a) Intravenous calcium infusions have been shown to be helpful, although response is often short lived. Optimal dosing is not established; start 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 starting with 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) and titrate as needed. 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. Patients with severe overdose have tolerated significant hypercalcemia (up to twice the upper limit of normal) without developing clinical or ECG evidence of hypercalcemia.

a) Administer a bolus of 1 unit/kg of insulin followed by an infusion of 0.1 to 1 unit/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 titrate insulin infusion. 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. 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.

a) Anecdotal reports suggest that epinephrine, vasopressin, metaraminol, or phenylephrine may occasionally be effective in patients who do not respond to dopamine or norepinephrine.

a) Lipid emulsion has been successful in animal studies and several case reports of patients with hypotension refractory to other therapies. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. 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. 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. Where possible, lipid resuscitation therapy 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.

a) DOSE: 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.

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.

a) There are case reports where a phosphodiesterase inhibitor (inamrinone, enoximone) appeared to improve blood pressure in patients unresponsive to other modalities.

a) BEPRIDIL: ADULT: 300 mg or less; CHILD: no safe dose
b) ISRADIPINE: ADULT: 20 mg or less; CHILD: 0.1 mg/kg or less
c) NICARDIPINE: ADULT: 40 mg or less IR or chewed SR, or 60 mg or less SR; CHILD: less than 1.25 mg/kg
d) NIMODIPINE: ADULT: 60 mg or less; CHILD: no safe dose
e) NISOLDIPINE: ADULT: 30 mg or less; CHILD: no safe dose

a) According to the AAPCC guidelines, patients with the following inadvertent single substance ingestions should be referred to a healthcare facility (IR = immediate release, SR = sustained release):

a) NIMODIPINE: Deaths and serious adverse events, including cardiac arrest, cardiovascular collapse, hypotension, and bradycardia have been reported following the intravenous administration of the contents of nimodipine capsules (US Food and Drug Administration, 2006).

a) SIGNS/SYMPTOMS: Hypotension is common following significant overdose. Hypotension may be quite severe and unresponsive to pressor agents. Syncopal episodes secondary to impaired perfusion may occur (Devasahayam et al, 2012; Wood et al, 2005; Saravu & Balasubramanian, 2004; Gerloni & Copetti, 2004; Durward et al, 2003; SamiKarti et al, 2002; Schwab et al, 2002; Vadlamudi & Wijdicks, 2002; Herbert et al, 2001; Meyer et al, 2001; Cavagnaro et al, 2000; Ori et al, 2000; Luscher et al, 1994; Ramoska et al, 1993; Welch et al, 1992) .
b) ONSET: Common within 1 to 5 hours postingestion, although delayed onset (more than 24 hours) and prolonged duration of symptoms can occur following sustained-release dosage forms (Tuka et al, 2009; Morimoto et al, 1999; Luscher et al, 1994; Buckley et al, 1993; Quezado et al, 1991; Spiller et al, 1991; Krick et al, 1990; de Faire & Lundman, 1978) .
c) DURATION: In one series, 80% of cases were asymptomatic for all cardiovascular effects after 24 hours (Ramoska et al, 1993).
d) LERCANIDIPINE/CASE REPORT: A 49-year-old man developed bradycardia and severe hypotension (77/40 mmHg), refractory to IV fluids, calcium and glucagon, after intentionally ingesting 560 mg of slow-release lercanidipine. Following hyperinsulinemic euglycemia therapy and norepinephrine administration, the patient's blood pressure normalized and he was discharged approximately 2 days post-ingestion (Hadjipavlou et al, 2011).

a) Electrophysiologic effects of calcium antagonists vary among verapamil, diltiazem, nifedipine, and amlodipine (Mitchell et al, 1982). In overdose, all agents can cause rhythm disturbances and conduction defects. Nifedipine, amlodipine, and other dihydropyridines lack the effects of other structural classes of calcium antagonists on AV nodal conduction. Therefore, these agents are more likely to result in reflex tachycardia secondary to diminished perfusion; bradycardia is twice as likely with verapamil and diltiazem. AV block, especially greater than first degree, is predominately a finding with verapamil.

a) FINDINGS: ECG manifestations may occur, including heart block, first-, second-, and third-degree AV block, junctional rhythm, QT interval prolongation, moderate S-T segment depression, low amplitude T-waves, prominent U-waves, and atrial fibrillation (Prod Info isradipine oral capsules, 2011; Henrikson & Chandra-Strobos, 2003; SamiKarti et al, 2002; Schwab et al, 2002; Ori et al, 2000; De Cicco et al, 1999; Howarth et al, 1994; Luscher et al, 1994; Quezado et al, 1991; McMillan, 1988; Moroni et al, 1980) .
b) ONSET: AV block usually occurs 4 to 24 hours postexposure (Spiller et al, 1991; da Silva et al, 1979) .
c) DURATION: Cardiac disturbances commonly persist for 9 to 48 hours, but have been reported to last as long as 7 days (Quezado et al, 1991). In one series, 80% of cases were asymptomatic for all cardiovascular effects after 24 hours (Ramoska et al, 1993).
d) MIBEFRADIL/CASE REPORT: Sinus arrest occurred in a 78-year-old woman 4 days after beginning mibefradil therapy, 100 mg daily. The patient was initially managed with transvenous pacing until return of normal sinus rhythm approximately 36 hours after discontinuation of mibefradil (Sanders et al, 1998).

