Calcium Channel Antagonists in Children

Rama B. Rao, MDNYU/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• P Neuronal, SR, other• Q• R

ß1

Gs

AC

ATP cAMP

PKA

Ca2+

SR

Ca2+

1

2

3

4

5

NORMAL MYOCARDIAL CELL

ß1

Gs

AC

ATP cAMP

PKA

Ca2+

SR

Ca2+

1

2

3

4

5

CCA

Result: Negative inotropy

0

12

34 4

Phase 2 Myocardial CellCa2+ inward (with K+ outward)

Result CCA: Diminished contractility

Contractile Cells

0

12

34 4

Phase 2 Myocardial Cell

Phase 4 Purkinje Fiber SA Node

Result CCA: Altered conduction Delayed initiation Depressed movement thru Purkinje fiber

Pacemaker Cells

Ca2+

Ca2+

Vascular Smooth Muscle

1Receptor operated

Voltage sensitive

Calmodulin

Ca2+Contraction of sm mm

Ca2+

Ca2+

CCA and Vascular Smooth MM

1Receptor operated

Voltage sensitive

Calmodulin

Ca2+Result : reduced vasoconstriction

CCA: Dihyrdopyridines

Smooth mm: peripheral vasodilation– In mild overdose:

• Hypotension• Tachycardia

– In children and severe OD• Hypotension • Bradycardia

CCA: Verapamil, CardizemPhenylalkylamines

• 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?

Ca2+

Ca2+

CCA and Vascular Smooth MM

1Receptor operated

Voltage sensitive

Calmodulin

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

CCA and Vascular Smooth MM

1Receptor operated

Voltage sensitive

Calmodulin

Ca2+

Ca2+

NE, Phenylephrine Ca2+

How does this affect cardiac output?

Rx: Vasodilation

Agent Vasoconstriction HR CONE ++++ ↓↓↓

PE ++++ ↓↓↓

HR = Heart rate; CO=Cardiac OutputNE= Norepinephrine PE= Phenylephrine

Clinical Evaluation

• Mental status• Peripheral circulation• Urine output• Lactate production• Acid/base status

Vasodilation

• Crystalloid• Calcium: variable efficacy• Direct acting α1 agonists

– Norepinephrine– Phenylephrine

• Caveat need to combine with inotropes

Bradycardia

What can we try?

Bradycardia• Atropine and calcium

– Variable efficacy

• ß1 agonists*– Direct: Epinephrine, Isoproterenol– Indirect: Glucagon

What do these do to blood pressure?

Bradycardia

Agent Vasoconstriction HR CO

Calcium ± ± ↑↑Atropine ↑±Isoproterenol ↓ ↑± ↑±Glucagon ↑± ↑±Epi ± ↑± ↑±

Inotropes

• Critical to cardiac output

• Allow titration of pressors

• Also have caveats

What kind of inotropes can we try?

ß1

Gs

AC

ATP cAMP

PKA

Ca2+

SR

Ca2+

1

2

3

4

5

NORMAL MYOCARDIAL CELL

ß1

Gs

AC

ATP cAMP

PKA

Ca2+

SR

Ca2+

1

3

4

CCACa2+

Epi, Dobutamine

Amrinone5’MP

Glucagon2

Inotropes

• ß1 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

CaCl2 10% (100 mg/mL)

• 20 mg/kg bolus over 3-5 minutes• Repeat in 10 minutes

• Dilute concentration to 20 mg/mL• 20-50 mg/kg/hr infusion

Calcium Gluconate 10% (100 mg/mL)

• 60-100 mg/kg bolus over 3 minutes• (remember this has less mEq Ca2+)• May repeat in 10 minutes

• Dilute to 50 mg/mL• Infusion 120-240 mg/kg/hr

Inotropes

• ß1 agonists– Direct– Indirect

• Phosphodiesterase inhibitors

• Calcium

What do these inotropes do to blood pressure?

InotropesAgent Vasoconstriction HR CO

Dobutamine* ↓ ↑± ↑Epi ± ↑↑± ↑±

Glucagon ↑± ↑±

Amrinone* ↓ ↑ ↑

Calcium ± ± ↑* Needs pressor

Agent Vasoconstriction HR CONE ++++ ↓↓↓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 Ca2+ 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

ß1

Gs

AC

ATP cAMP

PKA

Ca2+

SR

Ca2+

Myocardium under duress

FFA metabolism

ß1

Gs

AC

ATP cAMP

PKA

Ca2+

SR

Ca2+

Dextrose and Insulin

I

K+ Insulin/Glucose

GlucoseAerobic 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 D25 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 PCCLipidrescue.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– 0.1- 1 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