6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) Activated charcoal should be given to those who are able to reliably protect their airway, and intravenous fluids should be given for hypotension or tachycardia. 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) CHARCOAL ADMINISTRATION a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
2) CHARCOAL DOSE a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005). 1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
b) ADVERSE EFFECTS/CONTRAINDICATIONS 1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
B) GASTRIC LAVAGE 1) Gastric lavage is generally not indicated; however, in massive overdoses, this might be considered. 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.
6.5.3) TREATMENT
A) MONITORING OF PATIENT 1) Monitor vital signs and mental status.
2) Monitor electrolytes, renal function, troponin, and liver enzymes in patients with significant overdose.
3) Glucose should be monitored hourly in patients receiving high dose insulin/dextrose therapy.
4) Obtain an ECG and institute continuous cardiac monitoring.
5) Carvedilol blood concentrations are not clinically useful or readily available.
B) HYPOTENSIVE EPISODE 1) Administer intravenous fluids judiciously to avoid volume overload. Glucagon, calcium, catecholamines, insulin/dextrose, and phosphodiesterase inhibitors should be considered in patients who do not respond to intravenous fluids. 2) INTRAVENOUS FLUIDS a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer glucagon.
3) GLUCAGON a) Glucagon is considered a first-line antidotal therapy for beta-blocker poisoning (Shepherd, 2006). Administer an initial bolus of 50 to 150 micrograms/kilogram (usually about 10 milligrams in adults) over 1 minute; follow this with a continuous intravenous infusion of 50 to 100 micrograms/kilogram/hour (DeWitt & Waksman, 2004). Alternatively, administer a 5 mg glucagon bolus, and repeat every 5 to 10 minutes for up to 3 doses if necessary. If the patient has a response at a particular dose, start an hourly infusion of glucagon at the response dose (eg, if a patient responds to 10 mg, then start an infusion at 10 mg per hour). b) Glucagon may produce a positive chronotropic and inotropic cardiac effect, which occurs despite beta-blockage. The drug has been reported to increase myocardial contractility in patients refractive to isoproterenol. Glucagon is thought to activate the adenylate cyclase system at a different site than isoproterenol (Kosinski & Malindzak, 1973). c) In a case report of a carvedilol overdose, glucagon was used in addition to dopamine and fluid support to maintain blood pressure (Hantson et al, 1997). d) Numerous case reports describe hemodynamic improvement in patients treated with glucagon following beta blocker overdose (Ward & Jones, 1976; Illingsworth, 1979; Chen et al, 1985; Khan & Miller, 1985; Kosinski, 1971; O'Mahony et al, 1990; Ehgartner & Zelinka, 1988; Agura et al, 1986; Kenyon et al, 1988; Peterson et al, 1984; Wilkinson, 1986; Vadhera, 1992). 1) Most of these patients were receiving multiple therapeutic interventions at the time of hemodynamic improvement (e.g. fluids, atropine, dopamine, epinephrine, isoproterenol, and pacing).
2) Continuous intravenous infusion of 10 milligrams/hour of glucagon was associated with improvement in systolic blood pressure to normal levels during a 2 hour period in a 16-year-old girl following an 8 gram ingestion of oxprenolol (O'Mahony et al, 1990).
3) Glucagon has also been used to treat patients who developed symptomatic bradycardia while taking therapeutic doses of beta blocking drugs (Love & Howell, 1997).
4) CATECHOLAMINES a) Consider catecholamines in patients who do not respond to intravenous fluids, glucagon, and calcium. b) DOPAMINE 1) 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).