a) FINDINGS: Heart rates below 60 beats/min with accompanying hypotension at presentation are common (Prod Info nicardipine HCl oral capsules, 2013; Hadjipavlou et al, 2011; Durward et al, 2003; SamiKarti et al, 2002; Vadlamudi & Wijdicks, 2002; Schwab et al, 2002; Meyer et al, 2001; Snook et al, 2000; Howarth et al, 1994), but isolated bradycardia has also been noted (Krick et al, 1990).
b) ONSET: Common within 1 to 5 hours postingestion, although delayed onset (more than 6 hours) can occur following sustained-release dosage forms (Morimoto et al, 1999). (Barrow et al, 1994; Rodgers et al, 1989)
c) DURATION: Bradycardia for 36 to 52 hours after admission has been reported (Barrow et al, 1994; Howarth et al, 1994; Perkins, 1978). In one series, 80% of cases were asymptomatic for all cardiovascular effects after 24 hours (Ramoska et al, 1993). Ingestion of sustained-release products may result in prolonged or delayed effects (Barrow et al, 1994; Luscher et al, 1994).
d) CASE REPORTS

a) FINDINGS: A reflex tachycardia has primarily been reported with nifedipine overdose, but may occur with other dihydropyridine calcium antagonists (Prod Info isradipine oral capsules, 2011; Saravu & Balasubramanian, 2004; Lee et al, 2000; Stanek et al, 1997; Cosbey & Carson, 1997; Aya et al, 1996a; Castro JrG, Tsai PWC & Ozaki MM et al, 1994; Ferner et al, 1990; Whitebloom & Fitzharris, 1988).
b) INCIDENCE: In one series of 28 nifedipine toxicities, tachycardia was present in 16 (57%) as compared with approximately 25% of cases involving either verapamil or diltiazem (Ramoska et al, 1993).
c) ONSET: Common within 1 to 5 hours postingestion, although delayed onset (more than 6 hours) can occur following sustained-release dosage forms (Ramoska et al, 1993).
d) DURATION: In one series, 80% of cases were asymptomatic for all cardiovascular effects after 24 hours (Ramoska et al, 1993).
e) NICARDIPINE/CASE REPORT: Sinus tachycardia was reported in a 39-year-old woman who was 36 weeks pregnant and inadvertently received an overdose infusion of niCARdipine at 20 to 25 mg/hour over a 10-hour period, instead of the prescribed 2 mg/hour, to treat severe hypertension (Aya et al, 1996).
f) BENIDIPINE/CASE REPORT: Tachycardia (151 beats/min), metabolic acidosis, and fever were reported in a 16-month-old child following an inadvertent ingestion of two 4-mg benidipine tablets (0.8 mg/kg). With supportive therapy, the patient recovered and was discharged approximately 2 days post-ingestion (Akbayram et al, 2012).

a) ISRADIPINE/CASE REPORT: A 5-year-old child, who was taking isradipine 2.5 mg twice daily for treatment of hypertension, presented with bradycardia and abdominal distention. Thirty minutes after hospital admission, the patient developed a ventricular escape rhythm (20 bpm), became apneic, then developed asystole. The patient responded to cardiac resuscitation and temporary pacing, with spontaneous cardiac activity returning approximately 12 hours postadmission (Romano et al, 2002). Serum isradipine concentration, obtained 1 hour postadmission, was 260.7 ng/mL. Twenty hours later, a second serum isradipine concentration was 27.4 ng/mL. The normal therapeutic concentration in adults receiving multiple daily doses is 2.2 to 8.21 ng/mL.

a) BARNIDIPINE/CASE REPORT: A 25-year-old woman presented to the hospital with dizziness, syncope, lethargy, confusion, hypotension (60/30 mmHg), and tachycardia (130 bpm) after intentionally ingesting 500 mg of barnidipine. An ECG demonstrated ST-segment depression, and troponin I concentration was elevated, establishing a diagnosis of non-ST-segment elevation myocardial infarction. Coronary angiography was normal, so the myocardial ischemia was likely secondary to profound hypotension and tachycardia. With supportive care, the patient recovered and was discharged approximately 10 days postingestion (Guvenc et al, 2010).

a) NISOLDIPINE/CASE REPORT: Severe shock, hypothermia, and renal insufficiency were reported in a 72-year-old woman following a suspected overdose ingestion of nisoldipine. With supportive therapy, including administration of IV glucagon and calcium chloride, the patient recovered without sequelae. A serum nisoldipine concentration of 1544 mcg/L was obtained at admission, although the exact time of ingestion was unknown (Louagie et al, 1998).

a) Noncardiogenic pulmonary edema has been reported following calcium antagonist overdose (Durward et al, 2003; Humbert et al, 1991; Ori et al, 2000; Howarth et al, 1994; Leesar et al, 1994; Spurlock et al, 1991; Spiller et al, 2012; Ghosh & Sircar, 2008; Saravu & Balasubramanian, 2004).
b) RISK FACTORS: Fluid loading to maintain blood pressure and oliguria secondary to hypotension may contribute (Herrington et al, 1986; Barrow et al, 1994).

a) BENIDIPINE/CASE REPORT: Kussmaul respiration was reported in a 16-month-old child following an inadvertent ingestion of two 4-mg benidipine tablets (0.8 mg/kg) (Akbayram et al, 2012).

a) CASE REPORT: Hypoxemia (partial pressure oxygen (PO2) of 60 mmHg with fractional inspired oxygen of 50%) was reported in an 81-year-old woman following a suspected overdose ingestion of nimodipine. Transthoracic echocardiography demonstrated normal left ventricular systolic function and chest X-ray was normal. Within 20 minutes after receiving IV calcium gluconate, the patient's oxygenation improved to a PO2 of 113 mmHg with a fractional inspired oxygen of 50% (Gerloni & Copetti, 2004).

