Charcoal hemoperfusion: Principles and differences from hemodialysis

1. Charcoal hemoperfusion: Principles and differences from hemodialysis Alex Yartsev, 02/06/2011

2. What is hemoperfusion? the passage of blood through a column containing adsorbent particles The particles are typically activated charcoal or resin Muirhead, EE, Reid, AF. Resin artificial kidney. Lab Clin Med 1948; 33:841.

3. Canister with 300g of activated charcoal • Blood flow though the canister is driven by a normal dialysis machine • There is no ultrafiltration, no fluid removal, • no dialysis. The Charcoal Hemoperfusion Filter: Brochure from the “Adsorba C” range by Gambro, for the Prismaflex machines

4. Starts life as coconut shell • Controlled combustion in superheated O2 • Fine granules, ~ 0.1mm • Massive surface area in one 300g cartridge • 40 m2 external surface • 300,000m2 internally (pores) • Small diffusion distance Activated charcoal Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300.

5. ADsorption vs ABsorption: • Absorption is when atoms molecules or ions diffuse into a bulky volume • Adsorption is when the atoms molecules or ions settle on a surface • Charcoal or resin in the cartridge will compete with plasma proteins for the drug molecules; these molecules will adsorb onto the charcoal surface The principle of Charcoal Hemoperfusion: Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

6. The principle of Charcoal Hemoperfusion: • Hemoperfusion is effective at clearing protein-bound and lipid-soluble drugs (not just water soluble molecules) • Hemoperfusion has variable effectiveness at removing small water-soluble molecules, • Clearance of any given molecule depens not only on its size but also on the affinity of the charcoal or resin for that molecule Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

7. Blood must come in direct contact with the adsorption surface • The surface needs to be biocompatible, or terrible things will happen • Initial attempts were frustrated by the degradation of blood components • Subsequently, biopolymer coating was introduced to reduce platelet aggregation and fibrin adsorption – cellulose nitrate was the first. • High flows are used, and heparin or prostacyclin • Textbooks recommend anticoagulation to increase intra-circuit • whole blood clotting time to ~ 30 minutes! Preventing the clotting of the filter Dunea G. et al, Experience with the Yatzidis charcoal artificial kidney Trans Am Soc Artif Intern Organs 11:178, 1965 Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

8. In porous charcoal, molecules must diffuse from the 40m2 surface to the 300,000m2 inner pores • In older uncoated filters, this diffusion was the rate limiting step • In coated granule filters, the rate limiting step is diffusion through the biopolymer coat Diffusion from blood to charcoal Dunea G. et al, Experience with the Yatzidis charcoal artificial kidney Trans Am Soc Artif Intern Organs 11:178, 1965 Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

9. Solute adsorption into activated charcoal depends on the diffusion of solvent through the biopolymer coating. • Substances of low molecular mass have no problem and are only slightly delayed by the coating: • Creatinine (113 Da) • Uric acid (168 Da) • Vitamin B12 (1355 Da) • Thus, “middle molecule” solutes are well removed • Beyond ~ 3500 Da, a significant diffusion delay occurs Solute qualities Dunea G. et al, Experience with the Yatzidis charcoal artificial kidney Trans Am Soc Artif Intern Organs 11:178, 1965 Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

10. Hemoperfusion is more effective at clearing protein-bound drugs • Hemoperfusion is also more efficient than hemodialysis at clearing lipid-soluble drugs • Hemodialysis and hemodiafiltration are more efficient at clearing readily water-soluble substances and small molecules • If a substance is equally well removed by either hemodialysis or hemoperfusion, then hemodialysis is the modality of choice, because it has fewer complications. Charcoal Hemoperfusion vs. Hemodiafiltration: Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

11. EARLY PROBLEMS • Particle embolization in filters with uncontrolled granule diameter • Profound platelet depletion with uncoated filters • Anaphylactic reactions to dirty coconut charcoal • Deposition of hydrocarbons into the patient by treated charcoal • PROBLEMS REMAINING • Some platelet depletion with coated filters • Fibrinogen depletion • Decreased WCC: complement is activated even by coated filters, and this results in leucocyte margination and thus WCC is observed to fall • Hypotension: likely due to platelet activation in the filter, and resulting massive release of vasoactive amines • Removal of calcium • Removal of glucose • Removal of hormones, coagulation factors and trace elements Complications of Charcoal Hemoperfusion Dunea G. et al, Experience with the Yatzidis charcoal artificial kidney Trans Am SocArtif Intern Organs 11:178, 1965 Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

