Renal Replacement Therapy for Intoxications

Timothy E. Bunchman Timothy E. Bunchman

Pediatric Nephrology & TransplantationPediatric Nephrology & Transplantation

DeVos Children’s HospitalDeVos Children’s Hospital

Grand Rapids, MIGrand Rapids, MI

(thanks to Pat Brophy for his help and (thanks to Pat Brophy for his help and some slides) some slides)

Before we get going remember

Looking at therapeutic medications or Looking at therapeutic medications or intoxications there is an intoxications there is an Absorption process Absorption process

&& An elimination/metabolism processAn elimination/metabolism process

What is unique to Pediatric Intoxications? Vehicle in which the medication was Vehicle in which the medication was

delivereddelivered Metabolism of drug Metabolism of drug Volume of distributionVolume of distribution Variable size of the childVariable size of the child

Vehicle in which drug was administered

Oral liquid/mucosal absorptionOral liquid/mucosal absorption Rapid absorption fixed metabolismRapid absorption fixed metabolism

Short acting pill formShort acting pill form Slower absorption, fix metabolismSlower absorption, fix metabolism

Long acting pill formLong acting pill form Slowest absorption, fix metabolismSlowest absorption, fix metabolism

Drug absorption in a child

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0 2 4 6 12

liquidshort acting pilllong acting pill

CSA metabolism varies with Age

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adultchildinfant

Intoxications

2.2 million reported 2.2 million reported poisonings (1998) poisonings (1998)

• 67% in pediatrics67% in pediatrics

• Approximately 0.05% Approximately 0.05% required extracorporeal required extracorporeal elimination elimination

Kearns, G. L. et. al. N Engl J Med 2003;349:1157-1167

Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents

PHARMOCOKINETIC COMPARTMENTS

kidneybloodPeripheralliverGI TractDistribution Re-distribution

INPUT

ELIMINATION

A. J ör res 02/2001A. J ör res 02/2001

Factors affecting clearance

Delivery of drug to hemofilterDelivery of drug to hemofilter Blood flow, volume of distribution Blood flow, volume of distribution

(Vd)(Vd) Drugs unique ultrafiltration propertiesDrugs unique ultrafiltration properties Mol. Wt., Chemical structure, drug-Mol. Wt., Chemical structure, drug-

membrane interaction, protein membrane interaction, protein bindingbinding

Ultrafiltration rateUltrafiltration rate

Protein bindingProtein binding

Golper TA et al, Int J Art Organs, 1985

Extracorporeal MethodsExtracorporeal Methods• Peritoneal DialysisPeritoneal Dialysis• HemodialysisHemodialysis• HemofiltrationHemofiltration• Charcoal hemoperfusionCharcoal hemoperfusion

– No longer needed (historical No longer needed (historical perspective)perspective)

• HD followed by HFHD followed by HF

INDICATIONSINDICATIONS

>48 hrs on vent>48 hrs on vent ARFARF Impaired metabolismImpaired metabolism high probability of high probability of

significant significant morbidity/mortalitymorbidity/mortality

progressive clinical progressive clinical deterioration deterioration

INDICATIONSINDICATIONS severe intoxication severe intoxication

with abnormal vital with abnormal vital signs signs

complications of complications of coma coma

prolonged coma prolonged coma intoxication with an intoxication with an

extractable drugextractable drug

PERITONEAL DIALYSISPERITONEAL DIALYSIS 1st done in 1934 for 2 anuric patients after 1st done in 1934 for 2 anuric patients after

sublimate poisoning sublimate poisoning (Balzs et al; Wien Klin Wschr 1934;47:851 )(Balzs et al; Wien Klin Wschr 1934;47:851 )

Allows diffusion of toxins across peritoneal Allows diffusion of toxins across peritoneal membrane from mesenteric capillaries into membrane from mesenteric capillaries into dialysis solution within the peritoneal cavitydialysis solution within the peritoneal cavity

limited use in poisoning (clears drugs with low limited use in poisoning (clears drugs with low Mwt., Small Vd, minimal protein binding & those Mwt., Small Vd, minimal protein binding & those that are water soluble) that are water soluble) alcohols, NaCl intoxications, salicylatesalcohols, NaCl intoxications, salicylates

