6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) Prehospital gastrointestinal decontamination is not recommended because of the potential for abrupt deterioration.
6.5.2) PREVENTION OF ABSORPTION
A) SUMMARY 1) Because a diltiazem overdose can be life-threatening, all significant ingestions should receive activated charcoal. Patients with altered mental status should be intubated prior to administration. Gastric lavage should be considered in patients with recent large ingestions if the airway is protected. Late gastric lavage may be effective following sustained-release products. Whole bowel irrigation should be considered early for patients who are able to protect their airway or are intubated who have ingested sustained-release formulations. Whole bowel irrigation should NOT be performed in patients who are hemodynamically unstable.
2) If continued absorption is suspected in a symptomatic patient after these procedures, consider abdominal x-ray (if brand is radiopaque), ultrasound, or gastroscopy.
B) ACTIVATED CHARCOAL 1) Single doses of activated charcoal are recommended. While not proven effective, administration of a second dose should be considered especially in the setting of sustained-release dosage form ingestion or coingestion of drugs or chemicals which could delay gastric emptying or slow intestinal motility (Krenzelok, 1991; Pearigen & Benowitz, 1991). 2) Multiple doses, beginning 7 hours post ingestion, did not significantly enhance elimination in a 38-year-old woman who had ingested 900 mg of diltiazem (Roberts et al, 1991). 3) CHARCOAL ADMINISTRATION a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
4) CHARCOAL DOSE a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005). 1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
b) ADVERSE EFFECTS/CONTRAINDICATIONS 1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
C) GASTRIC LAVAGE 1) Gastric lavage, followed by administration of activated charcoal, is recommended in patients with significant ingestions. A large bore orogastric tube is preferred due to the large size of some sustained-release dosage forms. 2) Late gastric lavage may be effective following sustained-release products. 3) 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.
4) 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.
5) 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.
6) 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).
7) 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.
D) WHOLE BOWEL IRRIGATION 1) Consider whole bowel irrigation following activated charcoal to limit absorption from possible concretions and sustained release products. It should only be performed in patients who can protect their airway or who are intubated. Whole bowel irrigation should not be performed in patients that are hemodynamically unstable. Sustained-release formulations have produced concretions composed of alginate hydrocolloid matrix despite initial lavage (Rankin & Edwards, 1990; Sporer & Manning, 1993; Buckley et al, 1993; Hendren et al, 1989). 2) Repeat charcoal following whole bowel irrigation since the PEG/electrolyte solution may desorb drug from charcoal. If continued absorption is suspected in a symptomatic patient after these procedures, consider abdominal x-ray (if brand is radiopaque), ultrasound, or gastroscopy. 3) COMPLICATIONS: Complications were reported in one patient who was given whole bowel irrigation (WBI), and subsequently became hemodynamically unstable, after an overdose ingestion of sustained-release diltiazem (Cumpston et al, 2010). a) A 58-year-old man, received activated charcoal and whole bowel irrigation, at 2 L/hour, approximately 3 hours after reportedly ingesting 7.2 g of extended release diltiazem. Prior to WBI administration, the patient was hemodynamically stable. One hour later (4 hours post-ingestion), the patient developed bradycardia (50 bpm) and hypotension (70/40 mmHg), treated with atropine and IV fluids. After 7 hours of WBI (10 hours post-ingestion), the patient developed asystole, resolved with external pacing, and abdominal distension, resulting in cessation of WBI therapy. Despite aggressive supportive therapy, including vasopressors, calcium, and insulin, he continued to deteriorate and subsequently died. Autopsy was consistent with general hypoperfusion of the bowel without clear infarction.
a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose. 1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.
b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987). c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract. d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration. 6.5.3) TREATMENT
A) SUPPORT 1) MANAGEMENT OF MILD TO MODERATE TOXICITY a) Patients who have asymptomatic bradycardia can be admitted and observed with telemetry. Obtain peripheral intravenous access and an ECG. Mild hypotension may only require treatment with intravenous fluid administration.
2) MANAGEMENT OF SEVERE TOXICITY a) Patients with bradycardia and hypotension require standard ACLS treatment. Place a central line and consider placement of an arterial line. Standard first line treatment includes atropine for bradycardia although in a serious poisoning it is rarely effective. High dose insulin and dextrose have been effective in animal studies and multiple case reports in patients with hypotension refractory to other modalities, and should be considered early in patients with significant hypotension. Use intravenous calcium in severe poisonings although in these cases, beneficial effects of calcium infusion may be very minimal or short-lived. Repeat bolus doses or a continuous intravenous infusion are often needed. Standard vasopressors should be administered to maintain blood pressure. Lipid emulsion has been successful in animal studies and a few case reports of patients with hypotension refractory to other therapies. Intravenous glucagon has been used with variable success. In a patient whose hemodynamic status continues to be refractory despite the treatment described above, extracorporeal membrane oxygenation or cardiopulmonary bypass should be considered. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
B) MONITORING OF PATIENT 1) Monitor vital signs frequently.
2) Institute continuous cardiac monitoring and obtain serial ECGs.
3) In patients with significant hypotension or bradycardia, monitor serum electrolytes, renal function, arterial or venous blood gas, and urine output.
4) Monitor serum glucose. Serum glucose concentration correlates directly with the severity of calcium channel blocker intoxication; patients who develop hyperglycemia are likely to develop more severe cardiovascular manifestations of toxicity (Levine et al, 2007).
5) Obtain digoxin level in patients who also have access to digoxin.
6) Monitor cardiac enzymes in patients with chest pain.
7) Serum drug levels are not readily available and not helpful to guide therapy.
8) It has been suggested that continuous SvO2 monitoring using a fiber optic pulmonary artery catheter may be useful to monitor tissue oxygenation in cases of refractory hypotension secondary to calcium antagonist poisoning(Kamijo et al, 2006).
