1. Renal Replacement Therapy for Intoxications Timothy E. Bunchman Pediatric Nephrology & Transplantation DeVos Children’s Hospital Grand Rapids, MI (thanks to Pat Brophy for his help and some slides)

2. Before we get going remember Looking at therapeutic medications or intoxications there is an Looking at therapeutic medications or intoxications there is an  Absorption process &  An elimination/metabolism process

3. What is unique to Pediatric Intoxications? Vehicle in which the medication was delivered Vehicle in which the medication was delivered Metabolism of drug Metabolism of drug Volume of distribution Volume of distribution Variable size of the child Variable size of the child

4. Vehicle in which drug was administered Oral liquid/mucosal absorption Oral liquid/mucosal absorption  Rapid absorption fixed metabolism Short acting pill form Short acting pill form  Slower absorption, fix metabolism Long acting pill form Long acting pill form  Slowest absorption, fix metabolism

5. Drug absorption in a child

6. CSA metabolism varies with Age

7. Intoxications  2.2 million reported poisonings (1998) 67% in pediatrics67% in pediatrics Approximately 0.05% required extracorporeal eliminationApproximately 0.05% required extracorporeal elimination

8. 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

9. DistributionRe-distribution INPUTINPUT ELIMINATION

10. Factors affecting clearance Delivery of drug to hemofilter Delivery of drug to hemofilter Blood flow, volume of distribution (Vd) Drugs unique ultrafiltration properties Drugs unique ultrafiltration properties Mol. Wt., Chemical structure, drug- membrane interaction, protein binding Ultrafiltration rate Ultrafiltration rate Protein binding Golper TA et al, Int J Art Organs, 1985

11.  Extracorporeal Methods Peritoneal DialysisPeritoneal Dialysis HemodialysisHemodialysis HemofiltrationHemofiltration Charcoal hemoperfusionCharcoal hemoperfusion –No longer needed (historical perspective) HD followed by HFHD followed by HF

12. INDICATIONS 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

13. PERITONEAL DIALYSIS 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

14. HEMODIALYSIS 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)

15. Hemodialysis: Nl vs High Flux Normal is a smaller pore size (12 Kda) and dialysate runs at ~ 30 l/hr Normal is a smaller pore size (12 Kda) and dialysate runs at ~ 30 l/hr High flux is larger pore size (up to 50 Kda) and runs dialysate at ~ 50 l/hr High flux is larger pore size (up to 50 Kda) and runs dialysate at ~ 50 l/hr

16. Hemofiltration use for intoxications (primary or tandem) Hemofiltration allows for continuous therapy at bedside 24 hrs a day Hemofiltration allows for continuous therapy at bedside 24 hrs a day Can be Convective (CVVH), Diffusive (CVVHD), or combination (CVVHD) Can be Convective (CVVH), Diffusive (CVVHD), or combination (CVVHD) CVVHD does not add significantly to what can be done with maximizing CVVH or CVVHD alone CVVHD does not add significantly to what can be done with maximizing CVVH or CVVHD alone

17. Filtration vs. Dialysis Filtration: Clearance by convection Dependent on UFR and sieving coefficient Dialysis: Clearance by diffusion Dependent on concentration gradient

18. CVVH/CAVH CVVH/CAVH Convective clearance Convective clearance Replacement Solutions Replacement Solutions  Physiologic sterile solution that is either infused pre filter or post filter that infused at a set rate (Qr) CAVH/CVVH: Convective Clearance

19. CAVHD/CVVHD Diffusive Clearance CVVHD/CAVHD CVVHD/CAVHD Diffusive clearance Diffusive clearance Dialysate Dialysate  Physiologic sterile solution that is infused countercurrent to the blood flow rate (Qd)

20. Sieving Coefficients Solute (MW)Convective Coefficient Diffusion Coefficient Urea (60)1.01 ± 0.051.01 ± 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)adsorbedminimal clearance *P<0.05 **P<0.01

