Title: Calcium Channel Antagonists in Children
1Calcium Channel Antagonists in Children
- Rama B. Rao, MD
- NYU/Bellevue Hospital Center
- 2007
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4Physiology of Children
- GI
- Lower hepatic glycogen reserves
- Limited enzymatic capacity
- pH and motility
- Chew or bite tablets altering absorption
5Physiology of Children
- Respiratory
- Diminished reserves
- Metabolic
- Increased requirements
6Management Limitations
- No confirmatory assay
- Qualitative
- Quantitative
- Delayed onset toxicity
7Limitations
- Therapeutic interventions
- No antidote
- Variable outcomes
- Limited data in children
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9Pharmacology of CCA
- Most tablets exclusively dosed for adults
- Often slow release
- Hepatically metabolized
10Calcium Channels
- L type Myocardium, sm mm, ß Islet pancreas
- T
- N
- P Neuronal, SR, other
- Q
- R
11NORMAL MYOCARDIAL CELL
Ca2
3
SR
4
PKA
Ca2
5
ATP cAMP
2
AC
Gs
ß1
1
12CCA
Ca2
3
SR
4
PKA
Ca2
5
ATP cAMP
2
AC
Gs
ß1
Result Negative inotropy
1
13Contractile Cells
1
Phase 2 Myocardial Cell Ca2 inward (with K
outward)
2
0
3
4 4
Result CCA Diminished contractility
14Pacemaker Cells
1
Phase 2 Myocardial Cell
2
Phase 4 Purkinje Fiber SA Node
0
3
4 4
Result CCA Altered conduction Delayed
initiation Depressed movement thru Purkinje
fiber
15Vascular Smooth Muscle
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Contraction of sm mm
Ca2
16CCA and Vascular Smooth MM
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Result reduced vasoconstriction
Ca2
17CCA Dihyrdopyridines
- Smooth mm peripheral vasodilation
- In mild overdose
- Hypotension
- Tachycardia
- In children and severe OD
- Hypotension
- Bradycardia
18CCA Verapamil, CardizemPhenylalkylamines
- Greater binding at myocardial cells
- Negative inotrope
- Negative chronotrope
- Inhibit release of insulin in overdose
19CCA Management
- Assume ingestion
- Assess early/late or imminent
- IV, ECG, monitoring
Fingerstick blood glucose?
20Decontamination
- Activated charcoal 1 gm/kg
- MDAC 0.5 gm/kg q4?
- Whole bowel irrigation?
21Fellowship Case
- 30 month old male is found with an open bottle of
verapamil SR 240mg tabs. - New Rx 100 tabs
- 94 tabs found
22Verapamil
23Case continued
- Toddler has normal vital signs
- Playful
- Running around the ED
24Whole 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
25Management Conundrums
- Hypotension What can we try?
26Ca2
CCA and Vascular Smooth MM
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Ca2
Ca2
27Ca2
CCA and Vascular Smooth MM
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Ca2
NE, Phenylephrine
Ca2
28How does this affect cardiac output?
29Rx Vasodilation
- Agent Vasoconstriction HR CO
- NE ???
- PE ???
HR Heart rate COCardiac Output NE
Norepinephrine PE Phenylephrine
30Clinical Evaluation
- Mental status
- Peripheral circulation
- Urine output
- Lactate production
- Acid/base status
31Vasodilation
- Crystalloid
- Calcium variable efficacy
- Direct acting a1 agonists
- Norepinephrine
- Phenylephrine
- Caveat need to combine with inotropes
32Bradycardia
33Bradycardia
- Atropine and calcium
- Variable efficacy
- ß1 agonists
- Direct Epinephrine, Isoproterenol
- Indirect Glucagon
34What do these do to blood pressure?
35Bradycardia
- Agent Vasoconstriction HR CO
- Calcium ??
- Atropine ?
- Isoproterenol ? ? ?
- Glucagon ? ?
- Epi ? ?
36Inotropes
- Critical to cardiac output
- Allow titration of pressors
- Also have caveats
37What kind of inotropes can we try?
38NORMAL MYOCARDIAL CELL
Ca2
3
SR
4
PKA
Ca2
5
ATP cAMP
2
AC
Gs
ß1
1
39CCA
Ca2
Ca2
4
SR
PKA
Ca2
Amrinone 5MP
ATP cAMP
3
AC
Glucagon
Gs
2
ß1
Epi, Dobutamine
1
40Inotropes
- ß1 agonists
- Direct
- Indirect
- Phosphodiesterase inhibitors
- Calcium
41Calcium 10 100 mg/mL
- Calcium chloride
- 1.36 mEq/mL
- Central line important
- Calcium gluconate
- 0.43 mEq/mL
42CaCl2 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
43Calcium 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
44Inotropes
- ß1 agonists
- Direct
- Indirect
- Phosphodiesterase inhibitors
- Calcium
45What do these inotropes do to blood pressure?
46Inotropes
- Agent Vasoconstriction HR CO
- Dobutamine ? ? ?
- Epi ?? ?
- Glucagon ? ?
- Amrinone ? ? ?
- Calcium ?
Needs pressor
47 In CCA Toxicity
- Agent Vasoconstriction HR CO
- NE ???
- PE ???
- Calcium ??
- Atropine ?
- Isoproterenol ? ? ?
- Dobutamine ? ? ?
- Epi ?? ?
- Glucagon ? ?
- Amrinone ? ? ?
HR Heart rate COCardiac Output
48Insulin and Dextrose
- Increase energy efficiency
- Prolongs opening of Ca2 channels
- Potential anti-inflammatory effects
49Insulin 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
50Insulin 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
51Myocardium under duress
Ca2
SR
PKA
Ca2
ATP cAMP
FFA metabolism
AC
Gs
ß1
52Dextrose and Insulin
Ca2
SR
PKA
Ca2
Aerobic metabolism
ATP cAMP
Glucose
AC
Gs
I
ß1
Insulin/Glucose
K
53Insulin 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 lt200 mg/dL
- Potassium supplementation lt 2.5 Eq/mL
54Insulin 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
55Invasive Therapies
- ECMO/VAD
- Exchange transfusion?
- Balloon pump
56Intralipids The Future?
- Used in local anesthetic toxicity
- Mechanism uncertain
- Rat and canine models are promising
- With lipid soluble toxin
Lipidrescue.org
57Intralipid?
- 20 solution
- 1-2 mL/kg bolus
- 0.25 mL/kg/hr
- Call PCC
Lipidrescue.org
58Case
- Toddler with 6 missing tablets
- Discussed aggressive therapy with family, PCC
faculty, PICU faculty - WBI started
59Outcome
- All six tablets found in diapers within 7 hours
of starting the WBI - Baby discharged after 24 hours observation
60Dosing (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
61Dosing Infusions
- Epinephrine
- 0.1- 1 mcg/kg/minute
- Norepinephrine
- 0.05 0.1 mcg/kg/min
- Phenylephrine
- 0.1 0.5 mcg/kg/min
62Dosing 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