1. Hemodialysis and Hemofiltration in Pediatrics: An Approach to Intoxication Karen Papez MD University of Michigan Pediatric Nephrology, Dialysis & Transplantation 3rd annual PCRRT, Orlando, FL

2. 2002 Annual Report of American Association of Poison Control Centers Nearly 2.4 million human exposures reported by 64 participating poison centers in 2002. Nearly 2.4 million human exposures reported by 64 participating poison centers in 2002. 4.9% increase from 2001 4.9% increase from 2001 Children <3 yrs: 39% of all human exposures Children <3 yrs: 39% of all human exposures Children <6 yrs: 51.6% of all exposures Children <6 yrs: 51.6% of all exposures *Pediatricians and pediatric subspecialists need to be prepared to handle the majority of poison exposures. Watson WA et al. Am J Emerg Med 21: 2003 Watson WA et al. Am J Emerg Med 21: 2003 Litovitz TL et al. Am J Emerg Med 20: 2002 Litovitz TL et al. Am J Emerg Med 20: 2002

3. Enhanced Elimination Techniques for Poisonings Enhanced elimination techniques were used for 1457 cases (0.06%) in 2002. Enhanced elimination techniques were used for 1457 cases (0.06%) in 2002. A near 8% increase over 2001 reports A near 8% increase over 2001 reports Hemodialysis: 1400 [up 9% from 2001] Hemodialysis: 1400 [up 9% from 2001] Hemoperfusion: 30 [down 33% from 2001] Hemoperfusion: 30 [down 33% from 2001] Other Extracorporeal Procedures: 27 Other Extracorporeal Procedures: 27 *Pediatric nephrologists and intensivists need to be equipped with advanced techniques to handle such clinical situations.

4. Treatment Measures Available for Poisonings Enhance Elimination (Cont.) Enhance Elimination (Cont.) Extracorporeal Methods Extracorporeal Methods Hemodialysis Hemodialysis Standard Standard High Efficiency/High Flux High Efficiency/High Flux Hemofiltration Hemofiltration Hemoperfusion Hemoperfusion Exchange Transfusion Exchange Transfusion Plasma exchange Plasma exchange

5. Toxin Clearance What effects clearance? What effects clearance? Volume of distribution Volume of distribution Whether or not the drug is primarily renally excreted (competing pathways) Whether or not the drug is primarily renally excreted (competing pathways) Protein binding Protein binding Molecular size of the drug Molecular size of the drug Mode of therapy-HD, CVVH vs CVVHD vs CVVHDF Mode of therapy-HD, CVVH vs CVVHD vs CVVHDF Hemofilter membrane properties Hemofilter membrane properties Pond, SM - Med J Australia 1991; 154: 617-622 Pond, SM - Med J Australia 1991; 154: 617-622

6. HEMODIALYSIS HEMODIALYSIS Optimal drug characteristics for removal: Optimal drug characteristics for removal: Relative molecular mass < 500 Daltons Relative molecular mass < 500 Daltons Water soluble Water soluble Small Vd (< 1 L/Kg) Small Vd (< 1 L/Kg) Minimal plasma protein binding Minimal plasma protein binding Single compartment kinetics Single compartment kinetics Low endogenous clearance (< 4ml/Kg/min) Low endogenous clearance (< 4ml/Kg/min) Pond, SM - Med J Australia 1991; 154: 617-622 Pond, SM - Med J Australia 1991; 154: 617-622

7. HEMOFILTRATION HEMOFILTRATION Optimal drug characteristics for removal: Optimal drug characteristics for removal: Relative molecular mass less than the cut-off of the filter fibres (usually < 40,000 daltons) Relative molecular mass less than the cut-off of the filter fibres (usually < 40,000 daltons) Small Vd (< 1 L/Kg) Small Vd (< 1 L/Kg) Single compartment kinetics Single compartment kinetics Low endogenous clearance (< 4ml/Kg/min) Low endogenous clearance (< 4ml/Kg/min) Pond, SM - Med J Australia 1991; 154: 617-622 Pond, SM - Med J Australia 1991; 154: 617-622

8. Additional Factors when Considering Enhanced Elimination Methods Drug kinetics should be reviewed Drug kinetics should be reviewed Note: Kinetics may differ in an overdose situation Note: Kinetics may differ in an overdose situation Valproic acid: 90% protein bound with nl levels Valproic acid: 90% protein bound with nl levels Valproic acid: 70% bound at levels of 135 mcg/ml Valproic acid: 70% bound at levels of 135 mcg/ml : 35% bound at levels of 300 mcg/ml : 35% bound at levels of 300 mcg/ml *The higher the levels and the more unbound drug that exists, the more effectively it may be removed.

