Larger doses may be needed to reverse opioid effects. Generally, if no response is observed after 8 to 10 milligrams has been administered, the diagnosis of opioid-induced respiratory depression should be questioned (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). Very large doses of naloxone (10 milligrams or more) may be required to reverse the effects of a buprenorphine overdose (Gal, 1989; Jasinski et al, 1978). 1) Single doses of up to 24 milligrams have been given without adverse effect (Evans et al, 1973).
c) REPEAT DOSE: The effective naloxone dose may have to be repeated every 20 to 90 minutes due to the much longer duration of action of the opioid agonist used(Howland & Nelson, 2011). 1) OPIOID DEPENDENT PATIENTS: The goal of naloxone therapy is to reverse respiratory depression without precipitating significant withdrawal. Starting doses of naloxone 0.04 mg IV, or 0.001 mg/kg, have been suggested as appropriate for opioid-dependent patients without severe respiratory depression (Howland & Nelson, 2011). If necessary the dose may be repeated or increased gradually until the desired response is achieved (adequate respirations, ability to protect airway, responds to stimulation but no evidence of withdrawal) (Howland & Nelson, 2011). In the presence of opioid dependence, withdrawal symptoms typically appear within minutes of naloxone administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are dependant upon the naloxone dose and the degree and type of dependence.(Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
2) PRECAUTION should be taken in the presence of a mixed overdose of a sympathomimetic with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. Arrhythmogenic effects of naloxone may also be potentiated in the presence of severe hyperkalemia (McCann et al, 2002).
d) NALOXONE DOSE/CHILDREN 1) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/IM/subcutaneously maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008)
2) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg IV/intraosseous/IM/subcutaneouslymay repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010)
3) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
e) NALOXONE DOSE/NEONATE 1) The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kilograms of body weight (AAP, 1989; Kleinman et al, 2010).
2) Smaller doses (10 to 30 mcg/kg IV) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
3) POTENTIAL OF WITHDRAWAL: The risk of precipitating withdrawal in an addicted neonate should be considered. Withdrawal seizures have been provoked in infants from opioid-abusing mothers when the infants were given naloxone at birth to stimulate breathing (Gibbs et al, 1989).
4) In cases of inadvertent administration of an opioid overdose to a neonate, larger doses may be required. In one case of oral morphine intoxication, 0.16 milligram/kilogram/hour was required for 5 days (Tenenbein, 1984).
f) NALOXONE/ALTERNATE ROUTES 1) If intravenous access cannot be rapidly established, naloxone can be administered via subcutaneous or intramuscular injection, intranasally, or via inhaled nebulization in patients with spontaneous respirations. 2) INTRAMUSCULAR/SUBCUTANEOUS ROUTES: If an intravenous line cannot be secured due to hypoperfusion or lack of adequate veins then naloxone can be administered by other routes. 3) The intramuscular or subcutaneous routes are effective if hypoperfusion is not present (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). The delay required to establish an IV, offsets the slower rate of subcutaneous absorption (Wanger et al, 1998). 4) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration. It is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014). 5) INTRANASAL ROUTE: Intranasal naloxone has been shown to be effective in opioid overdose; bioavailability appears similar to the intravenous route (Kelly & Koutsogiannis, 2002). Based on several case series of patients with suspected opiate overdose, the average response time of 3.4 minutes was observed using a formulation of 1 mg/mL/nostril by a mucosal atomization device (Kerr et al, 2009; Kelly & Koutsogiannis, 2002). However, a young adult who intentionally masticated two 25 mcg fentanyl patches and developed agonal respirations (6 breaths per minute), decreased mental status and mitotic pupils did not respond to intranasal naloxone (1 mg in each nostril) administered by paramedics. After 11 minutes, paramedics placed an IV and administered 1 mg of IV naloxone; respirations normalized and mental status improved. Upon admission, 2 additional doses of naloxone 0.4 mg IV were needed. The patient was monitored overnight and discharged the following day without sequelae. Its suggested that intranasal administration can lead to unpredictable absorption (Zuckerman et al, 2014). a) Narcan(R) nasal spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray (Prod Info NARCAN(R) nasal spray, 2015).
b) FDA DOSING: Initial dose: 1 spray (4 mg) intranasally into 1 nostril. Subsequent doses: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized. Higher or repeat doses may be required for partial agonists or mixed agonist/antagonists (Prod Info NARCAN(R) nasal spray, 2015).
c) AMERICAN HEART ASSOCIATION GUIDELINE DOSING: Usual dose: 2 mg intranasally as soon as possible; may repeat after 4 minutes (Lavonas et al, 2015). Higher doses may be required with atypical opioids (VandenHoek et al, 2010).
d) ABSORPTION: Based on limited data, the absorption rate of intranasal administration is comparable to intravenous administration. The peak plasma concentration of intranasal administration is estimated to be 3 minutes which is similar to the intravenous route (Kerr et al, 2009). In rare cases, nasal absorption may be inhibited by injury, prior use of intranasal drugs, or excessive secretions (Kerr et al, 2009).
6) NEBULIZED ROUTE: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations (Weber et al, 2012). 7) ENDOTRACHEAL ROUTE: Endotracheal administration of naloxone can be effective(Tandberg & Abercrombie, 1982), optimum dose unknown but 2 to 3 times the intravenous dose had been recommended by some (Kleinman et al, 2010). g) NALOXONE/CONTINUOUS INFUSION METHOD 1) A continuous infusion of naloxone may be employed in circumstances of opioid overdose with long acting opioids (Howland & Nelson, 2011; Redfern, 1983).
2) The patient is given an initial dose of IV naloxone to achieve reversal of opioid effects and is then started on a continuous infusion to maintain this state of antagonism.
3) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis (Howland & Nelson, 2011; Mofenson & Caraccio, 1987). For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
4) Dose and duration of action of naloxone therapy varies based on several factors; continuous monitoring should be used to prevent withdrawal induction (Howland & Nelson, 2011).
5) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).
h) NALOXONE/PREGNANCY 1) In general, the smallest dose of naloxone required to reverse life threatening opioid effects should be used in pregnant women. Naloxone detoxification of opioid addicts during pregnancy may result in fetal distress, meconium staining and fetal death (Zuspan et al, 1975). When naloxone is used during pregnancy, opioid abstinence may be provoked in utero (Umans & Szeto, 1985).
6.5.2) PREVENTION OF ABSORPTION
A) ACTIVATED CHARCOAL 1) Administer activated charcoal for all substantial, recent ingestions if the patient is awake and can protect their airway. It is generally not recommended in patients with significant signs of opioid toxicity because of the risk of aspiration. 2) CHARCOAL ADMINISTRATION a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
3) CHARCOAL DOSE a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005). 1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
b) ADVERSE EFFECTS/CONTRAINDICATIONS 1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
4) EFFICACY a) Acetaminophen is well adsorbed by activated charcoal (Christophersen et al, 2002a; Hoegberg et al, 2002; Rose et al, 1991; Bainbridge et al, 1977; Van de Graff et al, 1982) and is most effective if given within one hour of ingestion of a liquid formulation (Anderson et al, 1999) or a tablet formulation (Christophersen et al, 2002). In normal volunteers, activated charcoal decreased the AUC of acetaminophen by 66% if administered one hour after acetaminophen ingestion (50 mg/kg) and by 22.7% when administered 2 hours after ingestion (Christophersen et al, 2002).
b) A series of 981 acetaminophen poisonings were analyzed. Patients ingesting less than 10 grams had very low risk for developing toxic serum concentrations. Patients who had ingested 10 grams or more and presented within 24 hours and were administered activated charcoal were significantly less likely to have probable or high risk serum concentrations (Buckley et al, 1999).
c) OPIOIDS: VOLUNTEER STUDIES demonstrate that activated charcoal can decrease opioid absorption (Laine et al, 1997).
6.5.3) TREATMENT
A) MONITORING OF PATIENT 1) ACETAMINOPHEN: Patients who present early (within 8 hours of ingestion) only require a serum acetaminophen determination. In those patients who require acetylcysteine treatment, liver enzymes, serum electrolytes, and renal function should be monitored. Patients who present with an unknown time of ingestion or more than 8 hours after an ingestion should have a serum acetaminophen determination, electrolyte measurements, renal function tests, liver enzymes, and an INR.
