Transcript CRRT in Ped Intoxication - Pediatric Continuous Renal

IMPLEMENTATION & USE of
CRRT in PEDIATRIC
INTOXICATIONS
Patrick D. Brophy MD
University of Michigan
Pediatric Nephrology
OBJECTIVES
Review pharmacokinetic properties
When to implement therapy
Review extracorporeal techniques for toxin
removal
Other factors involved
Address Dr. Bulloch’s chosen ingestions
Future directions!!
Introduction
• 2.2 million reported poisonings (1998)
67% in pediatrics
• Approximately 0.05% required
extracorporeal elimination
• Primary prevention strategies for acute
ingestions have been designed and
implemented (primarily with legislative
effort) with a subsequent decrease in
poisoning fatalities
Options & Pharmacokinetics
Extracorporeal Methods
– Peritoneal Dialysis
– Hemodialysis
– Hemofiltration
– Charcoal hemoperfusion
Considerations
– Volume of Distribution (Vd)/compartments
– molecular size
– protein/lipid binding
– solubility
Pharmacokinetics
GENERAL PRINCIPLES
– kinetics of drugs are based on therapeutic not
toxic levels (therefore kinetics may change)
– choice of extracorporeal modality is based on
availability, expertise of people & the
properties of the intoxicant in general
– Each Modality has drawbacks
– It may be necessary to switch modalities
during therapy (combined therapies inc:
endogenous excretion/detoxification methods)
Pharmacokinetics
PHARMOCOKINETIC COMPARTMENTS
ELIMINATION
I
N
P
U
T
Distribution
Re-distribution
kidney
blood
Peripheral
liver
GI Tract
Volume of Distribution (Vd)
Mathematical construct referring to the
volume a toxin/drug would occupy if the
body were a single homogenous vessel in
which toxin and plasma concentration
were equal
A large Vd has been arbitrarily defined as
>0.6 l/kg (the total body water space)
– Vd= Amount in the body/plasma concentration
Binding To Circulating Proteins
Albumin- primary culprit
Generally only unbound toxin/drug is available
for metabolism, excretion & elimination by CRRT
– In overdose-protein saturation may be 100%, so
free drug/toxin exists that is amenable to removal!
Binding altered by:
Uremic Toxin Retention; pH; hyperbilirubinemia
Drug displacement, heparin, free fatty acids
Molar ratio of drug/toxin to protein
Other Properties Altering CRRT
Removal
Gibbs-Donnan effect – drug charge
Molecular weight
Membrane Binding (Adsorption)-AN69
Membrane Properties
– Solute pore size
– Hydraulic Permeability
– Surface Area
When To Implement Therapy
INDICATIONS
– >48 hrs on vent
– ARF
– Impaired
metabolism
– high probability of
significant
morbidity/mortality
– progressive clinical
deterioration
INDICATIONS
– severe intoxication
with abnormal vital
signs
– complications of
coma
– prolonged coma
– intoxication with an
extractable drug
Options
PERITONEAL DIALYSIS
– 1st done in 1934 for 2 anuric patients after
sublimate poisoning (Balzs et al; Wien Klin Wschr 1934;47:851 )
– Allows diffusion of toxins across peritoneal
membrane from mesenteric capillaries into
dialysis solution within the peritoneal cavity
– limited use in poisoning (clears drugs with low
Mwt., Small Vd, minimal protein binding &
those that are water soluble)
alcohols, NaCl intoxications, salicylates
Options
HEMODIALYSIS
– optimal drug characteristics for removal:
relative molecular mass < 500
water soluble
small Vd (< 1 L/Kg)
minimal plasma protein binding
single compartment kinetics
low endogenous clearance (< 4ml/Kg/min)
(Pond, SM - Med J Australia 1991; 154: 617-622)
Options
Intoxicants amenable to Hemodialysis
– vancomycin (high flux)
– alcohols
diethylene glycol
methanol
– lithium
– salicylates
Options
High Flux Dialysis for
Vancomycin Overdose
250
200
150
Vanco Level (ug/ml)
100
50
0
0
3
15
18
30
33
Options
CHARCOAL HEMOPERFUSION
– optimal drug characteristics for removal:
Adsorbed by activated charcoal
small Vd (< 1 L/Kg)
single compartment kinetics
protein binding minimal (can clear some highly
protein bound molecules)
low endogenous clearance (< 4ml/Kg/min)
(Pond, SM - Med J Australia 1991; 154: 617-622)
Options
High Flux Dialysis for
Tegretol Overdose
35
30
25
20
15
10
5
51
35
30
28
25
16
7
0
0
Options
Intoxicants amenable to Charcoal
Hemoperfusion
– Carbamazepine (also high flux HD)
– phenobarbital (also High flux HD)
– phenytoin (also High Flux HD)
– Valproic Acid (CVVHDF) Minari et.al. Annals of Emer Med 39:2002
– theophylline
– Paraquat (poor clearance with all current
therapies) –HP+CVVH prolonged survivalKoo et.al.