9. Case 1 14 year old female with history of depression, found slurring words, intermittently confused in her bedroom. 14 year old female with history of depression, found slurring words, intermittently confused in her bedroom. During period of lucency, told mother she drank something a schoolmate gave her to “get high.” States this was 18 hours before presentation to local ER. During period of lucency, told mother she drank something a schoolmate gave her to “get high.” States this was 18 hours before presentation to local ER.

10. Physical Exam at Admission to PICU T 38.8 P 125 RR 32 BP 158/75 Wt 75 Kg T 38.8 P 125 RR 32 BP 158/75 Wt 75 Kg Generally: GCS variable, from verbal response to voice to mild response to pain. Generally: GCS variable, from verbal response to voice to mild response to pain. HEENT: Pupils equally round, sluggishly reactive to light, mucous membranes dry HEENT: Pupils equally round, sluggishly reactive to light, mucous membranes dry Resp: Deep, tachypneic, clear to auscultation Resp: Deep, tachypneic, clear to auscultation CV: RRR, no murmur, peripheral pulses 2/4 CV: RRR, no murmur, peripheral pulses 2/4 Abd: Soft, nondistended, hypoactive bowel sounds Abd: Soft, nondistended, hypoactive bowel sounds

11. Laboratory Analyses 148 121 13 98 148 121 13 98 5.4 7 2.1 5.4 7 2.1 9.4 38 0.3 9.4 38 0.3 4.8 4.0 59 143 4.8 4.0 59 143 11.7 16.8 163 11.7 16.8 163 50.4 50.4 7.24 / 18 / 113 / 8 UA SG 1.015, pH 5, normal for all substrates AG 20 Calc osm 306 Serum osm 311 CPK 388 NH 3 38 Ethanol negative Urine drug screen negative βhCG negative Salicylate <1 Acetaminophen <10 Ethylene glycol 24.2

12. Calculated Osmolality with Dialysis in Ethylene Glycol Intoxication HD Started CVVHDF Started CT-190 Prisma dialyzer Multiflo-100 BFR -HD 250 ml/min -CVVHDF 180 ml/min PO4 based dialysate - 4L/1.73m 2 /hr

13. Case 2 12 year old female with history of bipolar disorder had started an increased dose of lithium 6 weeks prior to admission. 12 year old female with history of bipolar disorder had started an increased dose of lithium 6 weeks prior to admission. Was slurring her speech on morning of admission, and had irregular constant movements of her arms and legs. Was slurring her speech on morning of admission, and had irregular constant movements of her arms and legs.

14. Physical Exam at Admission to PICU T afebrile P 82 RR 23 BP 104/46 Wt 33 Kg T afebrile P 82 RR 23 BP 104/46 Wt 33 Kg Generally: Confused, slurring speech Generally: Confused, slurring speech HEENT: NC, AT, Mucous membranes moist HEENT: NC, AT, Mucous membranes moist Resp: Clear to auscultation Resp: Clear to auscultation CV: Regular rate and rhythm, no murmur CV: Regular rate and rhythm, no murmur Abdomen: Soft, normoactive bowel sounds Abdomen: Soft, normoactive bowel sounds Skin: Erythematous rash over abdomen Skin: Erythematous rash over abdomen Neuro: Athetoid movements as noted in HPI Neuro: Athetoid movements as noted in HPI

15. Laboratory Analyses 133 107 31 73 133 107 31 73 4.3 22 1.2 4.3 22 1.2 6.8 7.0 35 0.6 6.8 7.0 35 0.6 4.1 25 215 4.1 25 215 10.5 12.1 176 10.5 12.1 176 34.4 34.4 7.36 / 50 / 28 / 28 UA SG 1.010, pH 6.5, pro 1+, ket 2+, LE 1+, otherwise normal AG 4 CPK 939 NH 3 38 Ethanol and volatile acids negative Urine drug screen negative βhCG negative Salicylate <1 Acetaminophen <10 Lithium 7.34 EKG First degree heart block, PR 188 ms, prolonged QTc 520 ms

