Calcium Channel Antagonists in Children Rama B. Rao, MD NYU/Bellevue Hospital Center 2007

Physiology of Children GI –Lower hepatic glycogen reserves –Limited enzymatic capacity –pH and motility –Chew or bite tablets altering absorption

Physiology of Children Respiratory –Diminished reserves Metabolic –Increased requirements

Management Limitations No confirmatory assay –Qualitative –Quantitative Delayed onset toxicity

Limitations Therapeutic interventions –No antidote –Variable outcomes –Limited data in children

Pharmacology of CCA Most tablets exclusively dosed for adults Often slow release Hepatically metabolized

Calcium Channels L type:Myocardium, sm mm, ß Islet pancreas T N PNeuronal, SR, other Q R

ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca NORMAL MYOCARDIAL CELL

ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca CCA Result: Negative inotropy

Phase 2 Myocardial Cell Ca 2+ inward (with K + outward) Result CCA: Diminished contractility Contractile Cells

Phase 2 Myocardial Cell Phase 4 Purkinje Fiber SA Node Result CCA: Altered conduction Delayed initiation Depressed movement thru Purkinje fiber Pacemaker Cells

Ca 2+ Vascular Smooth Muscle 11 Receptor operated Voltage sensitive Calmodulin Ca 2+ Contraction of sm mm

Ca 2+ CCA and Vascular Smooth MM 11 Receptor operated Voltage sensitive Calmodulin Ca 2+ Result : reduced vasoconstriction

CCA: Dihyrdopyridines Smooth mm: peripheral vasodilation –In mild overdose: Hypotension Tachycardia –In children and severe OD Hypotension Bradycardia

CCA: Verapamil, Cardizem Phenylalkylamines Greater binding at myocardial cells –Negative inotrope –Negative chronotrope Inhibit release of insulin in overdose

CCA: Management Assume ingestion Assess early/late or imminent* IV, ECG, monitoring *Fingerstick blood glucose?

Decontamination Activated charcoal: 1 gm/kg MDAC:0.5 gm/kg q4  Whole bowel irrigation?

Fellowship Case 30 month old male is found with an open bottle of verapamil SR 240mg tabs. New Rx : 100 tabs 94 tabs found

Verapamil

Case continued Toddler has normal vital signs Playful Running around the ED

Whole Bowel Irrigation PEG balanced salt solution Assess for bowel sounds NGT placement with confirmation –First AC –Follow with PEG 500* ml/hr (start at 100 ml/hr and rapidly titrate) –Q4  AC Continue until clear rectal effluent *Can give higher dose of up to 2L/hour as tolerated

Management Conundrums Hypotension: What can we try?

Ca 2+ CCA and Vascular Smooth MM 11 Receptor operated Voltage sensitive Calmodulin Ca 2+

CCA and Vascular Smooth MM 11 Receptor operated Voltage sensitive Calmodulin Ca 2+ NE, Phenylephrine Ca 2+

How does this affect cardiac output?

Rx: Vasodilation Agent Vasoconstriction HRCO NE++++↓↓↓ PE++++↓↓↓ HR = Heart rate; CO=Cardiac Output NE= Norepinephrine PE= Phenylephrine

Clinical Evaluation Mental status Peripheral circulation Urine output Lactate production Acid/base status

Vasodilation Crystalloid Calcium: variable efficacy Direct acting α 1 agonists –Norepinephrine –Phenylephrine Caveat need to combine with inotropes

Bradycardia What can we try?

Bradycardia Atropine and calcium –Variable efficacy ß 1 agonists* –Direct: Epinephrine, Isoproterenol –Indirect: Glucagon

What do these do to blood pressure?

Bradycardia Agent Vasoconstriction HRCO Calcium ±± ↑ ↑ Atropine ↑± Isoproterenol ↓↑±↑± Glucagon ↑±↑± Epi ±↑±↑±

Inotropes Critical to cardiac output Allow titration of pressors Also have caveats

What kind of inotropes can we try?

ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca NORMAL MYOCARDIAL CELL

ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca CCA Ca 2+ Epi, Dobutamine Amrinone 5’MP Glucagon 2

Inotropes ß 1 agonists –Direct –Indirect Phosphodiesterase inhibitors Calcium

Calcium 10% = 100 mg/mL Calcium chloride –1.36 mEq/mL –Central line important Calcium gluconate –0.43 mEq/mL

CaCl 2 10% (100 mg/mL) 20 mg/kg bolus over 3-5 minutes Repeat in 10 minutes Dilute concentration to 20 mg/mL mg/kg/hr infusion

Calcium Gluconate 10% (100 mg/mL) mg/kg bolus over 3 minutes (remember this has less mEq Ca 2+ ) May repeat in 10 minutes Dilute to 50 mg/mL Infusion mg/kg/hr

Inotropes ß 1 agonists –Direct –Indirect Phosphodiesterase inhibitors Calcium

What do these inotropes do to blood pressure?

Inotropes Agent VasoconstrictionHRCO Dobutamine* ↓↑±↑ Epi ±↑↑±↑± Glucagon ↑±↑± Amrinone* ↓↑↑ Calcium ± ± ↑ * Needs pressor

Agent Vasoconstriction HRCO NE++++↓↓↓ PE++++↓↓↓ Calcium ±± ↑ ↑ Atropine↑± Isoproterenol ↓↑±↑± Dobutamine ↓↑±↑ Epi ± ↑↑±↑± Glucagon ↑±↑± Amrinone ↓↑↑ HR = Heart rate; CO=Cardiac Output In CCA Toxicity

Insulin and Dextrose Increase energy efficiency Prolongs opening of Ca 2+ channels Potential anti-inflammatory effects

Insulin and Dextrose Canine models –Increase lethal dose verapamil –Delayed time to death –Not necessarily change in heart rate or MAP –Compared to saline, epi, glucagon groups

Insulin and Dextrose Human cases –No comparative trials –Often rescue medication –None as first line therapy –?Reporting bias of success –At least a dozen survivors –Bolus vs infusion

ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ Myocardium under duress FFA metabolism

ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ Dextrose and Insulin I K+K+ Insulin/Glucose Glucose Aerobic metabolism

Insulin and Dextrose First fluid, calcium, other interventions Insulin 1 U/kg bolus –0.5-1 u/kg/hour infusion (some even higher) Dextrose 0.25 g/kg of D 25 for glucose <200 mg/dL Potassium supplementation < 2.5 Eq/mL

Insulin and Dextrose Check blood glucose and K + q 20 min x 3 Then every hour Clinical response may be within 20 – 60 minutes Call PCC: when to start, stop, outcomes

Invasive Therapies ECMO/VAD Exchange transfusion? Balloon pump

Intralipids: The Future? Used in local anesthetic toxicity Mechanism uncertain Rat and canine models are promising With lipid soluble toxin Lipidrescue.org

Intralipid? 20% solution 1-2 mL/kg bolus 0.25 mL/kg/hr Call PCC Lipidrescue.org

Case Toddler with 6 missing tablets Discussed aggressive therapy with family, PCC faculty, PICU faculty WBI started

Outcome All six tablets found in diapers within 7 hours of starting the WBI Baby discharged after 24 hours observation

Dosing (please recheck) Atropine –0.02 mg/kg q 3 minutes up to 3 mg Isoproterenol –0.05 – 2 mcg/kg/min Potassium –0.5 mEq/kg/hour prn

Dosing: Infusions Epinephrine – mcg/kg/minute Norepinephrine –0.05 – 0.1 mcg/kg/min Phenylephrine –0.1 – 0.5 mcg/kg/min

Dosing Infusions Glucagon –50 mcg/kg and titrate to effective dose as bolus –If response then continue at that dose per hour as infusion Amrinone/Inamrinone –0.75 mcg/kg bolus over 3 minutes –5-10 mcg/kg/minute infusion –Should use with a vasoconstrictor