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

PHARMOCOKINETIC COMPARTMENTS

kidney

blood

Peripheral

liver

GI TractDistribution Re-distribution

INPUT

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: 617-622)

Intoxicants amenable to Hemodialysis vancomycin (high flux) alcohols

diethylene glycol methanol

lithium salicylates

Ethylene Glycol IntoxicationRx with Hemodialysis

0

100

200

300

400

500

600

700

800

900

0 2 4 6

Pt 1Pt 2

Duration of Rx (hrs)

Mg/

ml

(> 3

0 m

g/m

l tox

ic)

Vancomycin clearance High efficiency dialysis

membrane

0

50

100

150

200

250

0 3 12 15 27 30

Pt 1Pt 2

Time of therapy

Van

c le

vel

(m

ic/d

l)

Rx Rx Rx

Rebound Rebound

0

5

10

15

20

25

30

35

0 5 10 15 20 25 30 35 40

CBZ level(nl < 12)

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: 617-622)

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 ClearanceSolute (MW) Sieving Coefficient Diffusion Coefficient

Urea (60) 1.01 ± 0.05 1.01 ± 0.07

Creatinine (113) 1.00 ± 0.09 1.01 ± 0.06

Uric Acid (168) 1.01 ± 0.04 0.97 ± 0.04*

Vancomycin (1448) 0.84 ± 0.10 0.74 ± 0.04**

*P<0.05 vs sieving coefficient**P<0.01 vs sieving coefficient

HD to Convective HF

0

1

2

3

4

5

6

0 1 2 4 6 14 23 27 48

Li Level

Lithium mmol/l

8 liter CVVHDF

High Flux HD

4 liter CVVH

2 liter CVVH

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

Intoxicants amenable to Hemofiltration vancomycin methanol procainamide hirudin thallium lithium methotrexate

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 augmented Diffusive Hemofiltration

Carbamazine ClearanceNatural 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