2) OPIOIDS: Monitor vital signs frequently, pulse oximetry, and continuous cardiac monitoring. Monitor for CNS and respiratory depression. Opioid plasma levels are not clinically useful or readily available. Urine toxicology screens may confirm exposure, but are rarely useful in guiding therapy. Obtain a chest x-ray for persistent hypoxia. Consider a head CT and/or lumbar puncture to rule out an intracranial mass, bleeding or infection, if the diagnosis is uncertain.
B) NALOXONE 1) NALOXONE/SUMMARY a) Naloxone, a pure opioid antagonist, reverses coma and respiratory depression from all opioids. It has no agonist effects and can safely be employed in a mixed or unknown overdose where it can be diagnostic and therapeutic without risk to the patient.
b) Indicated in patients with mental status and respiratory depression possibly related to opioid overdose (Hoffman et al, 1991).
c) DOSE: The initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated due to the risk of opioid withdrawal in an opioid-tolerant individual; if delay in obtaining venous access, may administer subcutaneously, intramuscularly, intranasally, via nebulizer (in a patient with spontaneous respirations) or via an endotracheal tube (Vanden Hoek,TL,et al).
d) Recurrence of opioid toxicity has been reported to occur in approximately 1 out of 3 adult ED opioid overdose cases after a response to naloxone. Recurrences are more likely with long-acting opioids (Watson et al, 1998)
2) NALOXONE DOSE/ADULT a) INITIAL BOLUS DOSE: Because naloxone can produce opioid withdrawal in an opioid-dependent individual leading to severe agitation and hypertension, the initial dose of naloxone should be low (0.04 to 0.4 mg) with a repeat dosing as needed or dose escalation to 2 mg as indicated (Vanden Hoek,TL,et al). 1) This dose can also be given intramuscularly or subcutaneously in the absence of intravenous access (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008; Maio et al, 1987; Wanger et al, 1998).
b) Larger doses may be needed to reverse opioid effects. Generally, if no response is observed after 8 to 10 milligrams has been administered, the diagnosis of opioid-induced respiratory depression should be questioned (Howland & Nelson, 2011; Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). Very large doses of naloxone (10 milligrams or more) may be required to reverse the effects of a buprenorphine overdose (Gal, 1989; Jasinski et al, 1978). 1) Single doses of up to 24 milligrams have been given without adverse effect (Evans et al, 1973).
c) REPEAT DOSE: The effective naloxone dose may have to be repeated every 20 to 90 minutes due to the much longer duration of action of the opioid agonist used(Howland & Nelson, 2011). 1) OPIOID DEPENDENT PATIENTS: The goal of naloxone therapy is to reverse respiratory depression without precipitating significant withdrawal. Starting doses of naloxone 0.04 mg IV, or 0.001 mg/kg, have been suggested as appropriate for opioid-dependent patients without severe respiratory depression (Howland & Nelson, 2011). If necessary the dose may be repeated or increased gradually until the desired response is achieved (adequate respirations, ability to protect airway, responds to stimulation but no evidence of withdrawal) (Howland & Nelson, 2011). In the presence of opioid dependence, withdrawal symptoms typically appear within minutes of naloxone administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are dependant upon the naloxone dose and the degree and type of dependence.(Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
2) PRECAUTION should be taken in the presence of a mixed overdose of a sympathomimetic with an opioid. Administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects. Arrhythmogenic effects of naloxone may also be potentiated in the presence of severe hyperkalemia (McCann et al, 2002).
d) NALOXONE DOSE/CHILDREN 1) LESS THAN 5 YEARS OF AGE OR LESS THAN 20 KG: 0.1 mg/kg IV/intraosseous/IM/subcutaneously maximum dose 2 mg; may repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008)
2) 5 YEARS OF AGE OR OLDER OR GREATER THAN 20 KG: 2 mg IV/intraosseous/IM/subcutaneouslymay repeat dose every 2 to 5 minutes until symptoms improve (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Krauss & Green, 2006). Although naloxone may be given via the endotracheal tube for pediatric resuscitation, optimal doses are unknown. Some experts have recommended using 2 to 3 times the IV dose (Kleinman et al, 2010)
3) AVOIDANCE OF OPIOID WITHDRAWAL: In cases of known or suspected chronic opioid therapy, a lower dose of 0.01 mg/kg may be considered and titrated to effect to avoid withdrawal: INITIAL DOSE: 0.01 mg/kg body weight given IV. If this does not result in clinical improvement, an additional dose of 0.1 mg/kg body weight may be given. It may be given by the IM or subQ route if the IV route is not available (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008)
e) NALOXONE DOSE/NEONATE 1) The American Academy of Pediatrics recommends a neonatal dose of 0.1 mg/kg IV or intratracheally from birth until age 5 years or 20 kilograms of body weight (AAP, 1989; Kleinman et al, 2010).
2) Smaller doses (10 to 30 mcg/kg IV) have been successful in the setting of exposure via maternal administration of narcotics or administration to neonates in therapeutic doses for anesthesia (Wiener et al, 1977; Welles et al, 1984; Fischer & Cook, 1974; Brice et al, 1979).
3) POTENTIAL OF WITHDRAWAL: The risk of precipitating withdrawal in an addicted neonate should be considered. Withdrawal seizures have been provoked in infants from opioid-abusing mothers when the infants were given naloxone at birth to stimulate breathing (Gibbs et al, 1989).
4) In cases of inadvertent administration of an opioid overdose to a neonate, larger doses may be required. In one case of oral morphine intoxication, 0.16 milligram/kilogram/hour was required for 5 days (Tenenbein, 1984).
f) NALOXONE/ALTERNATE ROUTES 1) If intravenous access cannot be rapidly established, naloxone can be administered via subcutaneous or intramuscular injection, intranasally, or via inhaled nebulization in patients with spontaneous respirations. 2) INTRAMUSCULAR/SUBCUTANEOUS ROUTES: If an intravenous line cannot be secured due to hypoperfusion or lack of adequate veins then naloxone can be administered by other routes. 3) The intramuscular or subcutaneous routes are effective if hypoperfusion is not present (Prod Info naloxone HCl IV, IM, subcutaneous injection solution, 2008). The delay required to establish an IV, offsets the slower rate of subcutaneous absorption (Wanger et al, 1998). 4) Naloxone Evzio(TM) is a hand-held autoinjector intended for the emergency treatment of known or suspected opioid overdose. The autoinjector is equipped with an electronic voice instruction system to assist caregivers with administration. It is available as 0.4 mg/0.4 mL solution for injection in a pre-filled auto-injector (Prod Info EVZIO(TM) injection solution, 2014). 5) INTRANASAL ROUTE: Intranasal naloxone has been shown to be effective in opioid overdose; bioavailability appears similar to the intravenous route (Kelly & Koutsogiannis, 2002). Based on several case series of patients with suspected opiate overdose, the average response time of 3.4 minutes was observed using a formulation of 1 mg/mL/nostril by a mucosal atomization device (Kerr et al, 2009; Kelly & Koutsogiannis, 2002). However, a young adult who intentionally masticated two 25 mcg fentanyl patches and developed agonal respirations (6 breaths per minute), decreased mental status and mitotic pupils did not respond to intranasal naloxone (1 mg in each nostril) administered by paramedics. After 11 minutes, paramedics placed an IV and administered 1 mg of IV naloxone; respirations normalized and mental status improved. Upon admission, 2 additional doses of naloxone 0.4 mg IV were needed. The patient was monitored overnight and discharged the following day without sequelae. Its suggested that intranasal administration can lead to unpredictable absorption (Zuckerman et al, 2014). a) Narcan(R) nasal spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL intranasal spray (Prod Info NARCAN(R) nasal spray, 2015).
b) FDA DOSING: Initial dose: 1 spray (4 mg) intranasally into 1 nostril. Subsequent doses: Use a new Narcan(R) nasal spray and administer into alternating nostrils. May repeat dose every 2 to 3 minutes. Requirement for repeat dosing is dependent on the amount, type, and route of administration of the opioid being antagonized. Higher or repeat doses may be required for partial agonists or mixed agonist/antagonists (Prod Info NARCAN(R) nasal spray, 2015).
c) AMERICAN HEART ASSOCIATION GUIDELINE DOSING: Usual dose: 2 mg intranasally as soon as possible; may repeat after 4 minutes (Lavonas et al, 2015). Higher doses may be required with atypical opioids (VandenHoek et al, 2010).
d) ABSORPTION: Based on limited data, the absorption rate of intranasal administration is comparable to intravenous administration. The peak plasma concentration of intranasal administration is estimated to be 3 minutes which is similar to the intravenous route (Kerr et al, 2009). In rare cases, nasal absorption may be inhibited by injury, prior use of intranasal drugs, or excessive secretions (Kerr et al, 2009).
