1. IMPLEMENTATION & USE of CRRT in PEDIATRIC INTOXICATIONS Patrick D. Brophy MD University of Michigan Pediatric Nephrology

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

3. Introduction 2.2 million reported poisonings (1998) 67% in pediatrics 2.2 million reported poisonings (1998) 67% in pediatrics Approximately 0.05% required extracorporeal elimination 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 Primary prevention strategies for acute ingestions have been designed and implemented (primarily with legislative effort) with a subsequent decrease in poisoning fatalities

4. Options & Pharmacokinetics Extracorporeal Methods –Peritoneal Dialysis –Hemodialysis –Hemofiltration –Charcoal hemoperfusion Considerations –Volume of Distribution (Vd)/compartments –molecular size –protein/lipid binding –solubility

5. 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)

6. DistributionRe-distribution INPUTINPUT ELIMINATION Pharmacokinetics

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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)

13. Options Intoxicants amenable to Hemodialysis –vancomycin (high flux) –alcohols diethylene glycol methanol –lithium –salicylates

14. Options

15. 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

16. Options

17. 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 survival Koo et.al. AJKD 39:2002 Options

18. 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)

19. 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

20. Options Hours LimEq/LLimEq/L CVVHD following HD for Lithium poisoning HD started 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 PO 4 Based dialysate at 2L/1.73m 2 /hr Li Therapeutic range 0.5-1.5 mEq/L

21. Options Intoxicants amenable to Hemofiltration –vancomycin –methanol –procainamide –hirudin –thallium –lithium –methotrexate

22. 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

23. 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?)

24. 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 Fe+deferoxamine complex

25. 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

26. ACKNOWLEDGEMENTS –MELISSA GREGORY –ANDREE GARDNER –JOHN GARDNER –THERESA MOTTES –TIM KUDELKA –LAURA DORSEY & BETSY ADAMS (p. brophy)