C) HYPOTENSIVE EPISODE 1) FLUIDS a) INDICATION: Loss of systemic vascular resistance requires an increase in circulating volume. Complete response to fluids alone should not be expected, but volume replacement is a necessary component. Administer intravenous 0.9% saline or lactated ringers and place the patient in supine position. Central venous pressure monitoring is suggested to guide fluid therapy.
b) CAUTIONS: Monitor for signs of pulmonary edema (Pearigen & Benowitz, 1991).
2) CALCIUM a) INDICATIONS: Calcium is given to reverse hypotension and improve cardiac conduction defects. Calcium administration has been most effective in overcoming mild toxicity from small overdoses or therapeutic use and is less useful in massive overdose cases since calcium channel blockade is non-competitive (Pearigen & Benowitz, 1991; Krenzelok, 1991; Clark & Hanna, 1993) but was successful in 11 of 30 cases in one series (Hofer et al, 1993). b) DRUG OF CHOICE: In some studies, calcium chloride is thought to produce more predictable increases in extracellular ionized calcium and a greater positive inotropic response (White et al, 1976; Haynes et al, 1985), however, other sources have found no differences in efficacy of calcium chloride and calcium gluconate. Calcium chloride provides 3 times more elemental calcium (13.4 mEq) than calcium gluconate (4.3 mEq) in the commercially available 1 gram ampules (DeRoos, 2011) c) ADULT DOSE: Optimal dosing is not established; begin with an initial IV infusion of about 13 to 25 mEq of calcium (10 to 20 mL of 10% calcium chloride or 30 to 60 mL of 10% calcium gluconate) followed by either repeat boluses every 15 to 20 minutes up to 3 to 4 doses or a continuous infusion of 0.5 mEq/kg/hr of calcium (0.2 to 0.4 mL/kg/hr of 10% calcium chloride or 0.6 to 1.2 mL of 10% calcium gluconate) (DeRoos, 2011). Some authors advocate administering 1 gram of calcium salts every 2 to 3 minutes until conduction block is reversed or clinical evidence of hypercalcemia develops(Howarth et al, 1994; Buckley et al, 1994). Calcium dosing should be titrated to hemodynamic response rather than serum calcium concentration alone; central venous or pulmonary artery catheters may be useful to guide therapy. Monitor ECG and ionized calcium concentration (Howarth et al, 1994; Buckley et al, 1994). d) CASE SERIES: In one series, doses varied from 4.5 mEq to 95.2 mEq, with no evidence of a dose-response relation (Ramoska et al, 1993). e) HYPERCALCEMIA: Significant hypercalcemia may be necessary before severely intoxicated patients respond to aggressive calcium therapy, but the optimal calcium regimen has not been established. In patients who have received large doses of calcium for severe calcium channel blocker overdose (attaining serum calcium concentrations up to twice the upper limits of normal), hypercalcemia generally resolves within 48 hours without clinically apparent adverse effects (clinical or ECG) from hypercalcemia (Howarth et al, 1994; Buckley et al, 1994). 1) CASE REPORT: Hypercalcemia with levels as high as 19.2 mg/dL (9.9 mg/dL upper limit of normal) secondary to treatment with calcium salts are reported during aggressive therapy (Buckley et al, 1993). Such aggressive treatment with calcium salts may be necessary to reverse conduction defects (Howarth et al, 1994).
2) CASE REPORT: Hypercalcemia (16.3 mg/dL) occurred following aggressive calcium chloride treatment in a 45-year-old woman following an overdose ingestion of sustained-release diltiazem. There were no ECG manifestations due to the hypercalcemia and the patient recovered uneventfully over the next 4 days (Hantsch et al, 1997).
f) PRECAUTIONS: Hypotension generally does not respond as well as conduction disturbances to calcium. If a patient does not respond after a doubling of the ionized calcium concentration, further calcium treatment may not be beneficial. If the patient has also ingested digoxin, avoid administering calcium until after digoxin-specific Fab is administered to prevent worsening digoxin toxicity (DeRoos, 2011). g) ADVERSE EFFECTS: Calcium chloride can cause tissue injury following extravasation; administer calcium chloride via central venous catheter. Hypercalcemia or hypophosphatemia may also occur following repeat dosing or continuous infusion; monitor serum calcium and phosphate concentrations. Nausea, vomiting, flushing, constipation, confusion, and angina have also been reported in patients receiving calcium (DeRoos, 2011). 3) INSULIN/DEXTROSE a) DOSE 1) Intravenous insulin infusion with supplemental dextrose, and potassium as needed, is recommended in patients with severe or persistent hypotension after a calcium channel blocker overdose (DeWitt & Waksman, 2004).
2) Administer a bolus of 1 unit/kg of insulin followed by an infusion of 0.1 to 1 units/kg/hr, titrated to a systolic blood pressure of greater than 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to determine the need for higher rates of insulin infusion (Lheureux et al, 2006). 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 25 to 50 mL dextrose 50%, children 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hr 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. As the patient improves, insulin resistance abates and dextrose requirements will increase. 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 less than 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) Monitor blood pressure, pulse, ECG, mental status, serum glucose and potassium, urine output, and if possible cardiac function by way of echocardiogram/ultrasound, right heart catheter.
b) CASE REPORTS 1) GENERAL: Insulin/dextrose infusions were administered to five patients who experienced severe circulatory shock following intentional calcium channel blocker overdose ingestions and who were unresponsive to conventional treatment. Blood pressures normalized within hours after receiving the infusions and all five patients recovered without sequelae. In 3 of the 4 patients, insulin and dextrose were administered as bolus doses, 10 units and 25 grams, respectively, with the subsequent administration of insulin infusion, the dose ranging from 0.1 units/kg/hr to 1 unit/kg/hr, and dextrose (50% w/v) infusion, the dose ranging from 5 grams/hour to 15 grams/hr, via a central venous catheter. Each patient also received other supportive measures and inotropic agents (Yuan et al, 1999).
