IMPLEMENTATION

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IMPLEMENTATION USE of CRRT in PEDIATRIC
INTOXICATIONS

• Patrick D. Brophy MD
• University of Michigan
• Pediatric Nephrology

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OBJECTIVES

• Review pharmacokinetic properties
• When to implement therapy
• Review extracorporeal techniques for toxin
  removal
• Other factors involved
• Address Dr. Bullochs chosen ingestions
• Future directions!!

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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

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Options Pharmacokinetics

• Extracorporeal Methods
• Peritoneal Dialysis
• Hemodialysis
• Hemofiltration
• Charcoal hemoperfusion
• Considerations
• Volume of Distribution (Vd)/compartments
• molecular size
• protein/lipid binding
• solubility

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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)

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Pharmacokinetics
ELIMINATION
I N P U T
Distribution
Re-distribution
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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 gt0.6
  l/kg (the total body water space)
• Vd Amount in the body/plasma concentration

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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

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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

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When To Implement Therapy

• INDICATIONS
• gt48 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

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Options

• PERITONEAL DIALYSIS
• 1st done in 1934 for 2 anuric patients after
  sublimate poisoning (Balzs et al Wien Klin Wschr
  193447851 )
• 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

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Options

• HEMODIALYSIS
• optimal drug characteristics for removal
• relative molecular mass lt 500
• water soluble
• small Vd (lt 1 L/Kg)
• minimal plasma protein binding
• single compartment kinetics
• low endogenous clearance (lt 4ml/Kg/min)
• (Pond, SM - Med J Australia 1991 154 617-622)

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Options

• Intoxicants amenable to Hemodialysis
• vancomycin (high flux)
• alcohols
• diethylene glycol
• methanol
• lithium
• salicylates

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Options
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Options

• CHARCOAL HEMOPERFUSION
• optimal drug characteristics for removal
• Adsorbed by activated charcoal
• small Vd (lt 1 L/Kg)
• single compartment kinetics
• protein binding minimal (can clear some highly
  protein bound molecules)
• low endogenous clearance (lt 4ml/Kg/min)
• (Pond, SM - Med J Australia 1991 154 617-622)

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Options
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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 392002
• theophylline
• Paraquat (poor clearance with all current
  therapies) HPCVVH prolonged survivalKoo et.al.
  AJKD 392002

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Options

• HEMOFILTRATION
• optimal drug characteristics for removal
• relative molecular mass less than the cut-off of
  the filter fibres (usually lt 40,000)
• small Vd (lt 1 L/Kg)
• single compartment kinetics
• low endogenous clearance (lt 4ml/Kg/min)
• (Pond, SM - Med J Australia 1991 154 617-622)

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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

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Options
L i m E q / L
CVVHD following HD for Lithium poisoning
HD started
Li Therapeutic range 0.5-1.5 mEq/L
CVVHD started
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
Hours
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Options

• Intoxicants amenable to Hemofiltration
• vancomycin
• methanol
• procainamide
• hirudin
• thallium
• lithium
• methotrexate

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Options

• Plasmapheresis / Exchange Blood Transfusions
• Plasmapheresis (Seyffart G. Trans Am Soc Artif
  Intern Organs 1982 28673)
• role in intoxication not clearly established
• most useful for highly protein bound agents
• Exchange Blood Transfusions
• Pediatric experience gt than adult
• Methemoglobinemia
• overall very limited role in poisoning

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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?)

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Dr. Bullochs Overdoses

• Sulfonylureas-low MW, low PB, high renal
  excretion- YES to HF
• CCBs-high PB, large Vd, poor removal-possible if
  proteins saturated
• Ethylene Glycol/Methanol- YES
• BZDs-high PB, large Vd, poor removal
• Iron-difficult due to protein binding-likely can
  dialyze Fedeferoxamine complex

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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

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(p. brophy)

• ACKNOWLEDGEMENTS
• MELISSA GREGORY
• ANDREE GARDNER
• JOHN GARDNER
• THERESA MOTTES
• TIM KUDELKA
• LAURA DORSEY BETSY ADAMS