a) Seizure activity has been reported with calcium antagonist overdose and may result from acidosis, anoxia, or an existing predisposition (Hadjipavlou et al, 2011; Isbister, 2002; Wells et al, 1990; Malcolm et al, 1986; Passal & Crespin, 1984).

a) Headaches are a common adverse event with calcium antagonist therapy (Prod Info NYMALIZE(TM) oral solution, 2013; Prod Info nicardipine HCl oral capsules, 2013; Prod Info isradipine oral capsules, 2011; Prod Info Cleviprex(R) intravenous injection, 2011; Prod Info SULAR(R) extended release oral tablets, 2010).

a) CASE REPORT: Headache, palpitations, and flushing were reported in a 39-year-old 36 weeks pregnant woman who inadvertently received an infusion of 20 to 25 mg/hour of niCARdipine over a 10-hour period, instead of the prescribed 2 mg/hour, to treat severe hypertension. With supportive therapy, the patient's symptoms resolved. A cesarean section was performed, with the newborn exhibiting normal hemodynamic parameters (Aya et al, 1996).

a) Bowel necrosis and mesenteric ischemia may occur in the absence of prolonged hypotension (Donovan et al, 1999).

a) A case control study, performed by Kaplan et al (2000), indicated that therapeutic use of calcium channel blockers may be associated with a 2-fold increased risk of gastrointestinal bleeding as compared with users of beta-blockers (Kaplan et al, 2000).

a) Acute renal failure has been reported, usually in patients who develop prolonged hypotension and/or rhabdomyolysis after severe poisoning (Ghosh & Sircar, 2008; Gokel et al, 2000; Williamson & Dunham, 1996; Quezado et al, 1991; Pearigen & Benowitz, 1991; McMillan, 1988).
b) CASE REPORT: Renal insufficiency (serum creatinine of 2.67 mg/dL) was reported in a 72-year-old woman following a suspected overdose ingestion of nisoldipine. A serum nisoldipine concentration of 1544 mcg/L was obtained at admission, although the exact time of ingestion was unknown (Louagie et al, 1998).

a) Transient oliguria is associated with prolonged hypotension (Fauville et al, 1995; Barrow et al, 1994).
b) CASE REPORT: Anuria, as well as hypotension and hypoxemia, was reported in an 81-year-old woman following a suspected overdose ingestion of nimodipine. Following calcium gluconate administration, the patient's anuria resolved with improvement in her blood pressure and oxygenation (Gerloni & Copetti, 2004).

a) BENIDIPINE/CASE REPORT: Metabolic acidosis (pH 7.10, pCO2 40 mmHg, pO2 29 mmHg, HCO3 15 mmol/L), tachycardia, Kussmaul respiration, and fever were reported in a 16-month-old child following an inadvertent ingestion of two 4-mg benidipine tablets (0.8 mg/kg). With supportive therapy, the patient recovered and was discharged approximately 2 days post-ingestion (Akbayram et al, 2012).

a) Minor skin rashes are reported for most calcium channel agents (Sun et al, 1994).

a) Flushing has been reported (Prod Info isradipine oral capsules, 2011; Prod Info CARDENE(R) SR oral sustained release capsules, 2010; Aya et al, 1996).

a) Rhabdomyolysis may occur in conjunction with acute renal failure following overdose ingestions of calcium antagonists (Gokel et al, 2000; Quezado et al, 1991).

a) RABBITS: In 2 animal studies, nimodipine has been shown to cause teratogenic malformations in rabbits such as stunted fetal growth unrelated to dose. Increased incidences of malformation and stunted fetuses were observed in 1 study with oral administration from day 6 through day 18 of pregnancy at doses of 1 and 10 mg/kg/day but not at 3 mg/kg/day. An increased incidence of stunted fetuses were reported in a second study at 1 mg/kg/day but not at higher doses of 3 and 10 mg/kg/day (Prod Info NYMALIZE(TM) oral solution, 2013; Prod Info nimodipine oral capsules, 2012).
b) RATS: Resorption and stunted growth of fetuses were noted in rats administered oral nimodipine from day 6 through day 15 of pregnancy at doses of 100 mg/kg/day. Higher incidences of skeletal variation, stunted fetuses, and stillbirths were identified in 2 other rat studies using oral nimodipine from day 16 of gestation and continued until day 20 of pregnancy or day 21 postpartum at doses of 30 mg/kg/day, but no congenital malformations were evident at this dose (Prod Info NYMALIZE(TM) oral solution, 2013; Prod Info nimodipine oral capsules, 2012).

1) CLEVIDIPINE (Prod Info Cleviprex(R) intravenous injection, 2011)
2) ISRADIPINE (Prod Info isradipine oral capsules, 2011)
3) NICARDIPINE (Prod Info nicardipine HCl oral capsules, 2013)
4) NIMODIPINE (Prod Info NYMALIZE(TM) oral solution, 2013; Prod Info nimodipine oral capsules, 2012)
5) NISOLDIPINE (Prod Info SULAR(R) extended release oral tablets, 2010)

a) Pregnant, hypertensive women who were treated with IV niCARdipine experienced hypotension, reflex tachycardia, postpartum hemorrhage, tocolysis, headache, nausea, dizziness, and flushing. Fetal adverse effects ranged from none to transient fetal heart rate decelerations. In neonates, adverse events ranged from none to hypotension. During preterm labor, those treated with IV niCARdipine experienced pulmonary edema, dyspnea, hypoxia, hypotension, tachycardia, headache, and phlebitis at site of injection. Acidosis (pH less than 7.25) was reported in neonates (Prod Info nicardipine HCl intravenous injection solution, 2012).
b) CASE REPORT: Headache, palpitations, and flushing were reported in a 39-year-old 36 weeks pregnant woman who inadvertently received an infusion of 20 to 25 mg/hour of niCARdipine over a 10-hour period, instead of the prescribed 2 mg/hour, to treat severe hypertension. With supportive therapy, the patient's symptoms resolved. A cesarean section was performed, with the newborn exhibiting normal hemodynamic parameters (Aya et al, 1996).