2) Insulin infusions, with or without dextrose given concurrently, were administered to several hemodynamically unstable patients following calcium antagonist intoxication who were refractory to conventional therapy. Blood pressures in all patients normalized within hours after receiving the insulin (Agarwal et al, 2012; Hadjipavlou et al, 2011; Azendour et al, 2010; Verbrugge & vanWezel, 2007; Greene et al, 2007; Boyer et al, 2002).
3) One study reviewed 13 case reports where high-dose insulin (10 to 20 units in 6 patients; 1 patient received 1000 units inadvertently; infusion rates 0.1 to 1 unit/kg/hr; duration either a single bolus dose or infusions for 5 to 96 hours) with supplemental dextrose and potassium (HDIDK) were used to treat calcium channel blockers overdose. These patients failed to respond clinically to other therapies. Twelve patients survived. HDIDK therapy was beneficial in seriously intoxicated patients with CCB-induced hypotension, hyperglycemia, and metabolic acidosis. However, this therapy did not consistently reverse bradycardia, heart block and intraventricular conduction delay (Shepherd & Klein-Schwartz, 2005).
4) VASOPRESSOR AGENTS a) INDICATION: Direct acting alpha-agonists mediate vasoconstriction by mechanisms independent of calcium influx and are preferred (Jaeger et al, 1989) although normal vascular response cannot be expected. In case review series, dopamine is the most commonly cited agent, followed by epinephrine, isoproterenol, and norepinephrine (Watling et al, 1992; Erickson et al, 1991).
b) CASE REPORTS: Two patients developed severe hypotension following calcium antagonist poisoning. Despite administration of fluids and vasopressor agents, hypotension persisted. SvO2 was continuously monitored in both patients, using a fiberoptic pulmonary catheter, in order to detect tissue hypoxia. The SvO2 remained between 71% and 85%, indicating adequate tissue oxygenation, and metabolic acidosis did not occur. Gradually, the hypotension of both patients resolved without more aggressive administration of vasopressor therapy, suggesting that higher infusion rates of vasopressor agents may not be necessary in patients with refractory hypotension, provided that tissue hypoxia can be excluded after volume resuscitation. Continuous SvO2 monitoring, using a fiberoptic pulmonary artery catheter, may be a useful index of tissue oxygenation (Kamijo et al, 2006).
5) 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).
6) Case reports have described the use of higher than conventional doses of dopamine (up to 40 to 50 mcg/kg/min) in patients with refractory hypotension after calcium antagonist overdose (Evans & Oram, 1999). Consider high rates of infusion in patients with refractory hypotension. 7) NOREPINEPHRINE a) 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).
8) EPINEPHRINE a) EPINEPHRINE 1) ADULT a) BOLUS DOSE: 1 mg intravenously/intraosseously every 3 to 5 minutes to treat cardiac arrest (Link et al, 2015).
b) INFUSION: Prepare by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate) (Lieberman et al, 2010). Used primarily for severe hypotension (systolic blood pressure 70 mm Hg), or anaphylaxis associated with hemodynamic or respiratory compromise, may also be used for symptomatic bradycardia if atropine and transcutaneous pacing are unsuccessful or not immediately available (Peberdy et al, 2010).
2) PEDIATRIC a) CARDIOPULMONARY RESUSCITATION: INTRAVENOUS/INTRAOSSEOUS: OLDER INFANTS/CHILDREN: 0.01 mg/kg (0.1 mL/kg of 1:10,000 (0.1 mg/mL) solution); maximum 1 mg/dose. May repeat dose every 3 to 5 minutes (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sorrentino, 2005). ENDOTRACHEAL: OLDER INFANTS/CHILDREN: 0.1 mg/kg (0.1 mL/kg of 1:1000 (1 mg/mL) solution). Maximum 2.5 mg/dose (maximum total dose: 10 mg). May repeat every 3 to 5 minutes (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008). Follow ET administration with saline flush or dilute in isotonic saline (1 to 5 mL) based on the child's size (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
b) INFUSION: Used for the treatment of refractory hypotension, bradycardia, severe anaphylaxis. DOSE: 0.1 to 1 mcg/kg/min, titrate dose; start at lowest dose needed to reach desired clinical effects. Doses as high as 5 mcg/kg/min may sometimes be necessary. High dose epinephrine infusion may be useful in the setting of beta blocker poisoning (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
3) CAUTION a) Extravasation may cause severe local tissue ischemia (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008); infusion through a central venous catheter is advised.
b) One-time bolus doses of 1 mg have been used in addition to bolus-infusion regimens (Erickson et al, 1991). Epinephrine 1 mg bolus followed by 0.2 to 0.6 mcg/kg/min improved both SBP and urine flow for 18 hours (Henderson et al, 1992). Infusion rates up to 100 mcg/min have been reported (Anthony et al, 1986). c) ANIMAL STUDY: Intravenous epinephrine administration (1 to 2 mcg/kg bolus dose, followed by a maintenance infusion of 8 to 12 mcg/min for 30 minutes) was shown to be effective in significantly improving the mean arterial pressure (MAP) and both the systolic and diastolic blood pressures, as well as improving heart rate and A-V conduction, of anesthetized dogs who were given diltiazem infusions in high concentrations (Dimich et al, 1988). 9) 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).
10) DOBUTAMINE a) DOBUTAMINE 1) DOSE: ADULT: Infuse at 5 to 10 micrograms/kilogram/minute IV. PEDIATRIC: Infuse at 2 to 20 micrograms/kilogram/minute IV or intraosseous, titrated to desired effect (Peberdy et al, 2010; Kleinman et al, 2010).
2) CAUTION: Decrease infusion rate if ventricular ectopy develops (Prod Info dobutamine HCl 5% dextrose intravenous injection, 2012).