6) NEBULIZED ROUTE: DOSE: A suggested dose is 2 mg naloxone with 3 mL of normal saline for suspected opioid overdose in patients with some spontaneous respirations (Weber et al, 2012). 7) ENDOTRACHEAL ROUTE: Endotracheal administration of naloxone can be effective(Tandberg & Abercrombie, 1982), optimum dose unknown but 2 to 3 times the intravenous dose had been recommended by some (Kleinman et al, 2010). g) NALOXONE/CONTINUOUS INFUSION METHOD 1) A continuous infusion of naloxone may be employed in circumstances of opioid overdose with long acting opioids (Howland & Nelson, 2011; Redfern, 1983).
2) The patient is given an initial dose of IV naloxone to achieve reversal of opioid effects and is then started on a continuous infusion to maintain this state of antagonism.
3) DOSE: Utilize two-thirds of the initial naloxone bolus on an hourly basis (Howland & Nelson, 2011; Mofenson & Caraccio, 1987). For an adult, prepare the dose by multiplying the effective bolus dose by 6.6, and add that amount to 1000 mL and administer at an IV infusion rate of 100 mL/hour (Howland & Nelson, 2011).
4) Dose and duration of action of naloxone therapy varies based on several factors; continuous monitoring should be used to prevent withdrawal induction (Howland & Nelson, 2011).
5) Observe patients for evidence of CNS or respiratory depression for at least 2 hours after discontinuing the infusion (Howland & Nelson, 2011).
h) NALOXONE/PREGNANCY 1) In general, the smallest dose of naloxone required to reverse life threatening opioid effects should be used in pregnant women. Naloxone detoxification of opioid addicts during pregnancy may result in fetal distress, meconium staining and fetal death (Zuspan et al, 1975). When naloxone is used during pregnancy, opioid abstinence may be provoked in utero (Umans & Szeto, 1985).
C) AIRWAY MANAGEMENT 1) Administer oxygen and assist ventilation for respiratory depression. Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone, or in patients who develop severe acute lung injury.
2) REFRACTORY: A case of massive oxycodone controlled release ingestion refractory to naloxone (188 mg naloxone given over 14 hours) has been reported. In this case, naloxone was discontinued and the patient's trachea was intubated in order to maintain adequate ventilation. Mechanical ventilation was required for about 72 hours (Schneir et al, 2002).
D) ACETAMINOPHEN MEASUREMENT 1) Obtain a plasma level 4 hours after ingestion or as soon as possible thereafter. Patients with an initial level above the lower "treatment" line on the Rumack-Matthew Nomogram are at risk for delayed hepatotoxicity and should receive the full prophylactic NAC treatment regimen. Patients with subtoxic initial levels do not require NAC therapy. 2) Do not delay NAC therapy for lack of a level in patients presenting 8 hours or more postingestion or if time of ingestion is unknown. Administer loading dose and discontinue if the level comes back below the treatment line. Protection from fatal hepatotoxicity is generally considered complete if NAC therapy is begun within 10 hours of ingestion (Daly et al, 2008; Clark, 1998). 3) Patients presenting 24 hours or more after ingestion who have measurable acetaminophen levels or biochemical evidence of hepatotoxicity should receive NAC therapy. 4) In patients who develop biochemical evidence of hepatotoxicity, NAC should be continued until hepatotoxicity improves. 5) TIMING: The nomogram is used to interpret a single plasma level obtained between 4 and 24 hours after a single acute ingestion. Levels obtained before 4 hours or after 24 hours cannot be interpreted, nor can levels obtained after chronic overdose. a) Obtain a plasma acetaminophen level 4 or more hours after ingestion and plot it on the Rumack-Matthew Nomogram. Levels obtained prior to 4 hours may not represent peak plasma levels and CANNOT be used to predict hepatotoxicity and need for NAC therapy. Greatest accuracy is obtained with samples done between 4 and 12 hours.
6) CO-INGESTANTS: Suicidal overdoses often involve multiple ingestions, which may alter the pharmacokinetics of acetaminophen. Inaccurate histories of these overdoses are the general rule, and any patient "near" the treatment line in the Rumack-Matthew Nomogram should be treated (Clark, 1998). a) Concomitantly ingested drugs (particularly those with anticholinergic or opioid effects) or foods may affect gastric emptying and time to peak plasma level. Additional levels may be needed to determine the peak (Linden & Rumack, 1984; Tighe & Walter, 1994; Gesell & Stephan, 1996; Tsang & Nadroo, 1999).
7) CHRONIC ALCOHOLISM: Conflicting reports are found in the literature regarding whether or not a lower treatment line on the Rumack-Matthew Nomogram should be used for treating acute acetaminophen overdoses in chronic alcoholics. On the one hand, a review of the literature has shown in animal studies that a lower dose of acetaminophen is required to produce hepatotoxicity following chronic alcohol use due to induction of CYP enzymes and glutathione depletion. It is suggested that the animal results may apply to human cases, and some authors suggest a conservative guess of halving the dose/concentration for treatment (Buckley & Srinivasan, 2002). On the other hand, due to species differences in CYP expression, activity, and induction, results cannot always be extrapolated from animals to human cases. Also, a literature review does not conclusively substantiate that exposure to chronic excessive amounts of alcohol will predispose acetaminophen overdose patients to hepatotoxicity (Dargan & Jones, 2002). a) A number of investigators have suggested that chronic ethanol exposure increases the risk of acetaminophen-induced hepatic injury. Conservative interpretation of acetaminophen levels in alcoholics has been recommended by some authors (Cheung et al, 1994; Seeff et al, 1986; Lauterburg & Velez, 1988).
8) LATE PRESENTATION a) After 24 hours postingestion, the presence of acetaminophen in the plasma may be documented, but interpretation of these levels is difficult. Because of increasing evidence of the beneficial effect of NAC instituted more than 24 hours after overdose, its use is recommended in patients presenting 24 hours or more postingestion who have measurable acetaminophen levels or biochemical evidence of hepatic injury (Parker et al, 1990; Harrison et al, 1990; Keays et al, 1991; Tucker, 1998; Buckley et al, 1999a).
b) Certain serum acetaminophen assays are insensitive below 10 mcg/mL (greater than 66.16 Standard International Units (micromole/L)), rendering the Rumack-Matthew Nomogram invalid in patients who present greater than 19 hours after acetaminophen ingestion with no recordable levels. The authors recommend that these patients receive NAC therapy until 24 hours since the last acetaminophen ingestion, at which point it can be discontinued providing there is no detectable serum acetaminophen or clinical or biochemical evidence of hepatotoxicity (Donovan et al, 1999).
c) In a population-based incidence and outcome study of acetaminophen poisoning, it was determined that atypical presenters, those whose risk cannot be estimated using the Rumack-Matthew Nomogram, represented 44% of the hospitalized patients and 83% of those who suffered significant hepatic injury. This group represents patients with the poorest outcome (Bond & Hite, 1999).
d) In late presenters following acetaminophen overdose, the best prognostic marker in established hepatotoxicity is the prothrombin time. Extended courses of NAC may be given until the prothrombin time improves (Jones, 2000).
E) ACETYLCYSTEINE 1) N-ACETYLCYSTEINE PROTOCOLS, SUMMARY a) The most common protocol used in the US for prevention of acetaminophen-induced liver injury after acute overdose is the 72-hour oral protocol. In addition, the 21-hour IV NAC protocol is available in the US. Outside the US, the 20-hour intravenous protocol (Prescott protocol) is most commonly used. In patients who develop hepatic injury, NAC therapy should be continued until hepatic function improves.