a) Low-level placental transfer of niCARdipine was observed in 10 of 40 hypertensive women, with no cord or serum accumulations evident in the fetus. Adverse fetal or neonatal outcomes in this study were not associated with niCARdipine. NiCARdipine is superior to nifedipine in that it acts more selectively on blood vessels than on myocardium, has a lesser negative inotropic effect, and produces less reflex tachycardia (Carbonne et al, 1993).

a) A small-scale study (n=50) evaluating the use of niCARdipine for the treatment of hypertension in severe preeclampsia showed the drug to be safe and efficacious for both mother and fetus. NiCARdipine was administered for 7 days or less (n=10), 8 to 28 days (n=20), or 29 days or more (n=10). Long-term treatment appeared to be just as safe as short and medium-term protocols that were already established (Seki et al, 2002).

a) In a study describing 10 pre-eclamptic women, nimodipine administration near term was associated with effective control of blood pressure. The patients were treated with 30 mg nimodipine orally every 4 hours from the time of admission through 24 hours following delivery. Doppler findings were consistent with vasodilatation in maternal and fetal cerebral vessels. Systolic and diastolic blood pressure were reduced significantly without apparent fetal distress. All infants were developing normally at 6 weeks of age (Belfort et al, 1994).

a) RATS, RABBITS: A decrease in fetal survival during organogenesis was observed in rats and rabbits at doses of 0.7 times (on a body surface area basis) the maximum recommended human dose (MRHD) in rats and 2 times the MRHD in rabbits (Prod Info Cleviprex(R) intravenous injection, 2011).
b) RATS: Dose-related increases in maternal mortality, length of gestation, and prolonged parturition were observed during late gestation in pregnant rats at doses greater than or equal to one-sixth the maximum recommended human dose on a body surface area basis. Clevidipine crosses the placenta in rats (Prod Info Cleviprex(R) intravenous injection, 2011).

a) RATS: Oral administration of isradipine in rats decreased maternal weight gain at the highest and maternally toxic dose of 60 mg/kg/day (150 times the maximum human therapeutic dose), but was not associated with embryotoxicity or adverse fetal or maternal outcome (Prod Info isradipine oral capsules, 2011).
b) RABBITS: Reduction in maternal weight gain and increased fetal resorption were noted in rabbits administered isradipine 3 and 10 mg/kg/day (7.5 and 25 times, respectively, the maximum human therapeutic dose) (Prod Info isradipine oral capsules, 2011).

a) RATS, RABBITS: Embryotoxicity was not reported in rats exposed to oral niCARdipine doses 8 times the maximum recommended human dose (MRHD) based on body surface area (mg/m(2)), However, dystocia, reduced birth weights and neonatal weight gain, and reduced neonatal survival were reported. There was evidence of embryotoxicity and maternal toxicity (maternal weight gain suppression) in rabbits exposed to oral doses 24 times the MRHD. There was also evidence of embryotoxicity when rats and rabbits were exposed to niCARdipine at 0.27 and 0.05 times the MRHD, respectively. Significant maternal mortality, but no fetal harm, was reported when rabbits were exposed to oral doses up to 16 times the MRHD (Prod Info nicardipine HCl intravenous injection solution, 2012).

a) RATS: Increased fetal resorptions was noted following nisoldipine administration to pregnant rats at doses of 100 mg/kg/day (approximately 5 times the maximum recommended human dose (MRHD) on a mg/m(2) basis). Decreased fetal weight was also observed at doses of 30 mg/kg/day (approximately 16 times the MRHD on a mg/m(2) basis) and 100 mg/kg/day (Prod Info SULAR(R) extended release oral tablets, 2010).
b) RABBITS: Doses of 30 mg/kg/day (approximately 10 times the MRHD on a mg/m(2) basis) resulted in decreased fetal and placental weights when administered to pregnant rabbits (Prod Info SULAR(R) extended release oral tablets, 2010).

a) At the time of this review, no data were available to assess the potential effects of exposure to clevidipine, isradipine, or nisoldipine during lactation in humans (Prod Info Cleviprex(R) intravenous injection, 2011; Prod Info isradipine oral capsules, 2011; Prod Info SULAR(R) extended release oral tablets, 2010).

a) In a study of 11 nursing mothers who were treated with oral or IV niCARdipine 4 to 14 days postpartum (immediate-release, 40 to 80 mg/day (n=4); sustained-release, 100 to 150 mg/day (n=6); and IV 120 mg/day (n=1)), the peak milk concentration and mean milk concentration were 7.3 mcg/L (range, 1.9 to 18.8 mcg/L) and 4.4 mcg/L (range 1.3 to 13.8 mcg/L), respectively. Infants received an average of 0.073% and 0.14% of the weight-adjusted maternal oral and IV dose, respectively (Prod Info nicardipine HCl intravenous injection solution, 2012).
b) In another study of 7 nursing mothers who were administered IV niCARdipine for an average of 1.9 days to treat preeclampsia, niCARdipine was not detectable (less than 5 mcg/L) in 82% of the 34 milk samples that were collected at unspecified times. There were detectable niCARdipine levels (range, 5.1 to 18.5 mcg/L) in 6 milk samples collected from 4 women who received 1 to 6.5 mg/hour of niCARdipine. In 1 woman who was treated with 5.5 mg/hour of niCARdipine, there was a niCARdipine concentration of 18.5 mcg/L. Less than 0.3 mcg/day (between 0.015% to 0.004% of the therapeutic dose in a 1-kg infant) was the estimated maximum niCARdipine dose in a nursing infant (Prod Info nicardipine HCl intravenous injection solution, 2012).