2) 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).
c) NOREPINEPHRINE 1) 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). 2) DOSE a) 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).
b) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
c) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
5) INSULIN/DEXTROSE a) Consider high-dose insulin euglycemia therapy in patients who require catecholamines despite treatment with intravenous fluids, glucagon, and calcium. High-dose insulin euglycemia therapy may allow the practitioner to decrease the dose of catecholamines and avoid the adverse effects of prolonged high-dose catecholamines. b) DOSE 1) Intravenous insulin infusion with supplemental dextrose, and potassium as needed, is recommended in patients with severe or persistent hypotension after calcium channel blocker overdose, and may also be effective for beta blocker overdose. Before, during, and after the therapy, monitor for hypoglycemia and hypokalemia. 2) Administer a bolus of 1 unit/kilogram of insulin followed by an infusion of 0.1 to 1 units/kilogram/hour, titrated to a systolic blood pressure of > 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to determine the need for higher rates of insulin infusion. a) In some refractory cases, more aggressive high-dose insulin protocols have been suggested, starting with a 1 unit/kg insulin bolus, followed by a 1 unit/kg/hour continuous infusion. If there is no clinical improvement in the patient, the infusion rate may be increased by 2 units/kg/hour every 10 minutes, up to a maximum of 10 units/kg/hour (Engebretsen et al, 2011).
3) Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (adults 50 mL dextrose 50%, children 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hour in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued 4) Administer supplemental potassium initially if patient is hypokalemic (serum potassium <2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L. 5) CASE REPORT: Use of high-dose insulin (10 International Units/kg) was successful in a 5-gram metoprolol ingestion. Hypotension was unresponsive to conventional therapies (Page et al, 2009). 6) CASE REPORT: Administration of intravenous fat emulsion (IFE) combined with high-dose insulin was successfully used in a 48-year-old man who developed cardiac arrest following a suspected ingestion of nebivolol (300 mg), baclofen, and diazepam, as well as cocaine use. On presentation to the emergency department (approximately 3 hours postingestion), the patient was unresponsive with a Glasgow Coma score of 3, blood pressure of 92/52 mmHg, and a heart rate of 72 bpm. Approximately 5 hours later, the patient's heart rate decreased to 35 bpm, his systolic blood pressure decreased to 50 mmHg, and he developed bradyasystolic cardiac arrest. Resuscitative measures included CPR, 2 boluses each of atropine 1 mg and epinephrine 1 mg, administered 4 minutes apart, and 100 mL bolus of 20% IFE. Approximately 1 minute later, the patient's heart rate and blood pressure increased to 123 bpm and 251/162 mmHg, respectively, however bradycardia and hypotension recurred within 20 minutes, necessitating initiation of a 20% IFE infusion of 0.25 mL/kg/min continued over an hour, along with administration of an IV bolus of 100 units regular insulin, followed by a high-dose insulin infusion (up to 21.8 units/kg/hour). Supportive care included calcium (117 mEq) and dextrose (485 g) in order to maintain euglycemia. Over the next several days, the patient's hemodynamic status gradually normalized, and he was discharged on hospital day 11 without neurologic sequelae (Stellpflug et al, 2010). 6) LIPID EMULSION THERAPY a) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015). b) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011): 1) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
2) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
3) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
4) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
c) HUMAN CASE REPORTS 1) Administration of intravenous fat emulsion (IFE) combined with high-dose insulin was successfully used in a 48-year-old man who developed cardiac arrest following a suspected ingestion of nebivolol (300 mg), baclofen, and diazepam, as well as cocaine use. On presentation to the emergency department (approximately 3 hours postingestion), the patient was unresponsive with a Glasgow Coma score of 3, blood pressure of 92/52 mmHg, and a heart rate of 72 bpm. Approximately 5 hours later, the patient's heart rate decreased to 35 bpm, his systolic blood pressure decreased to 50 mmHg, and he developed bradyasystolic cardiac arrest. Resuscitative measures included CPR, 2 boluses each of atropine 1 mg and epinephrine 1 mg, administered 4 minutes apart, and 100 mL bolus of 20% IFE. Approximately 1 minute later, the patient's heart rate and blood pressure increased to 123 bpm and 251/162 mmHg, respectively, however bradycardia and hypotension recurred within 20 minutes, necessitating initiation of a 20% IFE infusion of 0.25 mL/kg/min continued over an hour, along with administration of an IV bolus of 100 units regular insulin, followed by a high-dose insulin infusion (up to 21.8 units/kg/hour). Supportive care included calcium (117 mEq) and dextrose (485 g) in order to maintain euglycemia. Over the next several days, the patient's hemodynamic status gradually normalized, and he was discharged on hospital day 11 without neurologic sequelae (Stellpflug et al, 2010).
