IMPLEMENTATION & USE of CRRT in PEDIATRIC INTOXICATIONS

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. Bulloch’s chosen ingestions • Future directions!!

3. 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

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. Pharmacokinetics ELIMINATION I N P U T Distribution Re-distribution

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. 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 When To Implement Therapy

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. 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)

16. Options

17. 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

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 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

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. Bulloch’s Overdoses • Sulfonylureas-low MW, low PB, high renal excretion- YES to HF • CCB’s-high PB, large Vd, poor removal-possible 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

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)