21. Dialysis Dose 0 1 2 3 4 5 6 7 8 9 10 Weekly stdKt/V 0.30.50.70.91.11.31.5 eKt/V each dialysis 2 3 4 5 6 7 No. of Days/weekEDD 35ml/kg45ml/kg20ml/kg Adapted from Gotch et al. Kidney Int 2000;58:S3-18 CRRT PD

22. So for any clearance moment to moment High (flux) efficiency HD > standard HD > CVVH > CVVHD > PD High (flux) efficiency HD > standard HD > CVVH > CVVHD > PD Thought process of acute RRT needs to ensure that pt does not become hypophosphatemic, hypokalemic, etc Thought process of acute RRT needs to ensure that pt does not become hypophosphatemic, hypokalemic, etc  Electrolyte components can be added to the dialysate “bath”

23. Intoxicants amenable to Hemodialysis Intoxicants amenable to Hemodialysis  alcohols  ethylene glycol  Methanol (beware that one does not clear the rescue drug)(beware that one does not clear the rescue drug)  vancomycin (high flux)  Highly protein bound seizure drugs  lithium  salicylates

24. A good Friday night Teens deciding that beer was to expensive so they went for anti-freeze instead Teens deciding that beer was to expensive so they went for anti-freeze instead Had metabolic acidosis and osmolar gap Had metabolic acidosis and osmolar gap Before use of (fomepizol) treated with IV alcohol and dialysis (may clear rescue drug) Before use of (fomepizol) treated with IV alcohol and dialysis (may clear rescue drug) Alcohols are in general small molecular wt poorly protein bound Alcohols are in general small molecular wt poorly protein bound

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

26. A bad Friday night If a little vancomycin is good a lot is better If a little vancomycin is good a lot is better Historically thought to be poorly dialyzable but with High efficient membrane clears easily Historically thought to be poorly dialyzable but with High efficient membrane clears easily Senario is in children with reduction in GFR dosed based upon nl GFR Senario is in children with reduction in GFR dosed based upon nl GFR Has a 2 compartment distribution Has a 2 compartment distribution

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

28. A fun Friday night Highly protein bound anti-seizure meds thought to be only cleared by CHP Highly protein bound anti-seizure meds thought to be only cleared by CHP CHP is where one removes blood from the pt, filters thru a charcoal filter, goes to a dialysate membrane back to the pt CHP is where one removes blood from the pt, filters thru a charcoal filter, goes to a dialysate membrane back to the pt Problem with CHP, large extracorporeal circuit, cold, hypocalcemic, coagulopathic.. Problem with CHP, large extracorporeal circuit, cold, hypocalcemic, coagulopathic.. essentially “they get ugly” essentially “they get ugly”

29. High flux hemodialysis for Tegretol Intoxication HD Rx Hrs from time of ingestion Mic/ml 2 compartment rebound

30. Tandem therapies: prevention of the rebound If one has a rapid generation rate or a large volume of distribution consider tandem therapies If one has a rapid generation rate or a large volume of distribution consider tandem therapies HD for rapid removal followed by HF for prevention of the rebound HD for rapid removal followed by HF for prevention of the rebound

31. HD Rx of Hyperammonemia ( Gregory et al, Vol. 5,abst. 55P,1994: ) NH 4 micromoles/l Time (Hrs) NH4 rebound with reinstitution of HD

32. HD to CRRT (prevention of the rebound) Time (Hrs) NH 4 micromoles/L Transition from HD to CVVHD

33. Tandem Therapies HD to HF 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 # 2 325 ml/min HD & 200 ml/min CVVHD PO 4 Based dialysate at 2L/1.73m 2 /hr Li Therapeutic range 0.5-1.5 mEq/L

34. Summary RRT can be an adjunct to normal elimination of drug or a substitution of drug removal (with concomitant ARF) RRT can be an adjunct to normal elimination of drug or a substitution of drug 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 PD No role for PD

35. Summary Tandem therapies allow for rapid and sustaining removal of drugs with prevention of rebound… Tandem therapies allow for rapid and sustaining removal of drugs with prevention of rebound… Vascular access already in place Vascular access already in place Early consideration of RRT Early consideration of RRT

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