16. Lithium Clearance on Dialysis CVVHD Started HD Started CVVHD Stopped CT-190 Prisma dialyzer Multiflo-100 BFR -HD 250 ml/min -CVVHDF 180 ml/min PO4 based dialysate - 4L/1.73m 2 /hr

17. Lithium Redistributes from Intracellular Compartment: Arrows indicate beginning and end of HD. A significant rebound in serum concentration occurred after a 5-hr HD treatment with recurrence of neurologic impairment. An additional 4-hour hemodialysis treatment was then begun. F rom Goldfarb DS in Goldfrank’s Toxologic Emergencies, 7 th Ed. 2002 Hemofiltration May Attenuate Rebound Phenomenon!

18. CVVHD Following HD for Lithium Poisoning HD started CVVHD started CT-190 (HD) Prisma dialyzer -Multiflo-60 (#1,2) -Multiflo-100 (#3) BFR- HD -pt # 1 200 ml/min -pt # 2 325 ml/min -pt # 3 250 ml/min BFR- CVVHD 200 ml/min - All 3 pts. PO 4 Based dialysate at 2L/1.73m 2 /hr (#1,2) 4L/1.73m2/hr (#3) Li Therapeutic range 0.5-1.5 mEq/L

19. DrugMW[Daltons] H2O Sol % Prot Bound Vol of Distrib [L/kg] Endogenous Clearance Lithium7Yes00.6-1.0 0.4 ml/min/kg Methanol32Yes00.7 0.7 ml/min/kg Ethylene Glycol 62Yes00.6 2.0 ml/min/kg Salicylates138Yes90%*0.15-0.2 0.88 ml/min/kg Valproic acid 144No90%* 0.19-0.23 Tot 1.3 Free 0.13 ml/min/kg 1.1 ml/min/kg Theophylline180Yes55%0.4-0.7 0.65 ml/min/kg Phenobarb232No24-60%0.5 0.1 ml/min/kg Carbamaz- epine 236No75%0.8-1.6 1.3 ml/min/kg Vancomycin1486Yes10-50%0.47-1.1

20. Conclusions High efficiency hemodialysis and hemofiltration may alter the current “treatment of choice”. High efficiency hemodialysis and hemofiltration may alter the current “treatment of choice”. Pediatric nephrologists need to be aware that more than one treatment option exists for many toxicology situations, and the modality selected should be that tailored to their patient’s needs. Pediatric nephrologists need to be aware that more than one treatment option exists for many toxicology situations, and the modality selected should be that tailored to their patient’s needs.

21. ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS THERESA MOTTES THERESA MOTTES TIM KUDELKA TIM KUDELKA BETSY ADAMS BETSY ADAMS TAMMY KELLY TAMMY KELLY ROBIN NIEVAARD ROBIN NIEVAARD DAVID KERSHAW DAVID KERSHAW PATRICK BROPHY PATRICK BROPHY

22. OTHER ISSUES OTHER ISSUES Optimal prescription Optimal prescription Biocompatible filters - may increase protein adsorption Biocompatible filters - may increase protein adsorption Maximal blood flow rates (i.e. good access) Maximal blood flow rates (i.e. good access) Physiological solution (ARF vs non ARF) Physiological solution (ARF vs non ARF) Potential removal of antidote Potential removal of antidote Counter-current dialysate maximal removal of toxins Counter-current dialysate maximal removal of toxins

23. Specific Antidotes Should be used adjunctively with supportive therapy. Examples: N-acetyl cysteine [for Acetaminophen] N-acetyl cysteine [for Acetaminophen] Benzodiazepines [for Flumazenil] Benzodiazepines [for Flumazenil] Flumazenil [for Benzodiazepines] Flumazenil [for Benzodiazepines] Naloxone [for Opiates] Naloxone [for Opiates] Calcium [for Calcium channel blockers] Calcium [for Calcium channel blockers] Atropine [for Acetylcholinesterase inhibitors] Atropine [for Acetylcholinesterase inhibitors] Fomepizole [for Ethylene glycol, Methanol, & Diethylene Glycol] Fomepizole [for Ethylene glycol, Methanol, & Diethylene Glycol] Ethanol [for Ethylene glycol, Methanol, & Diethylene Glycol] Ethanol [for Ethylene glycol, Methanol, & Diethylene Glycol]