2) N-ACETYLCYSTEINE, ORAL a) Patients receiving NAC therapy should meet the following criteria: 1) Plasma acetaminophen level in the potentially toxic range on the nomogram supplied with POISINDEX(R) or Mucomyst(R) package insert, OR
2) History of known or suspected acute ingestion of 10 g or 200 mg/kg or more acetaminophen if results of plasma levels cannot be obtained within 8 to 10 hours of ingestion, OR
3) In patients presenting more than 24 hours after an acute ingestion who have measurable acetaminophen levels, the use of NAC should be strongly considered.
1) TIME TO THERAPY: In patients with either a possible or probable risk for hepatotoxicity, as determined by the Rumack-Matthew Nomogram, NAC therapy should be initiated within 8 to 10 hours of ingestion if possible (Wolf et al, 2007). a) NAC efficacy decreased progressively from 8 to 16 hours postingestion in a study of 2540 cases of acute acetaminophen overdose (Smilkstein et al, 1988).
b) Studies have shown increases in hepatotoxicity from 2% to 41% (Prescott et al, 1979) and 7 to 29 percent (Rumack et al, 1981) if more than a 10 hour delay to treatment occurs. Also, 4.4% to 13.2% increases in hepatotoxicity were seen if more than an 8 hour delay to treatment occurred (Smilkstein et al, 1988).
2) LOADING DOSE: Give 140 mg/kg NAC as a 5% solution. a) DILUTION: NAC is available as a 20% and 10% solution and should be diluted to 5% in a soft drink, juice, or water for oral or nasogastric administration: 3) MAINTENANCE DOSE: 70 mg/kg every 4 hours, starting 4 hours after the loading dose, for a total of 17 doses. a) DILUTION: b) If the patient weighs less than 20 kg, calculate the dose of acetylcysteine. Each mL of 20% acetylcysteine solution contains 200 mg of acetylcysteine (Prod Info acetylcysteine oral solution, solution for inhalation, 2007). c) Maintenance doses may be discontinued if the INITIAL (4-hour) acetaminophen assay reveals a nontoxic level. d) In selected patients (not actively suicidal, deemed reliable to take medication and return for liver function tests, not requiring parenteral antiemetics, and without evidence of significant hepatotoxicity), outpatient therapy with oral NAC and careful follow-up may be a reasonable alternative (Dean & Krenzelok, 1994). e) In 131 cases of confirmed toxic acetaminophen poisoning, there were 6 patients who received 4 to 6 doses of NAC during hospitalization in one center, but were discharged to home with the remaining 11 to 13 doses. Follow-up at 1 to 3 weeks postdischarge determined dosing compliance to be 83%, suggesting that self-administration of NAC in the home setting may offer an acceptable alternative (Dean et al, 1996). b) EFFERVESCENT TABLET PREPARATION 1) Effervescent tablets are for ORAL administration only; not for nebulization or intratracheal instillation (Prod Info CETYLEV oral effervescent tablets for solution, 2016). 2) Once the tablet is dissolved, administer immediately. Once prepared for dilution, the effervescent formulation is interchangeable with 20% acetylcysteine solution, when given at the same dosage (Prod Info CETYLEV oral effervescent tablets for solution, 2016). 3) ADULTS and PEDIATRICS: The recommended LOADING DOSE of this formulation is 140 mg/kg. MAINTENANCE DOSE is 70 mg/kg administered 4 hours after the loading dose, and repeated every 4 hours for a total of 17 doses (Prod Info CETYLEV oral effervescent tablets for solution, 2016). a) PATIENTS WEIGHING 1 TO 19 KG: Create a 50 mg/mL solution with two 2.5 gram tablets and 100 mL water and use an oral syringe to administer the appropriate dose (Prod Info CETYLEV oral effervescent tablets for solution, 2016). 1) LOADING DOSE: Calculate the dose by multiplying the patient's kilogram weight by 140 mg/kg and divide by the concentration (50 mg/mL) of the solution. The resulting dose is in mL for administration via an oral syringe (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
2) MAINTENANCE DOSE: Calculate the dose by multiplying the patient's kilogram weight by 70 mg/kg and divide by the concentration (50 mg/mL) of the solution. The resulting dose is in mL for administration via an oral syringe (Prod Info CETYLEV oral effervescent tablets for solution, 2016).
b) PATIENTS WEIGHING 20 TO 59 KG: Dissolve the tablet in 150 mL of water (Prod Info CETYLEV oral effervescent tablets for solution, 2016). c) PATIENTS WEIGHING 60 KG OR GREATER: Dissolve the tablet in 300 mL of water (Prod Info CETYLEV oral effervescent tablets for solution, 2016). d) PATIENTS WEIGHING OVER 100 KG: Limited information. No studies have been conducted to determine if dose adjustments are needed in patients weighing over 100 kg (Prod Info CETYLEV oral effervescent tablets for solution, 2016). 4) PATIENTS WEIGHING 20 KG or GREATER: Dissolve the appropriate number of 2.5-gram and/or 500-mg tablets in water according to the following table (Prod Info CETYLEV oral effervescent tablets for solution, 2016): 5) SODIUM CONTENT a) Cetylev(TM) tablets contain sodium, which may be a concern for patients with conditions sensitive to excess sodium intake (eg, congestive heart failure hypertension, renal impairment). The amount of sodium per tablet is as follows (Prod Info CETYLEV oral effervescent tablets for solution, 2016): 1) 500 mg tablet: contains 320 mg sodium bicarbonate, of which 88 mg (3.8 mEq) is sodium.
2) 2.5 g tablet: contains 1600 mg sodium bicarbonate, of which 438 mg (19 mEq) is sodium.
c) ADVERSE EFFECTS 1) SUMMARY: Common adverse reactions to oral NAC include vomiting and diarrhea. Rarely, generalized urticaria has been described (Heard, 2008; Charley et al, 1987; Bateman et al, 1984). There is one reported case of a serum sickness-like reaction (fever, arthralgias, thrombocytopenia, and rash) temporally associated with NAC therapy and relieved with diphenhydramine and discontinuation of NAC (Mohammed et al, 1994). 2) PERSISTENT VOMITING: If any given dose is vomited within an hour of administration, the dose should be repeated. If recurrent vomiting develops, switch to the intravenous formulation. If the intravenous NAC cannot be administered, aggressive use of antiemetics is indicated for persistent vomiting, as NAC is less effective in preventing hepatotoxicity when administration is delayed. a) Make sure patient is receiving a 5% solution of NAC, not 10% or 20%.
b) METOCLOPRAMIDE (Reglan(R)) 1 mg/kg intravenously or intramuscularly 30 minutes before the NAC dose (may produce extrapyramidal reactions). Intravenous doses of more than 10 mg should be diluted in 50 mL of normal saline and administered as an infusion over 15 minutes. When used with emetogenic chemotherapy doses of 1 mg/kg may be repeated every 2 hours for 2 doses and then every 3 hours for 3 doses (Prod Info REGLAN(R) intravenous, intramuscular injection, 2009). The need for continued high doses should be assessed for the individual patient.
c) In adults and adolescents, prochlorperazine 10 mg intravenously (not to exceed 40 mg/day) and diphenhydramine 25 to 50 mg intravenously (not to exceed 400 mg/day) may be added to this regimen.
d) NASOGASTRIC TUBE: Insert a nasogastric tube and infuse dose over 30 to 60 minutes. If patient vomits and tube is in stomach, pass into duodenum if possible.
e) ONDANSETRON 0.15 mg/kg intravenously has also been used successfully in this setting (Tobias et al, 1992; Reed & Marx, 1994; Clark et al, 1996; Scharman, 1998).
f) INTRAVENOUS ADMINISTRATION OF ORAL NAC: The NAC preparation used for oral administration is NOT FDA approved for intravenous administration; however, it has been administered intravenously when the intravenous NAC formulation was not available (Amirzadeh & McCotter, 2002).
g) In a retrospective study of 76 patients treated intravenously with the oral NAC formulation, 4 patients (5.3%) developed mild adverse events (Yerman et al, 1995).