a) In 1 study, breast milk levels of nimodipine were negligible with a milk/serum nimodipine concentration of 0.06 to 0.15 (Carcas et al, 1996). The authors estimated that a nursing infant would receive between 0.063 to 0.705 mcg/kg/day of nimodipine. This corresponds to between 0.008% and 0.092% of the weight-adjusted dose administered to the mother. In another study, breast milk levels paralleled serum levels, in a ratio of approximately 1:3 (Tonks, 1995).

a) RATS: A dose-related increase in maternal mortality, length of gestation, and prolonged parturition was observed during lactation in pregnant rats at doses greater than or equal to 1-sixth the maximum recommended human dose on a body surface area basis (Prod Info Cleviprex(R) intravenous injection, 2011).

a) RATS: Nimodipine and/or its metabolites are excreted in the milk of lactating rats at concentrations much higher than in maternal plasma (Prod Info NYMALIZE(TM) oral solution, 2013; Prod Info nimodipine oral capsules, 2012).

a) RATS: No adverse effects on male or female fertility were observed in rats receiving up to 55 mg/kg/day (approximately equivalent to 504 mg/day maximum recommended human dose on a body surface area basis) (Prod Info Cleviprex(R) intravenous injection, 2011).

a) RATS: No evidence of fertility impairment in male and female rats receiving doses up to 60 mg/kg/day (Prod Info isradipine oral capsules, 2011).

a) RATS: There was no impairment of fertility in male or female rats exposed to oral niCARdipine at doses up to 8 times the maximum recommended human dose (Prod Info nicardipine HCl intravenous injection solution, 2012).

a) RATS: There was no impairment of fertility in male or female Wistar rats exposed to oral nimodipine at doses up to 30 mg/kg/day (about 4 times the recommended clinical dose in humans) when administered daily for more than 10 weeks in males and 3 weeks in females prior to mating and continued until day 7 of pregnancy (Prod Info nimodipine oral capsules, 2012).

a) RATS: No evidence of fertility impairment in male and female rats receiving doses up to 30 mg/kg/day (approximately 5 times the recommended human dose on a mg/m(2) basis) (Prod Info SULAR(R) extended release oral tablets, 2010).

a) Monitor cardiovascular status to include blood pressure, ECG, and urinary output.
b) Monitor respiratory function with blood gasses, pH, rate; pulmonary edema may occur.
c) Monitor mental status; CNS depression due to direct drug effects, cardiovascular disruptions, and coingestion of CNS depressants is common. Seizures are rare but may occur.
d) 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).

1) CARDIOVASCULAR: Hypotension or bradycardia (or tachycardia with nifedipine); heart block; A-V dissociation; asystole; congestive heart failure
2) RESPIRATORY: Pulmonary edema
3) GASTROINTESTINAL: Nausea or vomiting
4) NEUROLOGICAL: Seizures; altered mental status

1) BEPRIDIL: ADULT: 300 mg or less; CHILD: no safe dose
2) ISRADIPINE: ADULT: 20 mg or less; CHILD: 0.1 mg/kg or less
3) NICARDIPINE: ADULT: 40 mg or less IR or chewed SR, or 60 mg or less SR; CHILD: less than 1.25 mg/kg
4) NIMODIPINE: ADULT: 60 mg or less; CHILD: no safe dose
5) NISOLDIPINE: ADULT: 30 mg or less; CHILD: no safe dose

1) BEPRIDIL: ADULT: greater than 300 mg; CHILD: any amount
2) ISRADIPINE: ADULT: greater than 20 mg; CHILD: greater than 0.1 mg/kg
3) NICARDIPINE: ADULT: greater than 40 mg IR or chewed SR, or greater than 60 mg SR; CHILD: 1.25 mg/kg or more
4) NIMODIPINE: ADULT: greater than 60 mg; CHILD: any amount
5) NISOLDIPINE: ADULT: greater than 30 mg; CHILD: any amount

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

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.

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.

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).

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.

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.
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.

a) The first patient, 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.
b) The second patient, a 40-year-old man, received activated charcoal and WBI after ingesting 90 tablets of verapamil 240 mg sustained release (21.6 g). Prior to WBI, the patient was tachycardic (111 bpm), but otherwise asymptomatic. The patient began vomiting 3.5 hours post-ingestion, and developed hypotension (80/43 mmHg) and a decrease in heart rate (73 bpm) at 4 hours post-ingestion. WBI was eventually stopped at 6 hours post-ingestion, due to persistent vomiting and hypotension and the development of pulmonary edema. The patient developed aspiration pneumonia believed to be due to aspiration of activated charcoal, polyethylene glycol electrolyte lavage solution, and gastric secretions. With supportive treatment of his pneumonia and severe hypotension, the patient gradually recovered and was discharged.

a) Patients who have asymptomatic bradycardia can be admitted and observed with telemetry. Obtain peripheral intravenous access and monitor ECG. Mild hypotension may only require treatment with intravenous fluid administration.