HEMODIALYSISHEMODIALYSIS optimal drug characteristics for removal:optimal drug characteristics for removal:

relative molecular mass < 500 relative molecular mass < 500 water solublewater solublesmall Vd (< 1 L/Kg)small Vd (< 1 L/Kg)minimal plasma protein bindingminimal plasma protein bindingsingle compartment kineticssingle compartment kinetics low endogenous clearance (< 4ml/Kg/min)low endogenous clearance (< 4ml/Kg/min)

– (Pond, SM - Med J Australia 1991; 154: (Pond, SM - Med J Australia 1991; 154: 617-622)617-622)

Hemodialysis: Nl vs High Flux

Normal is a smaller pore size (12 Kda) and Normal is a smaller pore size (12 Kda) and dialysate runs at ~ 30 l/hrdialysate runs at ~ 30 l/hr

High flux is larger pore size (up to 50 Kda) High flux is larger pore size (up to 50 Kda) and runs dialysate at ~ 50 l/hrand runs dialysate at ~ 50 l/hr

Hemofiltration use for intoxications (primary or tandem) Hemofiltration allows for continuous Hemofiltration allows for continuous

therapy at bedside 24 hrs a daytherapy at bedside 24 hrs a day Can be Convective (CVVH), Diffusive Can be Convective (CVVH), Diffusive

(CVVHD), or combination (CVVHD)(CVVHD), or combination (CVVHD) CVVHD does not add significantly to what CVVHD does not add significantly to what

can be done with maximizing CVVH or can be done with maximizing CVVH or CVVHD aloneCVVHD alone

A. J ör res 02/2001A. J ör res 02/2001

Filtration vs. Dialysis

Filtration:Clearance by

convection

Dependent on UFR and

sieving coefficient

Dialysis:Clearance by diffusion

Dependent on concentration

gradient

CVVH/CAVHCVVH/CAVH Convective clearanceConvective clearance Replacement SolutionsReplacement Solutions

Physiologic sterile Physiologic sterile solution that is either solution that is either infused pre filter or infused pre filter or post filter that post filter that infused at a set rate infused at a set rate (Qr)(Qr)

CAVH/CVVH: Convective Clearance

CAVHD/CVVHDDiffusive Clearance

CVVHD/CAVHDCVVHD/CAVHD Diffusive clearanceDiffusive clearance DialysateDialysate

Physiologic sterile Physiologic sterile solution that is infused solution that is infused countercurrent to the countercurrent to the blood flow rate (Qd)blood flow rate (Qd)

Sieving Coefficients

Solute (MW) Convective 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**

Cytokines (large) adsorbed minimal clearance

*P<0.05 **P<0.01

Dialysis Dose

0123456789

10W

eek

ly s

tdK

t/V

0.3 0.5 0.7 0.9 1.1 1.3 1.5

eKt/V each dialysis

234567

No. of D

ays/week

EDDEDD

35ml/kg35ml/kg

45ml/kg45ml/kg

20ml/kg20ml/kg

Adapted from Gotch et al. Kidney Int 2000;58:S3-18Adapted from Gotch et al. Kidney Int 2000;58:S3-18

CRRTCRRT

PD

So for any clearance moment to moment High (flux) efficiency HD > standard HD > High (flux) efficiency HD > standard HD >

CVVH > CVVHD > PDCVVH > CVVHD > PD Thought process of acute RRT needs to Thought process of acute RRT needs to

ensure that pt does not become ensure that pt does not become hypophosphatemic, hypokalemic, etchypophosphatemic, hypokalemic, etc Electrolyte components can be added to Electrolyte components can be added to

the dialysate “bath”the dialysate “bath”