3) EFFICACY: Of 2540 patients treated with oral NAC, hepatotoxicity developed in 6.1% of patients with probable risk who began treatment within 10 hours of ingestion and 26.4% of those who began therapy between 10 and 24 hours following ingestion (Smilkstein et al, 1988). a) Probable risk was defined as initial plasma concentration above a line defined by 200 mcg/mL at 4 hours and 50 mcg/mL at 12 hours.
b) Hepatotoxicity developed in 41% of the 283 patients who did not begin therapy until 16 to 24 hours after ingestion.
c) A 7% incidence of liver damage was reported in 57 patients in whom therapy was begun within 10 hours of ingestion; a 29% incidence in 52 patients who began therapy 10 to 16 hours after ingestion; and a 62% incidence in 39 patients who began treatment 16 to 24 hours after ingestion (Rumack et al, 1981a).
3) SHORTER ORAL NAC PROTOCOL a) A shorter duration of oral NAC has been recommended for acute acetaminophen overdoses presenting within 24 hours of ingestion. Several small studies suggest that oral NAC loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours until the serum acetaminophen level is no longer detectable and aminotransferase levels are normal, is safe and effective (Betten et al, 2007; Tsai et al, 2005; Woo et al, 2000; Woo et al, 1995). Because of the shorter hospitalization and associated costs, this protocol may be preferable in patients presenting soon after an acute ingestion. 1) STUDIES a) In a retrospective case series study (n=27), the efficacy of a patient-tailored NAC protocol was evaluated by comparing the incidence of hepatotoxicity in patients receiving this protocol (using the above dosing) with that in historical controls receiving 1 of 2 fixed-duration protocols (oral NAC for 72 hours and intravenous NAC for 20 hours within 8 to 10 hours of acute acetaminophen intoxication). Overall, the incidence of hepatotoxicity was low in patient-tailored NAC therapy and was comparable to that in historical controls (Tsai et al, 2005)
b) In a retrospective study, 62 patients with acute acetaminophen overdose who presented within 24 hours of ingestion with normal liver function were treated with oral NAC 140-mg/kg loading dose followed by 70 mg/kg every 4 hours until the acetaminophen level was undetectable. Of these, 23 patients were treated for less than 24 hours, 17 were treated for between 24 and 36 hours and 22 were treated for between 37 and 63 hours. Five patients developed AST greater than 1000 units/L; two of these patients were treated within 10 hours of ingestion (Woo et al, 1995).
c) In a prospective observational study, 250 consecutive acetaminophen overdose patients were evaluated to test the hypothesis that patients with normal AST and ALT levels determined 36 hours following the overdose do not subsequently develop liver damage with discontinuation of NAC. The average length of therapy was 36 hours, and follow-up in 90% revealed no subsequent liver damage when NAC was stopped at 36 hr (Roth et al, 1999).
d) In a prospective case series (n=47) of acetaminophen toxic ingestions, all patients were treated with oral NAC for a minimum of 24 hours. In 79% of these cases (n=37), NAC was discontinued prior to 17 doses, with 49% of these patients receiving 6 NAC doses, 49% receiving 7 to 12 doses, and 3% receiving 13 to 16 doses. No adverse outcomes were reported following early NAC discontinuation (Clark et al, 2001).
4) 21-HOUR IV NAC PROTOCOL a) This is the standard FDA-approved dosing regimen used in Europe (Prescott protocol). NAC is used for prophylaxis/prevention of acetaminophen-induced hepatic injury. LOADING DOSE: 150 mg/kg in 200 mL of 5% dextrose, infuse intravenously over 60 minutes. MAINTENANCE DOSE: 50 mg/kg in 500 mL of 5% dextrose, infuse intravenously over 4 hours followed by 100 mg/kg in 1000 mL of 5% dextrose, infuse intravenously over 16 hours (Daly et al, 2008; Prod Info ACETADOTE(R) IV injection, 2006; Prescott et al, 1979). b) Acetadote(R) is available in 30-mL (200 mg/mL) single-dose glass vials(Prod Info ACETADOTE(R) IV injection, 2006). c) In patients who develop hepatic injury secondary to acetaminophen, NAC therapy should be continued until serum acetaminophen concentration is undetectable and liver function improves (Smith et al, 2008). d) To obtain more information, you can contact Cumberland Pharmaceuticals, Inc. at 1-866-767-5077. e) CASE REPORT: A 78-year-old man, with a past medical history of coronary artery disease and renal insufficiency, intentionally ingested approximately 48 g of acetaminophen (ninety-six (96) 500-mg tablets) over a 1-hour period. Baseline laboratory data, on hospital admission, revealed a serum creatinine of 3.4 mg/dL, but normal liver enzyme levels (AST, 8 units/L; ALT, 22 units/L), bilirubin level, and prothrombin time (13.5 seconds). A serum acetaminophen level, obtained 2.25 hours postingestion, was 264 mcg/mL. Intravenous NAC was initiated 5 hours postingestion and continued for 21 hours. Because of normal liver enzyme and bilirubin levels, NAC was discontinued after 21 hours of therapy despite a serum acetaminophen concentration of 116 mcg/mL at the time NAC was discontinued. Intravenous NAC was restarted 24 hours later, at which time the patient's AST and ALT levels were 395 and 453 units/liter, respectively. Over the next few days, AST and ALT levels peaked at 4350 and 5621 units/L and his PT was 51.4 seconds. IV NAC was continued until normalization of lab values. The authors conclude that because of a possibility of delayed and erratic absorption following massive acetaminophen overdose ingestions, it is recommended that intravenous NAC should be continued until serum acetaminophen concentrations are undetectable and liver function improves (Smith et al, 2008). f) PEDIATRIC 1) PRECAUTIONS: Standard intravenous dosing can cause hyponatremia and seizures secondary to large amounts of free water. To avoid this complication, the manufacturer has recommended the following dosing guideline (Prod Info ACETADOTE(R) IV injection, 2006): 2) CASE REPORT: Approximately 9 hours after the initiation of 20-hour intravenous NAC therapy, a 3.5-year-old female (13 kg) with acetaminophen poisoning (level 1701 mcmol/L) developed hyponatremia (118 mmol/L) and tonic-clonic seizures; the 20-hour intravenous NAC protocol, as outlined by the manufacturer, suggested a loading dose of 11.25 mL of 20% NAC mixed with 40 mL of 5% dextrose for administration over 15 minutes and a maintenance infusion dose of 3.75 mL of NAC in 500 mL of 5% dextrose over 4 hours, followed by 7.5 mL of NAC in 1 L of 5% dextrose over 16 hours. Following supportive care, the child made a complete neurological recovery (Sung et al, 1997). 3) If the protocol were completed, this patient would have received 1540 mL of 5% dextrose over 20.25 hours. The authors recommended that if the 20-hour IV protocol is chosen, instead of using an absolute volume in which to dilute the NAC, a final concentration of 40 mg/mL (1 mL of 20% NAC with 4 mL of diluent (5% dextrose) to obtain a final volume of 5 mL with a concentration of 40 mg/mL) should be used. This process will avoid both sudden decreases in serum sodium and fluid overload in small children (Sung et al, 1997). g) ADVERSE EFFECTS 1) ADVERSE DRUG REACTIONS reported to the Australian Adverse Drug Reactions Advisory Committee between January 1, 1979 and September 30, 1987 included: rash (26/30), pruritus (16/30), angioedema (9/30), nausea and vomiting (9/30), bronchospasm (8/30), tachycardia (4/30), hypotension (3/30), and hypertension (2/30). These adverse effects were also reported by the manufacturer (Prod Info Acetadote(R), 2004).
2) TIMING: Average time to onset of adverse effect following NAC infusion was 30 minutes (range, 5 to 70 minutes) (Dawson et al, 1989). The most serious adverse reactions, which are dose-related, occur during or shortly after the loading dose. Slowing the rate of the NAC infusion loading dose (give over 30 to 60 minutes) may avoid some of the adverse reactions (Buckley et al, 1999a).
3) Adverse reactions were reported in 8 of 56 (14%) Chinese patients treated with intravenous NAC by the European protocol. Rash was most likely to develop during the initial high dose infusion of NAC (6 of 7 patients with rash). One patient developed a fever (Chan & Critchley, 1994).
4) ASTHMA: Patients with asthma are considered to be at increased risk for the development of adverse reactions to intravenous NAC (odds ratio, 2.9; 95% confidence interval, 2.1 to 4.7) (Schmidt & Dalhoff, 2000).