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 (calcium chloride is preferred) 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 several 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.

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 IV 0.9% NaCl at 10 to 20 mL/kg and place the patient in supine position. Consider central venous pressure monitoring to guide further fluid therapy.
b) CAUTIONS: Monitor for signs of pulmonary edema (Pearigen & Benowitz, 1991).

a) INDICATIONS: Calcium is used 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 (DeRoos, 2011; 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.
d) 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).
e) 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).
f) Calcium therapy should be tailored to the individual patient. In one case report, a woman with a massive overdose of sustained-release nifedipine and severe hypotension was successfully treated with continuous IV calcium gluconate infusion, using an individually tailored protocol for dose titration of IV calcium infusion. In this protocol, the optimal calcium infusion rate was determined by achieving the lowest possible serum calcium concentration associated with a maximal contractility (ie, cardiac power index [CPI] = CI x MAP x 0.0022) rather than maintaining a predefined serum calcium concentration or using cardiac output (CO) or stroke volume (SV), as an indicator of cardiac function (ie, cardiac work). This allowed for a lower total dose of calcium used and a lower peak serum calcium concentration (Zhou et al, 2013).
g) CASE REPORT: A 37-year-old woman presented with hypotension (BP 80/45 mm Hg) and sinus tachycardia (115 beats/min) after ingesting 210 nifedipine 20 mg tablets (total dose: 4200 mg). Despite supportive therapy, including 2 doses of IV bolus injection of calcium gluconate (10 mL of 10% solution), her condition did not improve and she developed shortness of breath and circulatory shock (BP, 70/30 mm Hg). A chest radiograph revealed acute pulmonary edema. Serum glucose and ionized calcium concentration were 7.8 mmol/L and 1.14 mmol/L (normal range, 1.12 to 1.23 mmol/L), respectively. An echocardiography revealed normal left ventricular systolic function with ejection fraction of 62%. Despite treatment with multiple doses of calcium gluconate injections (10 mL of 10% solution; 0.3 mg/hr was the average dose within 24 hours; serum ionized calcium concentration was 1.27 mmol/L), her condition did not improve. At this time, she received continuous IV infusion of calcium chloride (rate: 20 mcg/min) started 25 hours after overdose, and titrated to maintain the serum ionized calcium concentration around 2 mmol/L. Her blood pressure improved soon after the calcium chloride solution was administered. Her pulmonary edema also improved following continuous calcium chloride infusion and diuretic therapy. Approximately 60 hours after presentation, her calcium chloride infusion was discontinued. Prior to discharge, debridement and skin grafting were required because of calcium chloride extravasation and skin necrosis over the peripheral drip site (Lam et al, 2001).
h) CASE REPORT: A 25-year-old woman intentionally ingested 3.6 grams of sustained-release nifedipine and, 3 hours later, presented to the emergency department comatose with agonal respirations, no carotid pulse, and no recordable blood pressure. Following administration of 1 g calcium chloride given intravenous push, the patient began to spontaneously breathe with the development of a carotid pulse and a BP of 82/40 mmHg. The patient's blood pressure continued to increase following further intravenous administration of calcium chloride over the next hour (Haddad, 1996).
i) 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).
j) 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).

a) DOSE
b) CASE REPORTS
c) ANIMAL DATA

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) RETROSPECTIVE STUDY: A retrospective chart review of patients admitted to a single tertiary care center for the treatment of verapamil or diltiazem overdose, confirmed by drug or urine drug screening, from 1987 through 2012 was conducted to evaluate the role of vasopressor therapy in the management and outcome of nondihydropyridine calcium-channel blocker overdoses. A total of 48 patients (median age 45 years, range 15 to 76 years) were included and 24 (50%) were verapamil ingestions; coingestions were also likely to occur (n=38 (79%)). A second group consisted of 12 patients that met inclusion criteria except for the absence of drug or urine testing. Vasopressors were given to 33 of 48 (69%) patients and most patients received multiple vasopressors (eg, epinephrine, dopamine, dobutamine, isoproterenol, phenylephrine or norepinephrine). Of these patients, the median number of vasopressors needed to treat hypotension was 2 (range, 1 to 5); norepinephrine (n=25 (52%) and dopamine (n=19 (40%)) were the 2 most common vasopressors used. High doses of vasopressors were needed in many patients:
c) 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).

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).

a) NOREPINEPHRINE

a) EPINEPHRINE
b) Epinephrine has been found to be useful in other cases of calcium channel blocker (ie, diltiazem, verapamil) overdose. However, multiple vasopressors are likely to be needed to maintain clinical improvement following a significant overdose (Levine et al, 2013).
c) Large doses may be required (Levine et al, 2013).
d) 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).
e) 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).

a) ISOPROTERENOL INDICATIONS

a) PHENYLEPHRINE

a) DOBUTAMINE

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).
d) In a canine model of severe verapamil overdose glucagon (2.5 mg bolus followed by an infusion of 2.5 mg over 1 hour) increased cardiac output and heart rate and restored sinus rhythm without affecting mean arterial pressure or total peripheral resistance (Stone et al, 1995).
e) CASE REPORT (CHILD): A 13-year-old girl intentionally ingested an unknown amount of 30 mg nifedipine and 0.1 mg clonidine and subsequently developed severe hypotension unresponsive to treatment with fluids, calcium chloride, and dopamine. Glucagon was then intravenously administered (a single dose of 5 mg followed by a continuous infusion of 3 mg/hr) with successful normalization of her blood pressure (Fant et al, 1997).