11) ISOPROTERENOL a) 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).
12) CAUTIONS: Normal vascular response may not be seen. Doses of isoproterenol, while beneficial to cardiac conduction (beta-1 effect), may worsen peripheral vascular resistance (beta-2 effects) (Krenzelok, 1991). 13) GLUCAGON a) INDICATIONS: Glucagon exerts chronotropic and inotropic effects and can help reverse hypotension but may not improve heart rate.
b) DOSES: ADULT: Optimal dosing in calcium antagonist poisoning is not established. Initially, 3 to 5 mg IV, slowly over 1 to 2 minutes; may repeat treatment with a dose of 4 to 10 mg if there is no hemodynamic improvement within 5 minutes. CHILD: 50 mcg/kg; repeat doses may be used due to the short half-life of glucagon (DeRoos, 2011).
c) Empiric dosing has ranged from single doses of 2 mg (Anthony et al, 1986) to 17 mg (Ramoska et al, 1993). Continuous infusion of up to 5 mg/hr have also been used (Doyon & Roberts, 1993; Takahashi et al, 1993; Mahr et al, 1997; Papadopoulos & O'Neil, 2000).
14) PHOSPHODIESTERASE INHIBITORS a) INAMRINONE 1) INAMRINONE a) PREPARATION: Dilute solution for infusion to a final concentration of 1 to 3 milligrams per milliliter in normal saline (Prod Info inamrinone intravenous solution, 2002).
b) ADULT DOSE: Loading dose of 0.75 milligram/kilogram over 2 to 3 minutes followed by a maintenance infusion of 5 to 10 micrograms/kilogram per minute titrate to hemodynamic response. Repeat initial loading dose after 30 minutes if necessary (Prod Info inamrinone intravenous solution, 2002).
c) PEDIATRIC DOSE: The safety and effectiveness of inamrinone in the pediatric population has not been established (Prod Info inamrinone intravenous solution, 2002).
d) CAUTIONS: May cause hypotension and dysrhythmias (Prod Info inamrinone intravenous solution, 2002).
b) ENOXIMONE 1) VERAPAMIL: After ingesting 2800 mg of atenolol and 1600 mg of verapamil, a 57-year-old man with a history of ischemic heart disease (two previous acute myocardial infarctions) 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. Despite treatment with fluid resuscitation, calcium salts, and norepinephrine/epinephrine inotropic support, only a modest hemodynamic effect was observed. Following treatment with a bolus of enoximone 1 mg/kg and a continuous infusion at 0.5 mcg/kg/min for 5 days, his hemodynamic status improved. The authors suggested that enoximone, a phosphodiesterase III inhibitor, may be an alternative agent to glucagon as they have an inotropic effect which is not mediated by a beta receptor (Sandroni et al, 2004).
15) L-CARNITINE a) L-carnitine may be useful to treat hypotension in the setting of calcium channel blocker overdose. It is not well studied but an animal study and one human case report suggest efficacy. The dose used in the human case report was 6 g IV followed by 1 g IV every 4 hours.
b) MECHANISM: Carnitine is synthesized in several human organs, including liver and kidneys. It is produced from amino acids lysine and methionine in 2 optical isomeric forms with only L-carnitine being the biological active isomer. It transports fatty acids from the cellular cytoplasm into the mitochondrial matrix by the carnitine shuttle. The fatty acids undergo beta-oxidation to form acetyl-CoA in the mitochondrial matrix. It then enters the Krebs cycle to produce cellular energy. In one animal study, it was proposed that verapamil toxicity changed the cardiac metabolism from free fatty acids to carbohydrate. It has been suggested that L-carnitine in combination with high-dose insulin can decrease insulin resistance, promote intracellular glucose transport, increase the uptake and hepatic beta-oxidation of fatty acids, and increase calcium channel sensitivity in patients with calcium channel blocker toxicity (Perez et al, 2011; St-Onge et al, 2013).
c) ANIMAL STUDY: In a controlled, blinded animal study, 16 male rats were anesthetized and received a constant infusion of 5 mg/kg/hr of verapamil to produce severe verapamil toxicity. All animals received a bolus of 50 mg/kg of either L-carnitine or normal saline 5 minutes later. Mean arterial pressures (MAP) and heart rates of animals were recorded at baseline and at 15 and 30 minutes after the start of the experiment. The survival time was evaluated using the length of time (in minutes) from the initiation of verapamil until either the MAP had reached 10% of the baseline values or 150 minutes had passed without a suitable reduction in blood pressure. Animals in the L-carnitine group survived a median time of 140.75 minutes (interquartile range [IQR] = 98.6 to 150 minutes) as compared with 49.19 minutes (IQR = 39.2 to 70.97 minutes; p=0.0001) in the normal saline group. All animals in the L-carnitine group and one in the saline group survived over 90 minutes. Four animals in the L-carnitine group also survived the 150-minute protocol. At 15 minutes, a higher mean MAP was observed in the carnitine group (63 mm Hg; SD +/- 19.4 mmHg) as compared with the saline group (42.6 mmHg; SD +/_ 22.9 mmHg; p=0.047; a difference of 20.4 mmHg; 95% CI = 0.25 to 40.65 mmHg) (Perez et al, 2011).
