Calcium Channel Antagonists in Children
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Transcript of Calcium Channel Antagonists in Children
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Calcium Channel Antagonists in Children
Rama B. Rao, MDNYU/Bellevue Hospital Center
2007
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Physiology of Children
• GI– Lower hepatic glycogen reserves– Limited enzymatic capacity– pH and motility– Chew or bite tablets altering absorption
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Physiology of Children
• Respiratory– Diminished reserves
• Metabolic– Increased requirements
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Management Limitations
• No confirmatory assay– Qualitative– Quantitative
• Delayed onset toxicity
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Limitations
• Therapeutic interventions
– No antidote
– Variable outcomes
– Limited data in children
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Pharmacology of CCA
• Most tablets exclusively dosed for adults
• Often slow release
• Hepatically metabolized
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Calcium Channels
• L type: Myocardium, sm mm, ß Islet pancreas
• T• N• P Neuronal, SR, other• Q• R
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ß1
Gs
AC
ATP cAMP
PKA
Ca2+
SR
Ca2+
1
2
3
4
5
NORMAL MYOCARDIAL CELL
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ß1
Gs
AC
ATP cAMP
PKA
Ca2+
SR
Ca2+
1
2
3
4
5
CCA
Result: Negative inotropy
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0
12
34 4
Phase 2 Myocardial CellCa2+ inward (with K+ outward)
Result CCA: Diminished contractility
Contractile Cells
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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
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Ca2+
Ca2+
Vascular Smooth Muscle
1Receptor operated
Voltage sensitive
Calmodulin
Ca2+Contraction of sm mm
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Ca2+
Ca2+
CCA and Vascular Smooth MM
1Receptor operated
Voltage sensitive
Calmodulin
Ca2+Result : reduced vasoconstriction
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CCA: Dihyrdopyridines
Smooth mm: peripheral vasodilation– In mild overdose:
• Hypotension• Tachycardia
– In children and severe OD• Hypotension • Bradycardia
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CCA: Verapamil, CardizemPhenylalkylamines
• Greater binding at myocardial cells– Negative inotrope– Negative chronotrope
• Inhibit release of insulin in overdose
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CCA: Management
• Assume ingestion
• Assess early/late or imminent*
• IV, ECG, monitoring
*Fingerstick blood glucose?
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Decontamination
• Activated charcoal: 1 gm/kg
• MDAC: 0.5 gm/kg q4
• Whole bowel irrigation?
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Fellowship Case
• 30 month old male is found with an open bottle of verapamil SR 240mg tabs.
• New Rx : 100 tabs
• 94 tabs found
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Verapamil
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Case continued
• Toddler has normal vital signs
• Playful
• Running around the ED
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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
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Management Conundrums
Hypotension: What can we try?
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Ca2+
Ca2+
CCA and Vascular Smooth MM
1Receptor operated
Voltage sensitive
Calmodulin
Ca2+
Ca2+
Ca2+
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Ca2+
Ca2+
CCA and Vascular Smooth MM
1Receptor operated
Voltage sensitive
Calmodulin
Ca2+
Ca2+
NE, Phenylephrine Ca2+
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How does this affect cardiac output?
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Rx: Vasodilation
Agent Vasoconstriction HR CONE ++++ ↓↓↓
PE ++++ ↓↓↓
HR = Heart rate; CO=Cardiac OutputNE= Norepinephrine PE= Phenylephrine
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Clinical Evaluation
• Mental status• Peripheral circulation• Urine output• Lactate production• Acid/base status
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Vasodilation
• Crystalloid• Calcium: variable efficacy• Direct acting α1 agonists
– Norepinephrine– Phenylephrine
• Caveat need to combine with inotropes
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Bradycardia
What can we try?
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Bradycardia• Atropine and calcium
– Variable efficacy
• ß1 agonists*– Direct: Epinephrine, Isoproterenol– Indirect: Glucagon
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What do these do to blood pressure?
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Bradycardia
Agent Vasoconstriction HR CO
Calcium ± ± ↑↑Atropine ↑±Isoproterenol ↓ ↑± ↑±Glucagon ↑± ↑±Epi ± ↑± ↑±
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Inotropes
• Critical to cardiac output
• Allow titration of pressors
• Also have caveats
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What kind of inotropes can we try?
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ß1
Gs
AC
ATP cAMP
PKA
Ca2+
SR
Ca2+
1
2
3
4
5
NORMAL MYOCARDIAL CELL
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ß1
Gs
AC
ATP cAMP
PKA
Ca2+
SR
Ca2+
1
3
4
CCACa2+
Epi, Dobutamine
Amrinone5’MP
Glucagon2
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Inotropes
• ß1 agonists– Direct– Indirect
• Phosphodiesterase inhibitors
• Calcium
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Calcium 10% = 100 mg/mL
• Calcium chloride– 1.36 mEq/mL– Central line important
• Calcium gluconate– 0.43 mEq/mL
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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
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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
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Inotropes
• ß1 agonists– Direct– Indirect
• Phosphodiesterase inhibitors
• Calcium
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What do these inotropes do to blood pressure?
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InotropesAgent Vasoconstriction HR CO
Dobutamine* ↓ ↑± ↑Epi ± ↑↑± ↑±
Glucagon ↑± ↑±
Amrinone* ↓ ↑ ↑
Calcium ± ± ↑* Needs pressor
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Agent Vasoconstriction HR CONE ++++ ↓↓↓PE ++++ ↓↓↓
Calcium ± ± ↑↑Atropine ↑±Isoproterenol ↓ ↑± ↑±
Dobutamine ↓ ↑± ↑Epi ± ↑↑± ↑±Glucagon ↑± ↑±Amrinone ↓ ↑ ↑
HR = Heart rate; CO=Cardiac Output
In CCA Toxicity
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Insulin and Dextrose
• Increase energy efficiency
• Prolongs opening of Ca2+ channels
• Potential anti-inflammatory effects
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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
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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
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ß1
Gs
AC
ATP cAMP
PKA
Ca2+
SR
Ca2+
Myocardium under duress
FFA metabolism
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ß1
Gs
AC
ATP cAMP
PKA
Ca2+
SR
Ca2+
Dextrose and Insulin
I
K+ Insulin/Glucose
GlucoseAerobic metabolism
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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
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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
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Invasive Therapies
• ECMO/VAD
• Exchange transfusion?
• Balloon pump
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Intralipids: The Future?
• Used in local anesthetic toxicity
• Mechanism uncertain
• Rat and canine models are promising
• With lipid soluble toxin
Lipidrescue.org
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Intralipid?
• 20% solution
• 1-2 mL/kg bolus
• 0.25 mL/kg/hr
• Call PCCLipidrescue.org
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Case
• Toddler with 6 missing tablets
• Discussed aggressive therapy with family, PCC faculty, PICU faculty
• WBI started
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Outcome
• All six tablets found in diapers within 7 hours of starting the WBI
• Baby discharged after 24 hours observation
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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
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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
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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