2) A 27-year-old woman presented to the emergency department approximately 1 hour after intentionally ingesting 7 g propranolol. She was comatose (GCS 3) with hypotension, bradycardia, and generalized tonic-clonic seizures. An ECG indicated severe sinus broad complex bradycardia. Despite supportive therapies, including administration of glucagon, insulin, and vasopressors, her hypotension and bradycardia persisted. IV lipid emulsion therapy was then initiated, 100 mL bolus of 20% intralipid followed by an infusion of 400 mL over 20 minutes. Following intralipid therapy, the patient recovered, with gradual discontinuation of vasopressor and glucagon therapy, and was referred for psychiatric care (Dean et al, 2010).
3) A 31-year-old woman presented to the emergency department comatose and hypotensive (80/45 mmHg), with generalized seizures, approximately 2 hours after ingesting 3.6 g propranolol and an unknown amount of ethanol. An ECG showed nonspecific intraventricular conduction delay followed by supraventricular tachycardia with wide QRS complex. Toxicological analysis of the patient's blood revealed a propranolol concentration of 4.21 mg/L and an ethanol concentration of 2.42 g/L. Despite treatment with glucagon, insulin, sodium bicarbonate, diazepam and dopamine, the patient continued to deteriorate clinically, prompting a decision to start IV lipid emulsion therapy, with a 100 mL bolus of 20% intralipid followed by an infusion of 400 mL over a 20-minute period. Following intralipid therapy, the patient's condition improved with discontinuation of seizures and an increase in blood pressure (110/50 mmHg); however, within 30 minutes after cessation of intralipid treatment, her blood pressure once again decreased to 70/30 mmHg. Intralipid therapy was restarted 60 minutes after the first dose, with an infusion of 500 mL 20% intralipid at a rate of 10 mL/min. The patient rapidly improved with a return of sinus rhythm and an increase in blood pressure to 120/60 mmHg. The patient remained stable, and was transferred to the psychiatric unit the next day (Jovic-Stosic et al, 2011).
7) CALCIUM a) Calcium chloride has been effective for some beta blocker overdoses that were refractory to conventional therapy (Sakurai et al, 2000; Koppel et al, 1995; Brimacombe et al, 1991). At high doses, propranolol blocks the calcium channels that may induce the asystole, AV block, and depressed myocardial contraction (Smith, 1991) .
b) Administer calcium chloride 0.2 mL/kg or calcium gluconate 0.6 mL/kg intravenously (DeWitt & Waksman, 2004). May repeat every 10 to 20 minutes for 3 or 4 doses, consider an infusion if patient responds.
c) In a canine model of severe propranolol toxicity calcium chloride (0.125 milliliters/kilogram of 10% CaCl bolus followed by an infusion of 0.375 milliliters/kilogram for 30 minutes) improved cardiac index and stroke volume, and induced earlier recovery of mean arterial pressure and peripheral vascular resistance (Love et al, 1996).
d) CASE REPORT: Calcium chloride was successfully used in a 56-year-old woman with shock and first-degree heart block after an intentional atenolol overdose. The following were administered without effect: glucagon, epinephrine, atropine, ephedrine, and high-dose dopamine. After 1 gram of calcium chloride, blood pressure improved. Recurrence of hypotension resolved after a second dose of calcium chloride (O'grady et al, 2001).
8) PHOSPHODIESTERASE INHIBITORS a) A phosphodiesterase inhibitor which also has theoretical benefit via decreasing breakdown of myocardial cAMP. The dosing is 1 mg/kg bolus then 3 to 6 mcg/kg/minute. It is very rarely used because, although it increases inotropy, it may induce peripheral vasodilation and is difficult to titrate due to a relatively long half-life. b) INAMRINONE 1) CASE REPORT: A 37-year-old woman developed hypotension, bradycardia, depressed mental status, decreased cardiac index and seizures after receiving 800 mg labetalol for severe hypertension. Treatment with intravenous fluids, dopamine, phenylephrine and glucagon was associated with an increase in blood pressure without improvement in mental status. Amrinone infusion was successful in increasing cardiac index, decreasing pulmonary capillary wedge pressure, and improved mental status (Kollef, 1994).