AJKD 39:2002
Options
HEMOFILTRATION
– optimal drug characteristics for removal:
relative molecular mass less than the cut-off of the
filter fibres (usually < 40,000)
small Vd (< 1 L/Kg)
single compartment kinetics
low endogenous clearance (< 4ml/Kg/min)
(Pond, SM - Med J Australia 1991; 154: 617-622)
Options
Continuous Detoxification methods
CAVHF, CAVHD, CAVHDF, CVVHF,
CVVHD, CVVHDF
Indicated in cases where removal of
plasma toxin is then replaced by
redistributed toxin from tissue
Can be combined with acute high flux HD
Options
CVVHD following HD for Lithium poisoning
L 6
i
HD started
5
CVVHD started
m 4
E
q 3
/
2
L
Pt #1
Pt #2
Li Therapeutic range
0.5-1.5 mEq/L
CT-190 (HD)
Multiflo-60
both patients
BFR-pt #1 200 ml/min
HD & CVVHD
-pt # 2 325 ml/min
HD & 200 ml/min
CVVHD
PO4 Based dialysate at
2L/1.73m2/hr
1
0
Hours
24
12
6
5
0
Options
Intoxicants amenable to Hemofiltration
– vancomycin
– methanol
– procainamide
– hirudin
– thallium
– lithium
– methotrexate
Options
Plasmapheresis / Exchange Blood
Transfusions
– Plasmapheresis (Seyffart G. Trans Am Soc Artif Intern Organs
1982; 28:673)
role in intoxication not clearly established
most useful for highly protein bound agents
– Exchange Blood Transfusions
Pediatric experience > than adult
Methemoglobinemia
overall very limited role in poisoning
Other Issues
Optimal prescription
Biocompatible filters - may increase
protein adsorption
Maximal blood flow rates (ie good access)
Physiological solution (ARF vs non ARF)
? Removal of antidote
Counter-current D maximal removal of
toxins (CVVHDF?)
Dr. Bulloch’s Overdoses
Sulfonylureas-low MW, low PB, high renal
excretion- YES to HF
CCB’s-high PB, large Vd, poor removalpossible if proteins saturated
Ethylene Glycol/Methanol- YES
BZD’s-high PB, large Vd, poor removal
Iron-difficult due to protein binding-likely
can dialyze Fe+deferoxamine complex
Future Directions
Liver Assist Devices
– Albumin dialysis with anionic and charcoal
recharge filters
– Can use a variety of hemofilters and perform
CVVH, CVVHD, CVVHDF
– Will begin looking at intoxications with this
device in Michigan in 2003
(p. brophy)
ACKNOWLEDGEMENTS
– MELISSA GREGORY
– ANDREE GARDNER
– JOHN GARDNER
– THERESA MOTTES
– TIM KUDELKA
– LAURA DORSEY & BETSY ADAMS