RRT and Intoxications Timothy E Bunchman

Case Study-1 17 y/o female with poly pharmacy overdose including risperidone, stratttera and long acting Lithium She is not on any medications chronically 12 hours post overdose she is semi comatose with QT interval changes on EKG

There is no hepatic nor renal dysfunction Lithium level was > 5.1 mmol/l (critical > 4) Case Study-2

Thought Process of RRT in Intoxication Is the drug long or short acting Is there any inhibition of the natural excretion of the drug What is the molecular weight? What is the protein binding? Is this single or double compartment?

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

DistributionRe-distribution INPUTINPUT ELIMINATION

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)

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

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: )

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

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

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

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

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: )

Hemofiltration Can be combined with acute high flux HD Indicated in cases where removal of plasma toxin is then replaced by redistributed toxin from tissue

Solute Molecular Weight and Clearance Solute (MW)Sieving Coefficient Diffusion Coefficient Urea (60)1.01 ± ± 0.07 Creatinine (113)1.00 ± ± 0.06 Uric Acid (168)1.01 ± ± 0.04* Vancomycin (1448)0.84 ± ± 0.04** *P<0.05 vs sieving coefficient **P<0.01 vs sieving coefficient

HD to Convective HF Lithium mmol/l 8 liter CVVHDF High Flux HD 4 liter CVVH 2 liter CVVH

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 # ml/min HD & 200 ml/min CVVHD PO 4 Based dialysate at 2L/1.73m 2 /hr Li Therapeutic range mEq/L

Intoxicants amenable to Hemofiltration vancomycin methanol procainamide hirudin thallium lithium methotrexate

Serum half-life (hr) Valproic Acid Total Unbound Total Baseline SievingCoefficient* CVVHD CVVHD Albumin Albumin augmented Diffusive Hemofiltration

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

Conclusion RRT with the use of high flux hemodialysis and convective hemofiltration may allow for continuous removal of intoxication Attention to single or double compartment kinetics will dertemine the length of time of excretion