d) AMLODIPINE/METFORMIN OVERDOSE: A 68-year-old man with a history of hypertension, type II diabetes, benign prostate hypertrophy, and chronic anemia, ingested 300 mg of amlodipine, 3500 mg of metformin, and ethanol in a suicide attempt. He presented pale, diaphoretic, and hemodynamically unstable (BP 56/42 mmHg, heart rate 77 beats/min). Laboratory results revealed a blood glucose concentration of 13 mmol/L, serum creatinine of 103 mcmol/L (normal, 50 to 100 mcmol/L), serum sodium of 126 mmol/L, and an increased CK of 871 mmol/L. The arterial blood gas analysis an hour later showed a pH of 7, pCO2 of 42, bicarbonate of 10 mmol/L, and lactate of 14.1 mmol/L (anion-gap of 22). Despite supportive therapy for 10 hours, including calcium, glucagon, vasopressors, high-dose insulin (HDI; even after more than 1 hour of infusion at 320 Units/hr), dextrose, lipid emulsion, and bicarbonate for metabolic acidosis, he remained in refractory shock (BP 110/50 mmHg, norepinephrine running at 80 mcg/min), hyperglycemic (33 mmol/L), oliguric, and acidotic. Continuous renal replacement therapy was not initiated because he was considered too unstable. About 11 hours after presentation, he received L-carnitine 6 g IV followed by 1 g IV every 4 hours. His condition began to improve about 30 minutes after L-carnitine loading dose and his norepinephrine requirement continued to decrease. Vasopressors were discontinued within 36 hours of initial presentation and he was extubated successfully within 4 days of presentation. His serum amlodipine concentration was 83 ng/mL (therapeutic: 3 to 11 ng/mL) on arrival and peaked at 160 ng/mL several hours later. His metformin concentration was 24 mcg/mL (therapeutic: 1 to 2 mcg/mL) at arrival (St-Onge et al, 2013).
16) METARAMINOL a) AMLODIPINE: A 43-year-old man developed hypotension (BP 65/40 mmHg) after ingesting 560 mg of amlodipine. Despite treatment with fluid resuscitation, calcium salts, glucagon and norepinephrine/epinephrine inotropic support, there was no hemodynamic response. Following treatment with metaraminol (a loading bolus of 2 mg [equivalent to 25 mcg/kg] and intravenous infusion of 1 mcg/kg/min [83 mcg/min] for 36 hours), there was improvement in his blood pressure, cardiac output and urine output (Wood et al, 2005).
17) TERLIPRESSIN a) FELODIPINE: A 61-year-old man developed hypotension (75/50 mmHg on admission) after ingesting 140 mg of felodipine. Despite administration of epinephrine and norepinephrine, the patient's hypotension persisted (mean arterial pressure 47 mmHg). A continuous infusion of 0.05 mcg/kg/min of terlipressin, a vasopressor, was initiated, resulting in the mean arterial pressure increasing from 47 to 95 mmHg; systemic vascular resistance and SvO2 also increased (Leone et al, 2005).
18) VASOPRESSIN a) AMLODIPINE AND DILTIAZEM: Two patients were given vasopressin infusions for treatment of refractory hypotension following intentional ingestions of 800 mg amlodipine and 4800 mg sustained-release diltiazem, respectively. The vasopressin infusion, in the first patient, was initiated at a rate of 2.4 international units (IU)/hour and titrated to 4.8 IU/hour over two hours. The second patient received a 20 IU bolus of vasopressin followed by a 4 IU/hour infusion. The hypotension resolved in both patients and they were subsequently discharged to rehabilitation facilities (Kanagarajan et al, 2007).
b) ANIMAL STUDY: In a porcine model, 18 anesthetized swine, each receiving a verapamil infusion of 1 mg/kg/hr until the mean arterial blood pressure (MAP) decreased to 70% of baseline, were divided into two groups: one group that received a vasopressin infusion of 0.01 units/kg/min (n=8) and the control group that received an equal volume of normal saline (n=10). MAP, heart rate, and cardiac output were then measured every 5 minutes until t=60 minutes. The results showed that there was no significant difference in MAP, heart rate, and cardiac output between the two groups. Four of 8 animals in the vasopressin group died as compared with 2 of 10 animals in the control group. Death appeared to be related to hypotension and low cardiac output. Based on the results of this study, the authors conclude that treatment with vasopressin actually decreased the survival of swine following verapamil intoxication as compared to the swine treated with normal saline alone (Barry et al, 2005)
19) SODIUM BICARBONATE a) ANIMAL DATA: In a study involving swine to determine the efficacy of hypertonic sodium bicarbonate in treating hypotension associated with severe verapamil toxicity, it was determined that swine, treated with 4 mEq/kg of 8.4% sodium bicarbonate given intravenously over 4 minutes, experienced a significant increase in mean arterial pressure and cardiac output as compared with animals in the control group, who were given 0.6% sodium chloride in 10% mannitol (Tanen et al, 2000).
D) FAT EMULSION 1) 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). 2) 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): a) 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.
b) 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.
c) 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.
d) 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.
3) CASE REPORTS a) A 57-year-old woman presented to the emergency department with hypotension and bradycardia after a multi-drug overdose ingestion, including an unknown amount of sustained release diltiazem 360 mg. An initial ECG showed sinus bradycardia without evidence of other ECG abnormalities, including AV block , wide QRS, or prolonged QT. The patient was given calcium chloride, glucagon, and vasopressors for persistent hypotension; however, 9 hours later, the patient developed chest pain with ECG changes. Her mean arterial pressure (MAP) was 60 mmHg. Intravenous lipid therapy 20% was initiated with a loading dose of 1.5 mg/kg, followed by an infusion of 0.25 mL/kg/min for a total dose of 8 mL/kg. Following completion of therapy, the patient's MAP increased to 68 mmHg, and vasopressor therapy was discontinued within 45 hours. The patient made a complete recovery and was discharged approximately 16 days post-ingestion (Wilson et al, 2012).