5) A randomized trial, conducted to evaluate the incidence of adverse effects following an initial NAC dose infused over a period of 60 minutes compared with an infusion period of 15 minutes in patients with acetaminophen poisoning, demonstrated that there was no significant reduction in drug-related adverse effects with the 60-minute infusion. The incidence of NAC-related adverse effects was 45% (n=109) in the 15-minute group and 38% (n=71) in the 60-minute group (Kerr et al, 2005).
h) ANAPHYLACTOID REACTIONS 1) Monitor closely for bronchospasm or anaphylaxis during administration of the first dose of NAC. Asthmatics appear to be more likely to develop adverse reactions, including anaphylaxis, to intravenous NAC than non-asthmatics (Daly et al, 2008; Schmidt & Dalhoff, 2000). 2) Severe anaphylactoid reactions to intravenous NAC therapy following acetaminophen overdoses have been reported (Heard, 2008; Bonfiglio et al, 1992; Vale & Wheeler, 1982; Walton et al, 1979), one of which resulted in death (Anon, 1984). 3) SYMPTOMS: Includes erythematous rash, itching, nausea, vomiting, dizziness, dyspnea, and tachycardia. Acute bronchospasm has been reported in 2 asthmatic patients within 15 minutes of receiving the loading dose of intravenous NAC (Ho & Beilin, 1983). Abrupt respiratory arrest occurred in one asthmatic prior to completion of her loading dose of NAC (Reynard et al, 1992). 4) INCIDENCE: In a non-randomized trial of 223 acute acetaminophen overdose patients, 32 (14.3%) experienced adverse reactions. Among the reactions, 91% were self-limited and consisted of transient erythema or mild urticaria (Smilkstein et al, 1991). 5) TREATMENT GUIDELINES: Based on a 6-year, retrospective case series of hospitalized patients with anaphylactoid reactions to NAC, Guidelines were developed for the treatment of NAC anaphylactoid reactions (Bailey & McGuigan, 1998): 1) Flushing: no treatment, continue NAC
2) Urticaria: diphenhydramine, continue NAC
3) Angioedema/respiratory symptoms: diphenhydramine, symptomatic care; stop NAC and restart 1 hr after diphenhydramine in the absence of symptoms
a) In a prospective series of 50 patients with reactions to intravenous NAC (31 cutaneous, 19 systemic) treated using these guidelines, only one patient (whose treatment deviated from the guidelines) developed a recurrence of symptoms (Bailey & McGuigan, 1998).
b) Anaphylactoid reactions may occur more frequently during the initial loading dose of NAC given in the emergency department. The risk of developing an anaphylactoid reaction appears to be lower with slower initial NAC infusion rates (60-minute vs 15-minute infusion rate); however, some patients may still develop reactions. Patients may tolerate repeat dosing at slower infusion rates when symptoms resolve and following administration of an antihistamine. If IV administration of NAC cannot be tolerated, oral dosing may be necessary (Pizon & LoVecchio, 2006).
i) FACIAL FLUSHING 1) Facial or chest flushing is common, beginning 15 to 75 minutes after initiation of infusion, and is associated with peak NAC plasma concentrations of 100 to 600 mcg/L (Donovan et al, 1988).
j) PROTHROMBIN INDEX 1) A decrease in the prothrombin index (which corresponds to an increase in prothrombin time or INR) has been reported following administration of IV NAC for treatment of patients with paracetamol poisoning who did not exhibit signs of hepatocellular injury. The time of the decrease appeared to be associated with the start of the NAC infusion instead of with the ingestion of paracetamol. Because prothrombin time is measured as a prognostic indicator in patients with paracetamol (acetaminophen) poisoning, the concern is that the decrease in prothrombin index may be misinterpreted as a sign of liver failure. The authors conclude that patient management decisions should not be based solely on the measurement of this value (Schmidt et al, 2002a; Pol & Lebray, 2002).
k) DISCONTINUATION CRITERIA 1) Discontinue intravenous acetylcysteine if a serious adverse reaction occurs.
5) NAC IN PATIENTS WITH HEPATIC INJURY a) It is recommended that NAC be given to those patients who develop acetaminophen-associated hepatic failure but cannot be risk stratified by the Rumack-Matthew Nomogram (Wolf et al, 2007). b) In patients with hepatotoxicity or hepatic failure prolonged courses of NAC therapy may be needed. NAC should be continued, using one of the above regimens, until clinical and biochemical markers of hepatic injury improve. 1) NAC therapy (intravenous) was shown to improve clinical outcome (progression of hepatic encephalopathy and/or fatality) when administered between 12 and 36 hours postingestion in a retrospective study of 100 patients with fulminant hepatic failure from acetaminophen overdose (Harrison et al, 1990). a) Survival was increased and the incidence of cerebral edema, fever, and hypotension decreased in a group of patients with acetaminophen-induced hepatic failure in whom intravenous NAC was started 36 to 80 hours postingestion compared with untreated controls presenting 22 to 96 hours postingestion (Keays et al, 1991a).
F) PATIENT CURRENTLY PREGNANT 1) CONCLUSION: Pregnant overdose patients with a toxic concentration of acetaminophen should be treated with NAC and delivery should not be induced in attempts to prevent fetal acetaminophen toxicity. a) In a series of 4 pregnant patients who delivered while receiving NAC therapy for acetaminophen overdose, it was found that the mean cord blood (in one case with fetal demise cardiac blood was used) NAC level at the time of delivery was 9.4 mcg/mL, which is within the range normally seen in patients receiving therapeutic NAC (Horowitz et al, 1997). Administering NAC to the mother as soon as possible after the overdose is the most effective means of preventing hepatotoxicity in mother and fetus (Riggs et al, 1989).
b) NAC therapy should be continued in the infant if delivered before the mother completes the entire course of therapy. Infants born with biochemical evidence of acetaminophen-induced hepatic injury should continue to receive NAC until clinical and biochemical parameters improve.
2) CASE REPORTS a) Sixty cases of acetaminophen overdose without evidence of teratogenesis have been reported. Twenty-four had serum levels above the nomogram line. Nine women had spontaneous abortions or stillbirths. One fetal death was recorded in the second and third trimesters. One third-trimester hepatotoxic patient delivered a 32 week stillborn during the course of NAC treatment. The plasma acetaminophen concentration in the stillborn was 360 mcg/mL (therapeutic range is 10 to 20 mcg/mL) and the autopsy showed massive hepatic necrosis (Riggs et al, 1989).
3) The majority of pregnancy outcomes (81%) were normal in 48 cases of acetaminophen overdose during pregnancy (McElhatton et al, 1990). 4) ANIMAL DATA: Fetal and neonatal liver cells have the ability to oxidize drugs during the first part of gestation and form reactive metabolites which could cause liver damage (Rollins et al, 1979a). Therefore, the human fetus may be at risk from acetaminophen overdose. G) HEPATIC FAILURE 1) Supportive measures should be instituted in the event that signs of hepatic failure develop. NAC therapy should be continued, using one of the above regimens, until biochemical and clinical evidence of hepatic injury improves. 2) HEMOPERFUSION a) CONCLUSION: Although one study demonstrates an increased survival rate (16 of 23 patients) following early hemoperfusion, more controlled clinical studies need to be performed before this procedure can be considered a routine treatment for acetaminophen-induced hepatic failure (Gimson et al, 1982).
3) ALBUMIN DIALYSIS a) A molecular adsorbent recirculating system (MARS), which is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchange columns, has been used following a massive acetaminophen overdose in a patient with hepatic encephalopathy (grade II), severe acidosis, INR of 7, and hepatorenal syndrome. The patient was rejected for liver transplantation. Albumin dialysis allowed time for hepatic regeneration during conventional supportive care in this case. A course of 5 consecutive 8-hour treatments was performed (McIntyre et al, 2002; Mitzner et al, 2000).
b) CASE REPORT: Single-pass albumin dialysis (SPAD) was successfully performed on a 41-year-old woman who developed hepatic failure following an acute acetaminophen overdose. Following ICU admission (hospital day 2), the patient had fulfilled King's criteria for transplantation (pH, 7.24; INR, 7.2; model for end-stage liver disease (MELD) score of 40); however, she was deemed unsuitable for transplantation due to psychosocial comorbidities. Approximately 10 hours post-ICU admission, the patient was started on continuous veno-venous hemodiafiltration for management of lactic acidosis and oliguria. On hospital day 3, SPAD was started, consisting of 14 hours/day for 4 days and 1 day of 21 hours for a total of 77 hours. Prior to SPAD, ALT and AST levels peaked at 6828 and 15,721 units/L, respectively. Following the last day of treatment, ALT and AST levels decreased to 596 and 126 units/L, respectively, and her INR was 2.1. The patient gradually recovered and was discharged 46 days post-presentation without sequelae (Karvellas et al, 2008).