2) STUDY: In a canine model of severe propranolol toxicity, amrinone infusion increased cardiac output and stroke volume, and decreased arteriolar resistance and left ventricular end diastolic pressure compared with controls, without affecting heart rate, mean arterial pressure or QRS duration (Love et al, 1992).
c) MILRINONE 1) STUDY: In a canine model of severe propranolol overdose, milrinone increased cardiac output, mean arterial pressure, and stroke volume and decreased central venous pressure and pulmonary capillary wedge pressure without affecting heart rate (Sato et al, 1994).
2) In a similar study, the combination of milrinone and glucagon increased cardiac output and mean arterial pressure but induced severe tachycardia in dogs with severe propranolol toxicity (Sato et al, 1995).
d) ENOXIMONE 1) ATENOLOL/VERAPAMIL: After ingesting 2800 mg of atenolol and 1600 mg of verapamil, a 57-year-old man with a history of an ischemic heart disease (two previous acute MIs) developed hypotension (BP 80/50 mmHg), and bradycardia (40 beats/min). An ECG revealed a sinus bradycardia with a first-degree heart block, previously absent. A chest X-ray revealed interstitial pulmonary edema. Despite treatment with fluid resuscitation, calcium salts, and norepinephrine/epinephrine inotropic support, only a modest hemodynamic improvement was observed. Following treatment with a bolus of enoximone 1 mg/kg and a continuous infusion at 0.5 mcg/kg/min, his hemodynamic status improved (Sandroni et al, 2004).
2) METOPROLOL: A 55-year-old man who ingested 10 grams of metoprolol developed bradycardia and hypotension refractory to epinephrine, calcium, glucagon, and atropine. Right heart catheterization revealed depressed cardiac output (1.3 liters/minute) and stroke volume (19 milliliters). She was treated with a bolus of 0.5 milligrams of enoximone followed by an infusion of 15 micrograms/kilogram/minute with subsequent improvement in her cardiac output and stroke volume, and her clinical status improved over 48 hours (Hoeper & Boeker, 1996).
3) PROPRANOLOL: Two patients developed cardiac arrest following propranolol exposure and recovered uneventfully following enoximone administration. The first patient, a 38-year-old woman, developed sinus bradycardia progressing to cardiac arrest following a 1.5 milligram IV bolus dose of propranolol. Despite aggressive cardiac resuscitative measures for 15 minutes, the patient's condition did not improve. Following administration of a 100-milligram IV bolus of enoximone, the patient's hemodynamic status improved and she was subsequently discharged without sequelae. The second patient, a 50-year-old man, developed cardiac arrest, after intentionally ingesting 1.6 grams of propranolol, as well as 150 milliliters of hydrochloric acid and an unknown amount of oxazepam. The patient gradually recovered following administration of a 100-milligram IV bolus dose of enoximone followed by an infusion of 5 micrograms/kilogram/minute, as well as inotropic support with dopamine and norepinephrine (Sandroni et al, 2006).
9) NON-PHARMACOLOGICAL THERAPIES a) Include cardiac pacing, placement of an intraaortic balloon pump, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO). b) INTRA-AORTIC BALLOON PUMP 1) Intra-aortic balloon pump has been used successfully after pharmacologic therapy failed in cases of severe propranolol and atenolol poisoning (Lane et al, 1987; Koppel et al, 1994).
c) EXTRACORPOREAL CIRCULATION 1) CASE REPORT: Extracorporeal support and hemoperfusion were used to treat a 20-year-old woman with bradycardia and hypotension unresponsive to fluids, atropine, glucagon, isoproterenol, epinephrine and cardiac pacing after propranolol overdose (McVey & Corke, 1991a). She survived neurologically intact.