Intoxicants amenable to HemodialysisIntoxicants amenable to Hemodialysis alcoholsalcohols

ethylene glycolethylene glycolMethanolMethanol

• (beware that one does not clear the rescue (beware that one does not clear the rescue drug)drug)

vancomycin (high flux)vancomycin (high flux) Highly protein bound seizure drugsHighly protein bound seizure drugs lithiumlithium salicylatessalicylates

A good Friday night

Teens deciding that beer was to expensive Teens deciding that beer was to expensive so they went for anti-freeze insteadso they went for anti-freeze instead

Had metabolic acidosis and osmolar gapHad metabolic acidosis and osmolar gap Before use of (fomepizol) treated with IV Before use of (fomepizol) treated with IV

alcohol and dialysis (may clear rescue drug)alcohol and dialysis (may clear rescue drug) Alcohols are in general small molecular wt Alcohols are in general small molecular wt

poorly protein boundpoorly protein bound

Ethylene Glycol IntoxicationRx with (std) Hemodialysis

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Pt 1Pt 2

Duration of Rx (hrs)

Mg/

ml

(> 3

0 m

g/m

l tox

ic)

A bad Friday night

If a little vancomycin is good a lot is betterIf a little vancomycin is good a lot is better Historically thought to be poorly dialyzable Historically thought to be poorly dialyzable

but with High efficient membrane clears but with High efficient membrane clears easilyeasily

Senario is in children with reduction in Senario is in children with reduction in GFR dosed based upon nl GFRGFR dosed based upon nl GFR

Has a 2 compartment distributionHas a 2 compartment distribution

Vancomycin clearance High efficiency dialysis membrane

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Pt 1Pt 2

Time of therapy

Van

c le

vel

(m

ic/d

l)

Rx Rx Rx

Rebound Rebound

A fun Friday night

Highly protein bound anti-seizure meds Highly protein bound anti-seizure meds thought to be only cleared by CHPthought to be only cleared by CHP

CHP is where one removes blood from the CHP is where one removes blood from the pt, filters thru a charcoal filter, goes to a pt, filters thru a charcoal filter, goes to a dialysate membrane back to the ptdialysate membrane back to the pt

Problem with CHP, large extracorporeal Problem with CHP, large extracorporeal circuit, cold, hypocalcemic, coagulopathic..circuit, cold, hypocalcemic, coagulopathic..

essentially “they get ugly”essentially “they get ugly”

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CBZ level(nl < 12;76%proteinbound))

High flux hemodialysis for Tegretol Intoxication

HD Rx

Hrs from time of ingestion

Mic

/ml

2 compartment rebound

Tandem therapies: prevention of the rebound If one has a rapid generation rate or a large If one has a rapid generation rate or a large

volume of distribution consider tandem volume of distribution consider tandem therapiestherapies

HD for rapid removal followed by HF for HD for rapid removal followed by HF for prevention of the reboundprevention of the rebound

HD Rx of Hyperammonemia(Gregory et al, Vol. 5,abst. 55P,1994: )

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NH4 rebound with reinstitution of HD

HD to CRRT(prevention of the rebound)

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Tandem TherapiesHD to HF

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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

Summary

RRT can be an adjunct to normal RRT can be an adjunct to normal elimination of drug or a substitution of drug elimination of drug or a substitution of drug removal (with concomitant ARF)removal (with concomitant ARF)

RRT therapies are safe RRT therapies are safe RRT machines are “pediatric friendly”RRT machines are “pediatric friendly” HF HD > HF > CVVH > CVVHD HF HD > HF > CVVH > CVVHD No role for PDNo role for PD

Summary

Tandem therapies allow for rapid and Tandem therapies allow for rapid and sustaining removal of drugs with prevention sustaining removal of drugs with prevention of rebound…of rebound…

Vascular access already in placeVascular access already in place Early consideration of RRT Early consideration of RRT

Conclusion

…………..if you can measure it, ..if you can measure it, we can clear it…we can clear it…