a) INAMRINONE
b) ENOXIMONE

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).

a) VERAPAMIL/LACK OF IMPROVEMENT: A 41-year-old woman intentionally ingested 80 tablets of sustained release verapamil (total dose 19.2 g) and developed severe toxicity about 14 hours after exposure. She became hypotensive and bradycardic with a third degree AV. Initial treatment included calcium, fluids, dopamine and isoproterenol; norepinephrine, epinephrine and vasopressin were added with only temporary clinical improvement in hypotension. Other treatments included intubation and transvenous pacing and hyperglycemia-euglycemia insulin therapy and glucagon. Acute renal failure developed and CVVH was started. On hospital day 4, lipid therapy was begun. Within 3 hours the norepinephrine dose was reduced and within 48 hours vasopressin was stopped. By day 6, transvenous pacing was no longer needed. Despite cardiac improvement, she developed further complications necessitating an urgent colectomy (Liang et al, 2011).
b) AMLODIPINE AND DILTIAZEM: Two patients were given vasopressin infusions for the 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).
c) 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)

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).

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).

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).

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.

a) VERAPAMIL: A 41-year-old woman intentionally ingested 80 tablets of sustained release verapamil (total dose 19.2 g). She was decontaminated with multiple doses of activated charcoal. Fourteen hours after exposure, the patient suddenly became lethargic with a decrease in oxygen saturation requiring a 100% non-rebreather. She became hypotensive and bradycardic; a third degree AV block was noted on ECG. Initial treatment included calcium, fluids, dopamine and isoproterenol; norepinephrine, epinephrine and vasopressin were added with only temporary clinical improvement in hypotension. Other treatments included intubation and transvenous pacing and hyperglycemia-euglycemia insulin therapy and glucagon. Acute renal failure developed and CVVH was started. On hospital day 4, lipid therapy (100 mL bolus of 20% intralipid followed by 0.5 mL/kg/h; total dose: 4200 mL over 7 days) was begun. Within 3 hours the norepinephrine dose was reduced and within 48 hours vasopressin was stopped. By day 6, transvenous pacing was no longer needed. Despite cardiac improvement, her clinical course was further complicated by the development of a pneumatosis intestinalis necessitating an urgent colectomy. On day 55, the patient was discharged to a skilled nursing facility (Liang et al, 2011).
b) AMLODIPINE: A 71-year-old woman with a medical history of hypertension, emphysema, and depression presented 1.5 hours after ingesting 27 tablets of amlodipine 5 mg. She was alert, oriented, and in no distress, and her vital signs were: temperature 36.6 degrees C, blood pressure (BP 85/44 mm Hg), pulse (heart rate, 79 beats/min), respiratory rate (20/min). An initial laboratory result revealed hyponatremia and anemia; all other laboratory results were normal. She developed hypotension (systolic BP, 79 mmHg) 2 hours later. Despite symptomatic therapy, she remained hypotensive in the ICU, and her urine output decreased to 10 mL/hr. Her condition deteriorated and pulmonary edema was noted clinically and on chest x-ray. She was intubated and her peri-intubation arterial blood gas (ABG) revealed pH=7.17, pCO2=31, and pO2=80. Based on a written lipid emulsion therapy protocol (written protocol: Intralipid 20%: 1.5 mL/kg over 1 min; then an infusion of 0.25 mL/kg/min; max total dose, 8 mL/kg. In practice, for an adult weighing 70 kg: take a 500 mL bag of Intralipid 20% and a 50 mL syringe; draw up 50 mL and give stat IV, x 2; then attach the bag to an IV administration set (macrodrip) and run it IV over the next 25 minutes), a maximum of 387.5 mL of intralipid for a 50 kg patient was ordered and treatment was started 12.5 hours after presentation. However, she inadvertently received a total of 2000 mL of 20% intralipid which ran for 4.5 hours (greater than 5 times the maximum suggested dose). Because of severe lipemia, no metabolic panel and CBC analysis could be obtained. There were no other obvious clinical affects from the intravenous lipid overdose On hospital day 2, the treatment team felt that recovery from the amlodipine overdose was unlikely. After her family decided to withdraw care, she died within the next 24 hours (West et al, 2010).
c) VERAPAMIL: A 32-year-old man intentionally ingested large quantities of multiple medications, one of which was 13.44 grams of verapamil. He was found 12 hours later to be poorly responsive with incoherent speech and hypotensive (69/26 mmHg) with a pulse of 55 beats/min. Fluids, pressors, calcium and glucagon were all administered, but he remained hypotensive with junctional bradycardia, metabolic acidosis and renal insufficiency. Then, upon transfer, 100 mL of 20% lipids was infused followed by a 0.5 mL/kg/hr infusion for 24 hours. Blood pressure improved within an hour of initiation of intravenous lipid emulsion, and he made a full recovery (Young et al, 2009).
d) VERAPAMIL: A 39-year-old woman presented to the emergency department with dyspnea, chest tightness, lethargy, diaphoresis, and hypotension (76/41 mmHg) after intentionally ingesting 17 240-mg tablets of extended release verapamil (total dose ingested 4.08 g). Despite treatment with IV fluids and norepinephrine therapy, the patient's hypotension persisted. Approximately 17 hours post-presentation, the patient was switched to dopamine, without effect, and, approximately 15 hours later, the patient was given 100 mL of 20% lipids, administered intravenously over 20 minutes, followed by a continuous infusion of 0.5 mL/kg/hour for the next 8 hours. During this time period, the patient's blood pressure improved and dopamine therapy was gradually discontinued (Franxman et al, 2011).

a) 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).
b) 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).

a) INDICATIONS: Calcium is used 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 (DeRoos, 2011; 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.
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).
e) 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).

a) INDICATION: Bradydysrhythmia contributing to hypotension. May be more effective after calcium administration (Howarth et al, 1994).
b) ATROPINE/DOSE
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.