2) CASE REPORT: Extracorporeal membrane oxygenation (ECMO) was used to provide hemodynamic support for a 28-year-old woman with dysrhythmias, hypotension and heart failure unresponsive to glucagon, dopamine, norepinephrine, epinephrine, and a pacemaker (Rooney et al, 1996). The patient's course was complicated by ischemic hepatitis, acute tubular necrosis and intravenous catheter related deep vein thrombosis, but she survived.
3) CASE REPORT: A 38-year-old woman, who intentionally ingested 5.32 grams of betaxolol, 30 grams of lorazepam, and an unknown amount of alcohol, was treated with ECMO after developing cardiogenic shock unresponsive to isoproterenol, dobutamine, epinephrine, norepinephrine, and glucagon. The patient's hemodynamic status improved, but her clinical course was complicated by development of a hematoma of her thigh, resulting in ischemia of the leg requiring surgical intervention (Bilbault et al, 2007).
4) CASE REPORT: Extracorporeal life support (ECLS) was used successfully in a 15-year-old girl with a mixed verapamil and propranolol ingestion. The patient presented to the hospital with asystole and, after 70 minutes of cardiopulmonary resuscitation, there was no clinical improvement. Cardiac arrest persisted and ECLS was initiated. Various dysrhythmias were observed while on ECLS. At approximately 70 hours, ECLS was terminated and the patient had a perfusing sinus rhythm with normal QRS and QTc. The patient made a complete recovery (Kolcz et al, 2007).
5) CASE REPORT: A 36-year-old man presented to the emergency department with decreased level of consciousness, dyspnea, hypoxemia (O2 sat 91%), and hypotension (80/40 mmHg) approximately 2 hours after intentionally ingesting 10 g atenolol and an unknown amount of nifedipine, lacidipine, fluoxetine, and sertraline. An ECG indicated prolonged QT interval and QRS widening. The patient rapidly deteriorated hemodynamically, developed cardiac arrest (successfully resuscitated), and persistent metabolic acidosis and shock with multiple organ failure despite aggressive decontamination and supportive therapies. ECMO was initiated 2 hours post-admission along with high-volume continuous veno-venous hemofiltration (HV-CVVH). Over the next 48 hours, the patient became hemodynamically stable and was weaned from ECMO; however, the patient's clinical course was complicated by the development of progressive neurologic impairment, resulting in a persistent reduction in motor skills, impaired coordination, gait ataxia, and mild aphasia (Rona et al, 2011).
10) ATROPINE a) Reduces vagal stimulation and subsequently increases heart rate. b) ATROPINE/DOSE 1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010). 2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg. a) There is no minimum dose (de Caen et al, 2015).
b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
11) PHENYLEPHRINE a) PHENYLEPHRINE 1) MILD OR MODERATE HYPOTENSION a) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
2) CONTINUOUS INFUSION a) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
b) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
c) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
3) ADVERSE EFFECTS a) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
12) ISOPROTERENOL a) CAUTION: Patients may be especially prone to isoproterenol induced hypotension due to the alpha-1 blocking effects of carvedilol. If isoproterenol is used, careful monitoring of blood pressure and titration of isoproterenol dose is necessary. Norepinephrine or dopamine may be preferable in severely hypotensive patients. b) ISOPROTERENOL INDICATIONS 1) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
3) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
4) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
C) HYPOGLYCEMIA 1) HYPOGLYCEMIA should be managed with intravenous dextrose (Frishman & Silvermon, 1979).
D) BRONCHOSPASM 1) BRONCHOSPASM SUMMARY a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.
2) ALBUTEROL/ADULT DOSE a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
3) ALBUTEROL/PEDIATRIC DOSE a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
4) ALBUTEROL/CAUTIONS a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.
5) CORTICOSTEROIDS a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).
E) SEIZURE 1) SUMMARY a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
2) DIAZEPAM a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
3) NO INTRAVENOUS ACCESS a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
4) LORAZEPAM a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; 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).
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