b) An 18-year-old woman presented with hypotension (71/40 mmHg) and tachycardia (102 bpm) approximately 8 hours after ingesting 3600 mg of sustained release diltiazem. Despite administration of fluids, and calcium chloride, the patient's hypotension persisted and she became oliguric. Four hours post-admission, she developed respiratory failure, necessitating intubation and mechanical ventilation. The patient was also receiving high-dose norepinephrine (6.66 mcg/kg/min), resulting in slight increases in her systolic and mean arterial blood pressures. Hyperinsulinemic euglycemia therapy was started with no significant improvement in her hemodynamic status and, 3 hours later, intravenous lipid emulsion (ILE) 20% was initiated with a bolus dose of 1.5 mL/kg, followed by a continuous infusion of 0.25 mL/kg over 1 hour. Following ILE therapy, the patient's hemodynamic status improved, with discontinuation of norepinephrine on hospital day 4. The patient made a complete recovery and was discharged approximately 9 days post-ingestion (Montiel et al, 2011).
c) A 53-year-old man developed bradycardia and hypotension (HR 30 beats/min; mean arterial pressure 40 mmHg) after ingesting diltiazem 3600 mg and propranolol 1200 mg. Despite treatment with calcium salts, catecholamines, high-dose insulin, bicarbonate, and atropine, his condition did not improve. Within 1 minute of receiving 150 mL of 20% IFE he developed brady-asystolic arrest, but his pulse returned to normal after 6 minutes of CPR. Despite aggressive supportive care, his condition deteriorated and he died of multisystem organ failure on day 7. Although the exact cause of arrest in this patient is uncertain, several possible causes were suggested: IFE interaction with other resuscitation drugs, a sudden increase in absorption of drug in the GI tract, a brief lack of oxygen in the lipid-laden blood circulating in the coronary vessels contributing to the arrests, fatal ingestions of drugs regardless of therapy (Cole et al, 2014).
ANIMAL DATA d) In a dog model of severe verapamil poisoning, dogs treated with 7 mg/kg 20% intravenous fat emulsion (after atropine and three doses of calcium chloride) had improved mean arterial pressure and 120 minute survival (100% vs 14%) compared with dogs treated with the same doses of atropine and calcium chloride, and 7 mg/kg 0.9% saline (Bania et al, 2007).
e) In a rat model of lethal verapamil overdose, intralipid treatment prolonged survival (44 +/-21 vs 24 +/- 9 minutes; p=0.003) and doubled median lethal dose (25.7 mg/kg [95% CI = 24.7 to 26.7] vs 13.6 mg/kg [95% CI = 12.2 to 15]). In addition, during verapamil infusion, a less marked decrease in heart rate was noted in the Intralipid-treated group (6.8 bpm [95% CI=8.3 to 5.2] for intralipid vs 10.7 bpm [95% CI = 12.6 to 8.9] for saline; p=0.001) (Tebbutt et al, 2006).
E) BRADYCARDIA 1) CALCIUM a) INDICATIONS: Calcium is given to reverse hypotension and improve cardiac conduction defects. Calcium administration has been most effective in overcoming mild toxicity from small overdoses or therapeutic use and is less useful in massive overdose cases since calcium channel blockade is non-competitive (Pearigen & Benowitz, 1991; Krenzelok, 1991; Clark & Hanna, 1993), but was successful in 11 of 30 cases in one series (Hofer et al, 1993). b) DRUG OF CHOICE: In some studies, calcium chloride is thought to produce more predictable increases in extracellular ionized calcium and a greater positive inotropic response (White et al, 1976; Haynes et al, 1985); however, other sources have found no differences in efficacy of calcium chloride and calcium gluconate. Calcium chloride provides 3 times more elemental calcium (13.4 mEq) than calcium gluconate (4.3 mEq) in the commercially available 1 gram ampules (DeRoos, 2011). c) ADULT DOSE: Optimal dosing is not established; begin with an initial IV infusion of about 13 to 25 mEq of calcium (10 to 20 mL of 10% calcium chloride or 30 to 60 mL of 10% calcium gluconate) followed by either repeat boluses every 15 to 20 minutes up to 3 to 4 doses or a continuous infusion of 0.5 mEq/kg/hr of calcium (0.2 to 0.4 mL/kg/hr of 10% calcium chloride or 0.6 to 1.2 mL of 10% calcium gluconate) (DeRoos, 2011). Some authors advocate administering 1 gram of calcium salts every 2 to 3 minutes until conduction block is reversed or clinical evidence of hypercalcemia develops(Howarth et al, 1994; Buckley et al, 1994). d) HYPERCALCEMIA: Some degree of hypercalcemia may be necessary before severely intoxicated patients respond to aggressive calcium therapy, but the optimal calcium regimen has not been established. In patients who have received large doses of calcium for severe calcium channel blocker overdose (attaining serum calcium concentrations up to twice the upper limits of normal), hypercalcemia generally resolves with in 48 hours without clinically apparent adverse effects from hypercalcemia (Howarth et al, 1994; Buckley et al, 1994). 1) CASE REPORT: Hypercalcemia with levels as high as 19.2 mg/dL (9.9 mg/dL upper limit of normal) secondary to treatment with calcium salts are reported during aggressive therapy (Buckley et al, 1993). Such aggressive treatment with calcium salts may be necessary to reverse conduction defects (Howarth et al, 1994).
2) CASE REPORT: Hypercalcemia (16.3 mg/dL) occurred following aggressive calcium chloride treatment in a 45-year-old woman following an overdose ingestion of sustained-release diltiazem. There were no ECG manifestations due to the hypercalcemia and the patient recovered uneventfully over the next 4 days (Hantsch et al, 1997).