4) EXTRACORPOREAL SORBENT-BASED DEVICES a) Acetaminophen-induced hepatitis or hepatic failure has been treated at 16 to 68 hours after an overdose for 4 to 6 hours with the Liver Dialysis System (a single-access hemodiabsorption system for treatment of serious drug overdose and for treatment of hepatic encephalopathy). During this treatment in 10 patients, acetaminophen levels dropped an average of 73%. If acetaminophen levels were still measurable in plasma, treatment was repeated 24 or 48 hours later. In this group, liver enzymes normalized 24 hours after the last treatment and no patient required a liver transplant. No adverse effects due to this treatment were noted (Ash et al, 2002).
5) MODULAR EXTRACORPOREAL LIVER SUPPORT a) CASE REPORT: A 26-year-old woman, who underwent liver transplantation, developed primary nonfunctioning of the graft on postoperative day 4, with minimal bile output, discolored bile, coagulopathy, renal failure, and a grade IV coma requiring mechanical ventilation. Due to her deteriorating clinical condition, the patient was treated with modular extracorporeal liver support (MELS), consisting of a bioreactor that is charged with human liver cells and integrated into an extracorporeal circuit with continuous single pass albumin dialysis and continuous veno-venous hemodiafiltration. The human liver cells were obtained from a discarded cadaveric graft. After a total application time of 79 hours, the patient's plasma levels of total bilirubin and ammonia significantly decreased (21.1 mg/dL and 100 mcmol/L at start of therapy, respectively, to 10.1 mg/dL and 22.7 mcmol/L at end of therapy, respectively). Her kidney function also improved with a urine output of 1325 mL/24 hours at the end of therapy compared with 45 mL/24 hours prior to therapy, and her neurological status improved from a coma grade IV to a coma grade I allowing for extubation. On postoperative day 8, a suitable graft was found, MELS was stopped, and liver transplantation was performed. The patient's recovery was uneventful (Sauer et al, 2003). While there are currently no reports of the use of this system with acetaminophen-induced fulminant hepatic failure, it might be useful as a bridge to liver transplantation.
6) TRANSPLANTATION a) Liver transplantation has a definite but limited role in the management of patients with hepatic failure from acetaminophen toxicity (Larsen et al, 1995; Makin et al, 1995). b) Of 14 patients with poor prognosis for survival after acetaminophen overdose who were registered for transplantation, 4 of 6 (67%) survived following transplant vs 1 of 8 (12.5%) who were not transplanted. Three of 15 (20%) control patients with similar prognosis who were not registered for transplantation survived (O'Grady et al, 1991). c) In another study of 17 patients with poor prognosis referred for liver transplant, 7 of 10 patients who received a liver transplant survived compared with 1 of 7 who did not receive a transplant (Mutimer et al, 1994). d) Reliable prognostic indicators for fatal outcome are needed, since those patients who recover without transplantation have complete recoveries(Harrison et al, 1990) (Tournaul et al, 1992). e) Acidosis (pH less than 7.3), a continuing rise in prothrombin time or INR on day 4, a peak prothrombin time of 180 seconds or more, and the combination of serum creatinine greater than 300 micromoles/Liter, PT greater than 100 seconds and grade III-IV encephalopathy have all shown strong correlations with fatal outcomes in patients with fulminant hepatic failure. Assuming a standard control PT of 15 seconds, then a peak International Normalized Ratio (INR) of approximately 12 or an INR greater than approximately 6.6 presumably have the same prognostic significance (Harrison et al, 1990a) (O'Grady et al, 1988) (O'Grady et al, 1989) (Janes & Routledge, 1992) (Vale, 1992) (Mutimer et al, 1994). 1) Others have not found these criteria to reliably predict fatal outcome in non-transplanted patients (Gow et al, 1997).
2) APACHE II (Acute Physiologic and Chronic Health Evaluation) is a multivariant scoring system that uses a list of vital signs and laboratories as well as premorbid health and age. One study found that an admission APACHE II score of 15 or more was associated with a mortality of 13 out of 20 patients (5 of the survivors received liver transplantation) (Mitchell et al, 1998).
f) The use of arterial lactate concentration may allow for earlier identification of patients at high risk of fatal acetaminophen induced liver failure and likely to benefit from listing early for liver transplantation. 1) In a retrospective study, an initial sample of 103 patients was identified followed by a prospective validation sample of 107 patients who had been transferred to a tertiary-referral intensive care unit for acetaminophen-induced liver failure. It was found that an early arterial lactate 4 hours after transfer (median of 43 hours after ingestion) above 3.5 mmol/L correlated with an increased risk of fatal outcome (14 of 18 patients meeting this criteria died; sensitivity 67%, specificity 95%). An arterial lactate concentration 12 hours after transfer and after adequate fluid resuscitation (guided by invasive hemodynamic monitoring) above 3 mmol/L also correlated with an increased risk of fatality (16 of 18 patients meeting this criteria died; sensitivity 76% specificity 87%). All patients had intracranial pressure monitoring as appropriate; norepinephrine was used as the primary vasopressor. NAC was infused at 150 mg/kg for 24 hours and continuous venovenous hemofiltration with lactate-free fluid was used for renal replacement. The authors have proposed criteria for liver transplantation in acetaminophen-induced acute liver failure as follows: 1) STRONGLY CONSIDER LISTING FOR TRANSPLANTATION IF arterial lactate concentration is greater than 3.5 mmol/L after early fluid resuscitation
2) LIST FOR TRANSPLANTATION IF arterial pH is less than 7.3 mmol/L or arterial lactate concentration is greater than 3 mmol/L after adequate fluid resuscitation
3) OR CONCURRENTLY IF serum creatinine is greater than 300 mcmol/L, INR is greater than 6.5 and there is encephalopathy of grade 3 or greater.