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).

a) INDICATION: Predominant beta-1 effects stimulate discharge rate at SA node, increase heart rate, and improve contractility (Krenzelok, 1991).
b) ISOPROTERENOL INDICATIONS

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).

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).

a) CASE REPORT: Cardiopulmonary bypass was used in a 25-month-old child after verapamil overdose. Serum verapamil concentrations 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).
c) CASE REPORT: A 47-year-old man died after ingesting 10.8 grams of diltiazem despite aggressive treatment with calcium, glucagon, epinephrine, pressors and cardiopulmonary bypass (Martin et al, 1994a).

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).

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 .

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).

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).

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).

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):

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)

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).

a) CASE REPORT: A 61-year-old woman developed a bezoar after intentionally ingesting 167 60-mg extended-release nifedipine tablets (total dose of approximately 10 grams). Despite removal of the bezoar via an esophagogastroduodenoscopy, the patient died from multisystem failure 3 days post-operatively (Wells et al, 2006).

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).

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).
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).

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).

a) IMMEDIATE-RELEASE CAPSULES: Initially, 20 mg orally three times daily, titrated up to a maximum dose of 40 mg orally three times daily (Prod Info nicardipine HCl oral capsules, 2013).
b) SUSTAINED-RELEASE CAPSULES: Initially, 30 mg orally twice daily; titrated up to a maximum of 60 mg twice daily (Prod Info CARDENE(R) SR oral sustained release capsules, 2010).
c) INJECTION: For patients not receiving oral niCARdipine, initially 50 mL/hour (5 mg/hour) via slow continuous IV infusion; may be increased by 25 mL/hour (2.5 mg/hour) every 5 to 15 minutes up to a maximum of 150 mL/hour (15 mg/hour) (Prod Info nicardipine HCl intravenous injection solution, 2012)

a) CAPSULES: The recommended dose is 60 mg orally every 4 hours for 21 consecutive days. Administer at least one hour before or 2 hours following a meal (Prod Info nimodipine oral capsules, 2012)
b) ORAL SOLUTION: The recommended dose is 20 mL (60 mg) orally every 4 hours for 21 consecutive days. Administer one hour before or 2 hours following a meal (Prod Info NYMALIZE(TM) oral solution, 2013).

a) Safety and effectiveness have not been established in pediatric patients (Prod Info Cleviprex(R) intravenous injection, 2011).

a) Rapid acting and useful for acute hypertension. Suspension may be compounded for infants and young children. Standard-release dosage form has shorter duration (6 to 8 hours) of effect in pediatric patients, requiring multiple daily dosing(Flynn & Pasko, 2000).
b) Suggested initial dose in children is 0.05 to 0.15 mg/kg every 6 to 8 hours; maximum dose is 0.8 mg/kg/day up to 20 mg/day (Flynn & Pasko, 2000).

a) HYPERTENSION, SEVERE ACUTE

a) ORAL SOLUTION: Safety and effectiveness have not been established in pediatric patients(Prod Info NYMALIZE(TM) oral solution, 2013).
b) TABLETS: Safety and effectiveness have not been established in pediatric patients (Prod Info nimodipine oral capsules, 2012).

a) Safety and efficacy in pediatric patients have not been established (Prod Info SULAR(R) extended release oral tablets, 2010).

1) The manufacturer reported lethargy and sinus tachycardia following overdose ingestions of 20 to 100 mg, and transient hypotension with the 100 mg dose. Reversible effects of flushing, tachycardia with ST depression, and hypotension were also reported following an overdose ingestion of 200 mg isradipine, with concomitant ethanol ingestion (Prod Info isradipine oral capsules, 2011).

1) A 2-year-old boy survived a single 2.5 mg dose, although blood pressure dropped to 68/40 mmHg. Therapy included lavage and charcoal, with fluids to maintain blood pressure. No conduction defects were observed, and recovery was complete within 24 hours (Spiller & Ramoska, 1992).

1) Two separate adult ingestions of 600 mg immediate-release niCARdipine and 2160 mg of sustained-release niCARdipine resulted in symptoms of hypotension, bradycardia, palpitations, flushing, drowsiness, confusion, and slurred speech. Both patients recovered without sequelae (Prod Info nicardipine HCl oral capsules, 2013; Prod Info CARDENE(R) SR oral sustained release capsules, 2010).
2) Headache, flushing, and sinus tachycardia were reported in a 39-year-old woman who was 36 weeks pregnant and inadvertently received an overdose infusion of niCARdipine at 20 to 25 mg/hour over a 10-hour period, instead of the prescribed 2 mg/hour, to treat severe hypertension (Aya et al, 1996).

1) A child who ingested half the contents of a 30 mg immediate-release capsule remained asymptomatic (Prod Info CARDENE(R) SR oral sustained release capsules, 2010).

a) BEPRIDIL
b) NICARDIPINE

a) ISRADIPINE

a) 216 mg/kg (RTECS , 2000)

a) >3 g/kg (RTECS , 2000)

a) 305 mg/kg (RTECS , 2000)

a) 320 mg/kg (RTECS , 2000)

a) 940 mg/kg (RTECS , 2000)

a) 2738 mg/kg (RTECS , 2000)

a) 411 mg/kg (RTECS , 2000)

a) 1257 mg/kg (RTECS , 2000)