e) CASE SERIES: In one series, doses varied from 4.5 mEq to 95.2 mEq, with no evidence of a dose-response relation (Ramoska et al, 1993). f) PRECAUTIONS: Hypotension generally does not respond as well as conduction disturbances to calcium. Significant hypercalcemia may be necessary before severely intoxicated patients respond to aggressive calcium therapy, but the optimal calcium regimen has not been established. If a patient does not respond after a doubling of the ionized calcium concentration, further calcium treatment may not be beneficial. If the patient has also ingested digoxin, avoid administering calcium until after digoxin-specific Fab is administered to prevent worsening digoxin toxicity (DeRoos, 2011). g) CASE REPORT/HIGH DOSE ADMINISTRATION: A 40-year-old woman, with chronic renal insufficiency, developed hypotension and bradycardia after ingesting 30 mg of amlodipine. The patient's blood pressure and heart rate normalized following high-dose intravenous administration of calcium chloride, consisting of 4 grams given in the emergency department followed by 1.5 grams every 20 minutes (for a total of 13 grams given over 2 hours) (Hung & Olson, 2007). h) ADVERSE EFFECTS: Calcium chloride can cause tissue injury following extravasation; administer calcium chloride via central venous access. Hypercalcemia or hypophosphatemia may also occur following repeat dosing or continuous infusion; monitor serum calcium and phosphate concentrations. Nausea, vomiting, flushing, constipation, confusion, and angina have also been reported in patients receiving calcium (DeRoos, 2011). 2) ATROPINE a) INDICATION: Bradydysrhythmia contributing to hypotension. May be more effective after calcium administration (Howarth et al, 1994). 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).
c) Up to 2 mg has been administered without effect (Ramoska et al, 1993). d) PRECAUTIONS: Atropine primarily blocks vagal effects at the SA node while calcium antagonists affect AV conduction; marked improvements in rate may not be seen. 3) GLUCAGON a) INDICATIONS: Glucagon exerts chronotropic and inotropic effects and can help reverse hypotension but may not improve heart rate in calcium antagonist intoxication.
b) DOSES: ADULT: Optimal dosing in calcium antagonist poisoning is not established. Initially, 3 to 5 mg IV, slowly over 1 to 2 minutes; may repeat treatment with a dose of 4 to 10 mg if there is no hemodynamic improvement within 5 minutes. CHILD: 50 mcg/kg; repeat doses may be used due to the short half-life of glucagon (DeRoos, 2011).
c) Empiric dosing has ranged from single doses of 2 mg (Anthony et al, 1986) to 17 mg (Ramoska et al, 1993). Continuous infusion of up to 5 mg/hr have also been used (Doyon & Roberts, 1993; Takahashi et al, 1993; Mahr et al, 1997; Papadopoulos & O'Neil, 2000).
4) ISOPROTERENOL a) INDICATION: Predominant beta-1 effects stimulate discharge rate at SA node, increase heart rate, and improve contractility (Krenzelok, 1991). 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).
5) PACEMAKER a) INDICATION: Consider using a pacemaker device in severely symptomatic patients (Rodgers et al, 1989; Quezado et al, 1991; MacDonald & Alguire, 1992; Bizovi et al, 1998; Sanders et al, 1998).
6) INTRA-AORTIC BALLOON PUMP a) CASE REPORT: Intra-aortic balloon counterpulsation was required in addition to pacing in a 17-year-old girl who had taken an unknown quantity of acebutolol 400 mg capsules in addition to 480 mg sustained-release verapamil (Welch et al, 1992). Other successful applications have been reported (Melanson et al, 1993; Williamson & Dunham, 1996).
7) CARDIOPULMONARY BYPASS a) CASE REPORT: Cardiopulmonary bypass was used in a 25-month-old child after verapamil overdose. Serum verapamil levels fell during the procedure, allowing successful pacing, but rose again after discontinuation of the procedure, and he subsequently died (Hendren et al, 1989).
b) CASE REPORT: A 41-year-old man ingested 4800 to 6400 mg of verapamil in a suicide attempt and developed cardiac arrest. Despite cardiopulmonary resuscitation, percutaneous cardiopulmonary bypass was required 2.5 hours after cardiac arrest. Complete recovery was reported 6 months after exposure (Holzer et al, 1999).
F) EXTRACORPOREAL MEMBRANE OXYGENATION 1) CASE REPORT: A 16-year-old girl experienced multiple asystolic cardiac arrests with atrial standstill, refractory to therapy with high-dose epinephrine and transcutaneous cardiac pacing, after intentionally ingesting 12 grams of sustained-release diltiazem tablets. The patient's hemodynamic status significantly improved, with a return of brainstem reflexes, following a 48-hour period of extracorporeal membrane oxygenation (ECMO) (Durward et al, 2003).
G) SEIZURE 1) SUMMARY a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
2) DIAZEPAM a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
3) NO INTRAVENOUS ACCESS a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
4) LORAZEPAM a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
5) PHENOBARBITAL a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
6) OTHER AGENTS a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012): 1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
H) 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). 8) PARTIAL LIQUID VENTILATION a) CASE REPORT: A 27-year-old man, who ingested approximately 24 grams of sustained-release verapamil and subsequently developed hypotension, bradycardia, and respiratory distress requiring mechanical ventilation, was enrolled in a phase II clinical trial and was given partial liquid ventilation (PLV) with Perflubron(R), a fluorocarbon, administered intratracheally every 2 hours for 4 days. The patient's pulmonary function significantly improved within hours of PLV administration (Szekely et al, 1999). 1) Theoretically, the dense fluorocarbon improves ventilation: perfusion by redistribution of blood to the anterior portions of the lungs, eases pulmonary toilet (aids in the removal of exudate), and reduces potential further lung injury secondary to lower ventilator settings.
I) EXPERIMENTAL THERAPY 1) 4-AMINOPYRIDINE a) SUMMARY: Preliminary investigation suggests that 4-aminopyridine (a potassium channel inhibitor) may antagonize the effects of calcium channel blockers by facilitating inward calcium movement (Pearigen & Benowitz, 1991). 1) Additional clinical studies are needed to demonstrate the safety and efficacy of 4-aminopyridine for treatment of calcium antagonist overdose. 2) HUMAN/CASE REPORTS a) Equivocal benefits were reported following 10 mg of 4-aminopyridine in a 67-year-old man poisoned with verapamil (ter Wee et al, 1985).
b) A 47-year-old woman intentionally ingested 20 1-mg tablets of lorazepam and 40 5-mg tablets of amlodipine and presented to the emergency department 7 hours later with a blood pressure of 124/65 mmHg and a heart rate of 75 bpm. Despite activated charcoal administration, the patient's blood pressure and heart rate continued to decrease to 90/38 mmHg and 58 bpm, respectively. Following intravenous administration of 4-aminopyridine at a dosage regimen of 50 mcg/kg/hour over a 3-hour period, her blood pressure increased to 110/50 mmHg and her heart rate increased to 68 bpm (Wilffert et al, 2007).