g) Another study has seriously questioned the King's College lactate criteria for liver transplant. In a series of 40 patients who presented with acetaminophen-induced fulminant hepatic failure (FHF), 2 patients received transplants. Nine patients died overall: 1 who had received a transplant, 6 who arrived moribund or developed severe cerebral edema soon after presentation and transplantation was never feasible, and 2 died without transplantation. Non-transplant survival in patients who met one or both of the King's College lactate criteria (early lactate greater than 3.5 or post resuscitation lactate greater than 3) was 68% in these patients. In a series of 56 FHF patients from a related center, non-transplant survival in patients who met one or both of the King's College lactate criteria was 62%. The authors suggest that improvements in the management of FHF (particularly the prevention of cerebral edema) may make liver transplantation in acetaminophen-induced FHF necessary less often than previously believed (Gow et al, 2007). h) A meta-analysis was conducted that compared the different prognostic criteria that were used to determine the need for liver transplantation in patients with fulminant hepatic failure secondary to acetaminophen poisoning. The criteria that was analyzed included King's criteria (pH less than 7.3 or a combination of prothrombin time (PT) of greater than 100 sec plus creatinine of greater than 300 mcmol/L plus encephalopathy grade 3 or greater), pH less than 7.3 only, PT greater than 100 sec only, PT greater than 100 sec plus creatinine greater than 300 mcmol/L plus encephalopathy grade 3 or greater, an increase in PT day 4, factor V of less than 10%, APACHE II score of greater than 15, and Gc-globulin less than 100 mg/L. Overall, in the meta-analysis, King's criteria had moderate sensitivity at 69% (range 55% to 100%), as compared with the other criteria analyzed, but it had high specificity at 92% (range 43% to 100%). Further analysis, utilizing Q values (a Q value of 1 reflects a perfect test and a Q value of 0.5 reflects an uninformative test) showed that the ability of the King's criteria to distinguish between patients requiring transplantation and those who do not seems limited, with a Q value of 0.61. However, using likelihood ratios, as an alternative method for evaluating the accuracies of diagnostic criteria (the greater the positive likelihood ratio and the lower the negative likelihood ratio, the better the criteria), the King's criteria had a positive:negative likelihood ratio of 12.33:0.29, indicating that it is a fairly accurate prognostic indicator. In comparison, the APACHE score greater than 15 criteria had a sensitivity of 81% and a specificity of 92% on the first day of patient's admission. The APACHE criteria also had the highest positive and lowest negative likelihood ratios of any criteria analyzed in the meta-analysis (16.4:0.19); however, the APACHE criteria was evaluated in only one study. Because there was only one study available, the authors concluded that further studies are needed to evaluate the efficacy of APACHE II score criteria, and in the interim, King's criteria should be used as the standard criteria, despite its moderate sensitivity (Bailey et al, 2003). i) One study found a factor V concentration of less than 10% in patients with grade 3/4 encephalopathy and a factor VIII/factor V ratio greater than 30 to correlate with fatal outcome (Pereira et al, 1992). Another study found that, in a group of patients who did not all have grade 2 or 4 encephalopathy, these markers were not useful if measured less than 72 hours after overdose (Bradberry, 1994) (Bradberry et al, 1995). j) In a retrospective study of 21 patients who underwent liver transplant for acetaminophen-induced liver failure 16 survived to 2 months and 5 did not. In survivors the time from ingestion to transplant was shorter (4 days vs. 6 days in non-survivors) and the pH at the time of transplant was higher (7.38 vs. 7.21 in non-survivors). A pH below 7.3 at transplantation had a sensitivity of 80% and a specificity of 94% for 2-month mortality (Devlin et al, 1995). k) A model was developed, based on a prospective and validated study, to predict hepatic encephalopathy in acetaminophen overdose and to identify high-risk patients for early transfer to a liver intensive care unit/transplantation facility. The most accurate model for encephalopathy included: log10 (hours from overdose to antidote treatment), log10 (plasma coagulation factors on admission), and platelet count x hours from overdose (chi-square=41.2; p less than 0.00001). Hepatic encephalopathy was not seen in patients treated within 18 hours after overdose (Schiodt et al, 1999). l) A variety of biochemical markers (ie, hemoglobin, pyruvate, calcium, and phenylalanine levels) were identified which were combined to form a prognostic model that, when applied to patients at hospital admission, appeared to accurately predict the outcome of patients with fulminant hepatic failure. The prognostic tool was derived used a cohort of 97 patients and prospectively validated with a second cohort of 86 patients admitted to the Scottish Liver Transplant Unit for acetaminophen-induced fulminant hepatic failure. Hemoglobin, pyruvate, and phenylalanine levels were significantly lower in patients who either subsequently died or underwent transplantation compared with patients who spontaneously survived. This prognostic model of outcome in acetaminophen-induced fulminant hepatic failure appears to be as accurate a predictor as utilizing King's College Hospital criteria, but at an earlier stage of the patient's condition (Dabos et al, 2005). 1) Based on the prognostic model that was developed using stepwise forward logistic regression analysis the following formula was created to predict outcome: 1) (400 x pyruvate mmol/L) + (50 x phenylalanine (mmol/L) - (4 x hemoglobin g/dL)
m) PEDIATRIC PATIENTS: Based on a retrospective review of paracetamol-induced hepatotoxicity in pediatric patients, the following indicators were associated with a poor prognosis and a need for liver transplantation (Mahadevan et al, 2006): 1) Delayed presentation to the emergency department
2) Delay in treatment
3) Prothrombin time greater than 100 seconds
4) Serum creatinine greater than 200 mcmol/L
5) Hypoglycemia
6) Metabolic acidosis
7) Hepatic encephalopathy grade 3 or higher
H) RENAL FAILURE SYNDROME 1) CONTINUOUS HEMOFILTRATION may be preferable to intermittent hemodialysis in patients with acetaminophen induced hepatic and renal failure. Use of intermittent hemodialysis is associated with increases in intracranial pressure in these patients due to both cytotoxic and vasogenic cerebral edema. Continuous arteriovenous hemofiltration was associated with a smaller increase from baseline ICP in a group of patients with acetaminophen induced hepatic and renal failure in one study (Davenport et al, 1991).
2) Continuous veno-venous hemofiltration was used in a case of acetaminophen toxicity in an alcoholic patient presenting with liver and renal failure. Oral NAC therapy was initiated. Following aggressive supportive therapy, the patient recovered (Agarwal & Farber, 2002).
I) EXPERIMENTAL THERAPY 1) MANGAFODIPIR: An in vivo study, involving mice, showed that intraperitoneal injection of 10 mg/kg of mangafodipir 2 hours prior to administration of acetaminophen increased survival rates to 67% after 24 hours compared with a survival rate of 17% after 24 hours in mice following administration of a lethal dose of acetaminophen only (1000 mg/kg). The survival rate in mice pretreated with mangafodipir was equivalent to the survival rate of mice pretreated with NAC. Curative treatment with mangafodipir administered 6 hours after administration of 1000 mg/kg of acetaminophen resulted in a survival rate of 58% as compared with NAC administration which resulted in a survival rate of 8% (Bedda et al, 2003). Mangafodipir is a contrast agent currently used in MRI of the liver. It is believed that it has antioxidant activity and can prevent mitochondrial damage induced by reactive oxygen species.
2) METHIONINE: Treatment with oral methionine has been compared with intravenous NAC and supportive care therapy in patients with acetaminophen-induced hepatotoxicity. There is no evidence that oral methionine is more effective than IV NAC in preventing liver damage in patients with acetaminophen poisoning. However, one systematic review showed that oral methionine (2.5 grams every 4 hours for 4 doses) was more effective in preventing grade 3 hepatic necrosis (0/9 (0%)) in patients with acetaminophen poisoning compared with patients who only received supportive care (6/10 (60%)) (Buckley & Eddleston, 2004; Alsalim & Fadel, 2003).
3) Constitutive androstane receptors (CAR) INHIBITORS: CARs have been shown to be key regulators of acetaminophen metabolism and hepatotoxicity. One study of CAR-null mice and wild type mice showed that exposure to CAR activators (ie, phenobarbital) as well as high doses of acetaminophen, resulted in hepatotoxicity in the wild-type mice, but not in the CAR-null mice. The CAR-null mice appeared to be resistant to acetaminophen toxicity. Administration of a CAR inhibitor, androstanol (an inverse agonist ligand), 1 hour following acetaminophen administration was effective in preventing hepatotoxicity in the wild type mice, indicating that CAR inhibitors may be an alternative method for treating acetaminophen toxicity, although further studies are warranted (Zhang et al, 2002).
4) ANIMAL STUDY: Mice with acetaminophen-induced hepatic and renal injury, were given either NAC, orally or intraperitoneally, or ribose-cysteine, also orally or intraperitoneally, as rescue therapy, in order to determine the efficacy of thiol rescue therapy, particularly in the setting of acetaminophen-induced renal toxicity. Both treatment regimens demonstrated protection against acetaminophen-induced hepatotoxicity, but only ribose-cysteine, administered intraperitoneally, was effective in protecting the mice against acetaminophen-induced renal toxicity as well. The authors conclude that other thiol rescue agents may have a therapeutic advantage over NAC administration in cases of acetaminophen-induced hepatotoxicity and renal toxicity; however, further studies are warranted (Slitt et al, 2004).
J) ACUTE LUNG INJURY 1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases. 2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011). a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011). 4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998). 5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995). 6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005). 7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015). K) SEIZURE 1) Seizures are rare, but may be a result of hypoxia or due to properties of certain agents . If CNS depression is present, administer naloxone and correct hypoxia. Administer intravenous, benzodiazepines, barbiturates or propofol if seizures persist. 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).
L) HYPOTENSIVE EPISODE 1) If CNS depression is present, administer naloxone and correct hypoxia. Hypotension should initially be treated with a saline bolus, if patient can tolerate a fluid load, then adrenergic vasopressors to raise mean arterial pressure. 2) 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.
3) 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).
4) 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).
M) RHABDOMYOLYSIS 1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
6) Continuous venovenous hemodiafiltration (CVVH-D) and fasciotomy for patients with severe compartments syndrome complicated by rhabdomyolysis has been described. This aggressive method may improve renal function in the face of acute renal failure (Russo et al, 1995).
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