1. TREATMENT OF INTOXICATIONS WITH RENAL REPLACEMENT THERAPY Timothy E. Bunchman Professor Pediatric Nephrology & Transplantation

2. 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

3. Poison Management DECONTAMINATION/TREATMENT OPTIONS FOR OVERDOSE Standard Airway, Breathing and Circulatory measures take precedent Oral Charcoal Bowel Cleansing Regimens Antidotes IV or PO when applicable IV Hydration

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

5. DistributionRe-distribution INPUTINPUT ELIMINATION

6. 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)

7. 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

8. 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

9. 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)

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

11. Ethylene Glycol Intoxication Rx with Hemodialysis Duration of Rx (hrs) Mg/ml (> 30 mg/ml toxic)

12. Vancomycin clearance High efficiency dialysis membrane Time of therapy Vanc level (mic/dl) Rx Rebound

13. High flux hemodialysis for Carbamazine Intoxication Rx Hrs from time of ingestion Mic/ml

14. 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)

15. Intoxicants amenable to Charcoal Hemoperfusion Carbamazepine phenobarbital phenytoin theophylline paraquat

16. 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)

17. Continuous Detoxification methods CAVHF, CAVHD, CAVHP, CVVHF, CVVHD, CVVHP Indicated in cases where removal of plasma toxin is then replaced by redistributed toxin from tissue Can be combined with acute high flux HD

18. Serum half-life (hr) Valproic Acid Total Unbound Total Baseline 10.3 10.0 SievingCoefficient* CVVHD 7.7 4.5 0.12 CVVHD 4.0 3.0 0.32 +Albumin Albumin Hemofiltration

19. Carbamazine Clearance Natural Decay Clearance with Albumin Dialysis Askenazi et al, Pediatrics 2004

20. 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. Intoxicants amenable to Hemofiltration vancomycin methanol procainamide hirudin thallium lithium methotrexate

22. 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

24. Novel Approaches to facilitating intoxicant removal during hemofiltration Addition of albumin to dialysate Enhancement of Valproic Acid removal during CVVHD by the addition of albumin to dialysate A 6-1/2 month old infant was hospitalized with a serum valproic acid level of 1043 mcg/mL. He received CVVHD (blood flow 80 mL/min; prefilter replacement fluid: 400mL/hr; dialysate: 450 mL/hr) without and with albumin 45 gm/L) in the dialysate. Serial serum levels were obtained before and during dialysis. (PRISMA- M60) V Chadha et al. pCRRT- Orlando 2002 Albumin Hemofiltration