3) ANIMAL DATA a) The effectiveness of 4-aminopyridine (4-AP) and Bay K 8644 (calcium channel activator) were evaluated in verapamil-poisoned Wistar rats. Both agents were able to increase survival time with 70% of the animals surviving in the 4-AP-treated group and 50% surviving in the Bay K 8644-treated group. Average survival in the control groups was 20% for the calcium group and 40% for the adrenaline group, respectively.
b) MECHANISM: 4-AP has an indirect effect on calcium channels and is able to block potassium K(1) channels on the cytoplasm side leading to depolarization and opening of voltage-dependent calcium channels resulting in improved blood pressure and heart rate. Bay K 644 evokes the release of calcium from endoplasmic reticulum and activation of the calcium ion influx to improve the contraction of the vascular smooth muscle and myocardium and electrical conduction in the heart.
c) The authors concluded that despite its dose-dependent epileptogenic action (easily controlled in this study with antiepileptic therapy), 4-AP was the most effective therapy (Magdalan, 2003).
d) 4-Aminopyridine reversed verapamil toxicity in artificially ventilated cats (Agoston et al, 1984).
2) LEVOSIMENDAN a) CASE REPORTS: Two patients who overdosed on calcium antagonists and developed cardiovascular collapse, unresponsive to conventional therapies, improved and then recovered without sequelae following levosimendan infusions (Varpula et al, 2009). 1) The first patient, a 47-year-old woman, became severely hypotensive and developed asystole, that required ventricular pacing, after ingesting 16 grams of verapamil. Despite calcium, glucagon, epinephrine boluses, norepinephrine, continuous vasopressin infusion, insulin and glucose infusion, intra aortic balloon pump, her mean arterial pressure (MAP) could not be maintained above 50 mmHg. Levosimendan was then initiated at an initial loading dose of 2 mcg/kg followed by an infusion of 0.2 mcg/kg/hour that was continued for 30 hours. Within 2 hours of initiating levosimendan, MAP could be maintained at 60 mmHg without epinephrine boluses, and she eventually recovered with normal neurologic function.
2) The second patient, a 38-year-old man, became comatose and acidotic, with an unmeasurable mean arterial pressure (MAP), after ingesting 630 mg amlodipine, 300 mg of zopiclone, and an unknown amount of citalopram and acetaminophen. Despite conventional treatment with glucagon, calcium, vasopressors, and insulin and glucose, the patient's condition deteriorated, with persistent hypotension, worsening acidosis, right ventricular dilation, and a left ventricle ejection fraction (LEVF) of 38%. Levosimendan was then initiated at an infusion rate of 0.1 to 0.2 mcg/kg/min. Ninety minutes after initiation of therapy, the patient's LVEF improved to 72%. The patient gradually recovered and was discharged approximately 11 days post-ingestion.
b) ANIMAL DATA: The efficacy of levosimendan, an inotropic agent, on cardiac output, blood pressure, and heart rate was assessed in rats following intoxication with verapamil, infused at 6 mg/kg/hr until mean arterial blood pressure decreased to 50% of baseline, then the infusion was reduced to 4 mg/kg/hr. There were 5 treatment groups evaluated: normal saline infusion (control), calcium chloride as a loading dose and infusion, levosimendan 24 mcg/kg loading dose and 0.6 mcg/kg/min infusion (Levo-24), levosimendan 6 mcg/kg loading dose and 0.4 mcg/kg/min infusion (Levo-6), and levosimendan 0.4 mcg/kg/min infusion with calcium chloride loading dose and infusion (Levo + CaCl2). The results showed that although the Levo-6 and Levo-24 groups showed statistically significant improvement in blood pressure compared to the control group (p <0.05) from t=20 minutes, the rats continued to be hypotensive with no improvement in blood pressure from that observed at t=0 minutes (peak verapamil toxicity prior to treatment administration). Cardiac output was significantly higher in all treatment groups as compared with the control group from t=20 minutes, except for Levo-6, which showed a significant improvement from t=30 minutes, and heart rate was maintained at pre-toxicity levels in all treatment groups. Based on the results of this study, the authors conclude that further investigation is warranted in order to consider levosimendan as an effective agent for the treatment of verapamil poisoning (Graudins et al, 2008). 3) METHYLENE BLUE a) CASE REPORT: A 25-year-old woman presented to the emergency department 1 hour after intentionally ingesting 40 10-mg amlodipine tablets. Vital signs indicated normal blood pressure (120/86 mmHg), but elevated pulse rate (110 bpm), and an ECG revealed sinus tachycardia. Approximately 2 to 3 hours after receiving activated charcoal, the patient became hypotensive (75/40 mmHg) and her pulse rate increased to 120 bpm. Despite supportive treatment with calcium gluconate, glucagon, vasopressors, and high dose insulin therapy, the patient's condition progressively worsened, resulting in shock. Approximately 16 hours post-ingestion, methylene blue was administered at 2 mg/kg over 20 minutes, followed by 1 mg/kg/hour infusion. One hour after initiating therapy, the patient's blood pressure increased to 90/75 mmHg and her pulse rate decreased to 90 bpm. The patient was gradually weaned off all vasopressors and high-dose insulin therapy, and methylene blue therapy was discontinued. She was discharged 6 days later without sequelae (Jang et al, 2011).
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