1. Renal Replacement Therapy in Intoxications Maria Ferris, MD, MPH, PhD University of North Carolina Kidney Center Chapel Hill, North Carolina USA 7/17/2015 - 14:45 to 15:00 Hrs.

2. Intoxications in USA Children Accidental/intentional intoxications occur in about 7.5 million cases per year and about 10,000 deaths/yr. Borkan SC in Crit Care Clin. 2002;18:393 The Toxic Exposure Surveillance System of the American Association of Poison Control Centers – 57 of the nation’s poison centers upload case data automatically) Bronstein in Clin Toxicol 2012 Dec;50(10):911 – 65% in people < 20 y.o.a. but only 11% of deaths

3. Data loaded every 8 minutes at the American Association of Poison Control Centers 2015 Annual Report www.aapcc.org

4. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System AgeMaleFemaleTotal (%)Cumulative (%) < 1 year314 (0.4) 1 year112 (0.2)6 (0.5) 2 years448 (0.7)14 (1.2) 3 years101 (0.1)15 (1.3) 4 years123 (0.3)18 (1.6) 5 years202 (0.2)20 (1.7) 6-12 years516 (0.5)26 (2.3) 13-19 years242044 (3.8)70 (6.0) 20-29 years10556161 (14)231 (20.0) Bronstein in Clin Toxicol 2012 Dec;50(10):911

5. USA Human Exposure Call Increases by Year 2000 – 2011 – Top 4 Categories AnalgesicsCNS agents CardiovascularAntihistaminic Bronstein in Clin Toxicol 2012 Dec;50(10):911

6. Molecular Wt. of Common Xenobiotics Xenobiotics = drugs and toxins Convective removal of molecules In CVVHDF diffusive transport of molecules is combined with convective removal to improve solute clearance Fertel et al J Intens Care Med. 2010; 25(3):139

7. Kim Z et al Nephron Clin Practice (2010) 115:c1-6 Bunchman and Ferris in Pediatr Nephrol.Bunchman and Ferris in Pediatr Nephrol. 2011 Apr;26(4):535-41. Xenobiotic Removal Determinants Molecular weight Natural Clearance Volume of Distribution Protein bound percent

8. Kim Z et al Nephron Clin Practice (2010) 115:c1-6 Bunchman and Ferris in Pediatr Nephrol.Bunchman and Ferris in Pediatr Nephrol. 2011 Apr;26(4):535-41. Xenobiotic Removal Determinants Molecular weight – Newer membranes have size limitation ~ 12, 000 Daltons Natural Clearance – Liver or kidney? – Is there kidney injury?

9. Kim Z et al Nephron Clin Practice (2010) 115:c1-6 Bunchman and Ferris in Pediatr Nephrol.Bunchman and Ferris in Pediatr Nephrol. 2011 Apr;26(4):535-41. Volume of Distribution (VD) - ↑VD = ↓in blood compartment -VD < 0.6 L/kg body weight - VD >1.0 L/kg not for extra corporeal removal (Digoxin’s VD = 5-12 L/kg)

10. Low Volume of Distribution (VD) Alcohols Phenobarbital Lithium Salicylates **Lithium: 2 compartment distribution with a small initial VD (despite a large ultimate VD and a long half-life). If dialysis is initiated while still in the plasma, it would be removable. Fertel et al J Intens Care Med. 2010; 25(3):139

11. Extracorporeal Treatment for ASA Poisoning: EXTRIP Workgroup Recs. Indications for extracorporeal treatment are poorly defined in 84 manuscripts, including a single controlled clinical trial RECOMMENDATIONS: 1.Extracorporeal treatment for severe poisoning (altered mental status, acute respiratory distress syndrome, or failure to respond to standard therapy) 2.Asymptomatic patients with significantly elevated salicylate level also merit consideration of extracorporeal treatment 3.Hemodialysis: preferred treatment method Ann of Emerg Med May 2015

12. Protein Bound Percent ↑ protein binding = ↓ dialysis diffusion – Except Aspirin: At toxic levels, protein binding threshold is exceeded so ↑ free aspirin in plasma In uremic patients in whom protein binding of xenobiotics is reduced, clearance might be ↑ Fertel et al J Intens Care Med. 2010; 25(3):139

13. Kim Z et al Nephron Clin Practice (2010) 115:c1-6

14. CRRT and HD CharacteristicCRRTHD Membrane PermeabilityGreaterLower Molecular size (Daltons)1, 00020 K - 40,000 Clearance rateLowerGreater Speed of RemovalSlowerFaster Rebound from intra-cellular to plasma LessMore Coagulation exposureGreaterLower Electrolyte disturbancesMoreLess Equipment, training, staff & costGreaterLower

16. Theophylline Toxicity and Acute Hemodialysis in a Preterm Neonate A 1,220-g neonate w/status epilepticus due to a theophylline overdose. Theophylline T 1/2 of 30 hr. in neonates. T ½ was 0.7 h during our dialysis session, similar to hemoperfusion (used in adults) Our experienced nurse made it possible Gitomer, Kahn and Ferris Pediatr Nephrol. 2001 Oct;16(10):784-6.

17. Peritoneal Dialysis in Intoxications Toxic clearance is by diffusion The advantages of PD vs. other forms of RRT – Relatively simple – Availability – Avoids anticoagulation – Lower cost – Can eliminate Lithium (small molecular weight) Berkovitch M, Ther Drug Monit. 1994;16:531–533

18. Peritoneal Dialysis in Intoxications Toxic clearance is by diffusion The advantages of using PD vs. other forms of RRT – Relatively simple/available – Avoids anticoagulation – Lower cost/staff – Can eliminate Lithium (small molecular weight) PD should be used only when other options are not available Berkovitch M, Ther Drug Monit. 1994;16:531–533