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• 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

(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

(p. brophy)

• Extracorporeal Methods– Peritoneal Dialysis– Hemodialysis– Hemofiltration– Charcoal hemoperfusion

• Considerations– Volume of Distribution (Vd)/compartments– molecular size– protein/lipid binding– solubility

(p. brophy)

PHARMOCOKINETIC COMPARTMENTS

kidneybloodPeripheralliverGI Tract

Distribution Re-distribution

INPUT

ELIMINATION

(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)

(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

(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)

(p. brophy)

• Intoxicants amenable to Hemodialysis– vancomycin (high flux)– alcohols

• diethylene glycol

• methanol

– lithium– salicylates

(p. brophy)

High Flux Dialysis forVancomycin Overdose

0

50

100

150

200

250

0 3 15 18 30 33

Vanco Level (ug/ml)

(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)

High Flux Dialysis forTegretol Overdose

0

5

10

15

20

25

30

35

(p. brophy)

• Intoxicants amenable to Charcoal Hemoperfusion– Carbamazepine– phenobarbital – phenytoin – theophylline– paraquat

(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)

(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

(p. brophy)

0

1

2

3

4

5

6Pt #1Pt #2

Hours

Li

mEq/ L

CVVHD following HD for Lithium poisoning

HD started

CVVHD started CT-190 (HD)Multiflo-60both patientsBFR-pt #1 200 ml/minHD & CVVHD -pt # 2 325 ml/minHD & 200 ml/min

CVVHDPO4 Based dialysate at

2L/1.73m2/hr

Li Therapeutic range0.5-1.5 mEq/L

(p. brophy)

• Intoxicants amenable to Hemofiltration– vancomycin– methanol– procainamide– hirudin– thallium– lithium– methotrexate

(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

(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

(p. brophy)

• DIALYZE EARLY ! DIALYZE OFTEN !

• “PHYSIOLOGY ? ITS GOT NOTHING TO DO WITH PHYSIOLOGY ! HELL, THIS IS CHEMISTRY” – T. Bunchman - 1999

(p. brophy)

• ACKNOWLEDGEMENTS– TIMOTHY BUNCHMAN– DIANE HILFINGER– ANDREE GARDNER– JOHN GARDNER– THERESA MOTTES– TIM KUDELKA– LAURA DORSEY & BETSY ADAMS

(p. brophy)