TREATMENT OF INTOXICATIONS WITH CONTINUOUS RENAL REPLACEMENT THERAPY Patrick D Brophy MD FRCPC University of Michigan June 23, 2000 1st annual PCRRT, Orlando, FL

INTRODUCTION 2.2 million reported poisonings (1998) 67% in pediatrics (p. brophy) 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

Poison Management DECONTAMINATION/TREATMENT OPTIONS FOR OVERDOSE (p. brophy) 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

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

(p. brophy) ELIMINATION I N P U T Distribution Re-distribution

(p. brophy) 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)

high probability of significant morbidity/mortality (p. brophy) 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

(p. brophy) 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

HEMODIALYSIS optimal drug characteristics for removal: (p. brophy) 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)

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

(p. brophy)

CHARCOAL HEMOPERFUSION (p. brophy) 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)

(p. brophy)

Intoxicants amenable to Charcoal Hemoperfusion (p. brophy) Intoxicants amenable to Charcoal Hemoperfusion Carbamazepine phenobarbital phenytoin theophylline paraquat

HEMOFILTRATION optimal drug characteristics for removal: (p. brophy) 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)

Continuous Detoxification methods (p. brophy) 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

CVVHD following HD for Lithium poisoning (p. brophy) L i m E q / 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

Intoxicants amenable to Hemofiltration (p. brophy) Intoxicants amenable to Hemofiltration vancomycin methanol procainamide hirudin thallium lithium methotrexate

Plasmapheresis / Exchange Blood Transfusions (p. brophy) 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 (p. brophy) 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

DIALYZE EARLY ! DIALYZE OFTEN ! (p. brophy) DIALYZE EARLY ! DIALYZE OFTEN ! “PHYSIOLOGY ? ITS GOT NOTHING TO DO WITH PHYSIOLOGY ! HELL, THIS IS CHEMISTRY” T. Bunchman - 1999

ACKNOWLEDGEMENTS TIMOTHY BUNCHMAN DIANE HILFINGER ANDREE GARDNER (p. brophy) ACKNOWLEDGEMENTS TIMOTHY BUNCHMAN DIANE HILFINGER ANDREE GARDNER JOHN GARDNER THERESA MOTTES TIM KUDELKA LAURA DORSEY & BETSY ADAMS