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Calcium Channel Antagonists in Children

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Calcium Channel Antagonists in Children. Rama B. Rao, MD. NYU ... Contractile Cells. 0. 1. 2. 3. 4 4. Phase 2 Myocardial Cell. Phase 4. Purkinje Fiber. SA Node ... – PowerPoint PPT presentation

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Title: Calcium Channel Antagonists in Children


1
Calcium Channel Antagonists in Children
  • Rama B. Rao, MD
  • NYU/Bellevue Hospital Center
  • 2007

2
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3
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4
Physiology of Children
  • GI
  • Lower hepatic glycogen reserves
  • Limited enzymatic capacity
  • pH and motility
  • Chew or bite tablets altering absorption

5
Physiology of Children
  • Respiratory
  • Diminished reserves
  • Metabolic
  • Increased requirements

6
Management Limitations
  • No confirmatory assay
  • Qualitative
  • Quantitative
  • Delayed onset toxicity

7
Limitations
  • Therapeutic interventions
  • No antidote
  • Variable outcomes
  • Limited data in children

8
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9
Pharmacology of CCA
  • Most tablets exclusively dosed for adults
  • Often slow release
  • Hepatically metabolized

10
Calcium Channels
  • L type Myocardium, sm mm, ß Islet pancreas
  • T
  • N
  • P Neuronal, SR, other
  • Q
  • R

11
NORMAL MYOCARDIAL CELL
Ca2
3
SR
4
PKA
Ca2
5
ATP cAMP
2
AC
Gs
ß1
1
12
CCA
Ca2
3
SR
4
PKA
Ca2
5
ATP cAMP
2
AC
Gs
ß1
Result Negative inotropy
1
13
Contractile Cells
1
Phase 2 Myocardial Cell Ca2 inward (with K
outward)
2
0
3
4 4
Result CCA Diminished contractility
14
Pacemaker 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
15
Vascular Smooth Muscle
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Contraction of sm mm
Ca2
16
CCA and Vascular Smooth MM
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Result reduced vasoconstriction
Ca2
17
CCA Dihyrdopyridines
  • Smooth mm peripheral vasodilation
  • In mild overdose
  • Hypotension
  • Tachycardia
  • In children and severe OD
  • Hypotension
  • Bradycardia

18
CCA Verapamil, CardizemPhenylalkylamines
  • Greater binding at myocardial cells
  • Negative inotrope
  • Negative chronotrope
  • Inhibit release of insulin in overdose

19
CCA Management
  • Assume ingestion
  • Assess early/late or imminent
  • IV, ECG, monitoring

Fingerstick blood glucose?
20
Decontamination
  • Activated charcoal 1 gm/kg
  • MDAC 0.5 gm/kg q4?
  • Whole bowel irrigation?

21
Fellowship Case
  • 30 month old male is found with an open bottle of
    verapamil SR 240mg tabs.
  • New Rx 100 tabs
  • 94 tabs found

22
Verapamil
23
Case continued
  • Toddler has normal vital signs
  • Playful
  • Running around the ED

24
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
25
Management Conundrums
  • Hypotension What can we try?

26
Ca2
CCA and Vascular Smooth MM
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Ca2
Ca2
27
Ca2
CCA and Vascular Smooth MM
Ca2
Voltage sensitive
Ca2
Calmodulin
Receptor operated
?1
Ca2
NE, Phenylephrine
Ca2
28
How does this affect cardiac output?
29
Rx Vasodilation
  • Agent Vasoconstriction HR CO
  • NE ???
  • PE ???

HR Heart rate COCardiac Output NE
Norepinephrine PE Phenylephrine
30
Clinical Evaluation
  • Mental status
  • Peripheral circulation
  • Urine output
  • Lactate production
  • Acid/base status

31
Vasodilation
  • Crystalloid
  • Calcium variable efficacy
  • Direct acting a1 agonists
  • Norepinephrine
  • Phenylephrine
  • Caveat need to combine with inotropes

32
Bradycardia
  • What can we try?

33
Bradycardia
  • Atropine and calcium
  • Variable efficacy
  • ß1 agonists
  • Direct Epinephrine, Isoproterenol
  • Indirect Glucagon

34
What do these do to blood pressure?
35
Bradycardia
  • Agent Vasoconstriction HR CO
  • Calcium ??
  • Atropine ?
  • Isoproterenol ? ? ?
  • Glucagon ? ?
  • Epi ? ?

36
Inotropes
  • Critical to cardiac output
  • Allow titration of pressors
  • Also have caveats

37
What kind of inotropes can we try?
38
NORMAL MYOCARDIAL CELL
Ca2
3
SR
4
PKA
Ca2
5
ATP cAMP
2
AC
Gs
ß1
1
39
CCA
Ca2
Ca2
4
SR
PKA
Ca2
Amrinone 5MP
ATP cAMP
3
AC
Glucagon
Gs
2
ß1
Epi, Dobutamine
1
40
Inotropes
  • ß1 agonists
  • Direct
  • Indirect
  • Phosphodiesterase inhibitors
  • Calcium

41
Calcium 10 100 mg/mL
  • Calcium chloride
  • 1.36 mEq/mL
  • Central line important
  • Calcium gluconate
  • 0.43 mEq/mL

42
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

43
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

44
Inotropes
  • ß1 agonists
  • Direct
  • Indirect
  • Phosphodiesterase inhibitors
  • Calcium

45
What do these inotropes do to blood pressure?
46
Inotropes
  • 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
48
Insulin and Dextrose
  • Increase energy efficiency
  • Prolongs opening of Ca2 channels
  • Potential anti-inflammatory effects

49
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

50
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

51
Myocardium under duress
Ca2
SR
PKA
Ca2
ATP cAMP
FFA metabolism
AC
Gs
ß1
52
Dextrose and Insulin
Ca2
SR
PKA
Ca2
Aerobic metabolism
ATP cAMP
Glucose
AC
Gs
I
ß1
Insulin/Glucose
K
53
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 lt200 mg/dL
  • Potassium supplementation lt 2.5 Eq/mL

54
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

55
Invasive Therapies
  • ECMO/VAD
  • Exchange transfusion?
  • Balloon pump

56
Intralipids The Future?
  • Used in local anesthetic toxicity
  • Mechanism uncertain
  • Rat and canine models are promising
  • With lipid soluble toxin

Lipidrescue.org
57
Intralipid?
  • 20 solution
  • 1-2 mL/kg bolus
  • 0.25 mL/kg/hr
  • Call PCC

Lipidrescue.org
58
Case
  • Toddler with 6 missing tablets
  • Discussed aggressive therapy with family, PCC
    faculty, PICU faculty
  • WBI started

59
Outcome
  • All six tablets found in diapers within 7 hours
    of starting the WBI
  • Baby discharged after 24 hours observation

60
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

61
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

62
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
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