12. In 1948, Muirhead and Reid killed several lab animals • Cation and anion exchange resin filters shown to remove 3.5 G urea • 1958: Schreiner removed a useful • amount of pentobarbital out of an • overdose patient with 2 x 15-minute • sessions on a lactated anion resin column. • Massive hemolysis, electrolyte derangement and death quoted • as the main obstacle to therapy History of Hemoperfusion: Muirhead et al, Resin artifical kidney J lab Clin Med 33:841 1948 Schreiner et al, the role of hemodialysis in acute poisoning Arch Intern Med 102:896 1958 Yatzidis et al, Treatment of severe barbiturate poisoning lancet 2: 216 1963 Chang et al, Serum middle molecule levels in uremia during long term intermittent hemopefusion with ACAD (coated charcoal) microcapsule artficial kidney Trans Am SocIrtifint Organs 20:364, 1974 Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

13. 1964, Yatzidis et al treated barbiturate overdoses with • coconut shell charcoal • both patients regained consciousness. • Anaphylactoid side effects eg facial flushing and wheezy dyspnoea • 50% platelet count drop following 5 x 1 hr sessions • 1973, Chang et al demonstrate that though uremic toxin removal is greater with hemoperfusion than with hemodialysis, urea itself could not be removed in clinically useful quantities. History of Hemoperfusion: Muirhead et al, Resin artifical kidney J lab Clin Med 33:841 1948 Schreiner et al, the role of hemodialysis in acute poisoning Arch Intern Med 102:896 1958 Yatzidis et al, Treatment of severe barbiturate poisoning lancet 2: 216 1963 Chang et al, Serum middle molecule levels in uremia during long term intermittent hemopefusion with ACAD (coated charcoal) microcapsule artficial kidney Trans Am SocIrtifint Organs 20:364, 1974 Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

14. Notable drugs: • Theophylline • Barbiturates • Tricyclics (incl. Carbamazepine) • Digoxin • Salicylates • Paraquat • Organophosphates Hemoperfusion in Overdose Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

15. Clearance of Drugs: comparison of conventional hemodialysis with charcoal hemoperfusion • Specialised adsorption resins Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439

16. Clearance of Drugs: comparison of conventional hemodialysis with charcoal hemoperfusion • With charcoal, • at least a modest benefit Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6 Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439

17. Criteria for Hemoperfusion • Of note: • Impairment of excretory function • Substance is more easily extracted than excreted • Hemodialysis ineffective Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

18. WELL ESTABLISHED INDICATIONS for hemoperfusion • PARAQUAT • Near-continuous charcoal hemoperfusion prevents progression to pulmonary fibrosis and improves mortality • ORGANOPHOSPHATES • Indicated in SEVERE massive overdose • less beneficial in mild overdose • CARBAMAZEPINE • - Indicated in SEVERE massive overdose • THEOPHYLLINE • Charcoal hemoperfusion decreases progression to seizures and improves mortality Holubek et al, Use of hemodialysis and hemoperfusion in poisoned patients idney International (2008) 74, 1327–1334; Winchester, JF, Boldur, A, Oleru, C, Kitiyakara, C. Use of dialysis and hemoperfusion in treatment of poisoning. In: Handbook of Dialysis, 4th ed, Daugirdas, JT, Blake, PG, Ing, TS (Eds), Lippincott Willliams & Wilkins, Philadelphia 2007. p. 300. Replacement of renal function by dialysis: a textbook of dialysis  By John Francis Maher, the 20th chapter by james F. Winchester (pp 439) Pilapil M, Petersen J. Efficacy of hemodialysis and charcoalhemoperfusion in carbamazepine overdose. Clin Toxicol (Phila) 2008;46:342-3.

19. Methotrexate • Better with uncoated charcoal • Diltiazem • Especially sustained release • Phenytoin • Half life reduced from 100 to 7 hrs • Valproate • Chloramphenicol in children • Muscarine (from Amanita Muscaria) LESS WELL ETABLISHED APPLICATIONSof hemoperfusion Parish RC, Treatment of Amanita mushroom poisoning: a review. Vet Hum Toxicol. 1986 Aug;28(4):318-22. Grafft et al, High-dose continuous venovenous hemofiltration combined with charcoal hemoperfusion for methotrexate removal NDT Plus (2011) 4 (2): 87-89 Greenberg et al, Severe theophylline toxicity: Role of conservative measures, antiarrhythmic agents, and charcoal hemoperfusion The American Journal of Medicine Volume 76, Issue 5 , Pages 854-860, May 1984 Molina, Fabian, et al; Use of charcoal hemoperfusion to reduce serum methotrexate levels in a patient with acute renal insufficiency Am J Med 82: 350, 1987 Roberts et al, Lessons learnt in the pharmacokinetic analysis of the effect of haemoperfusion for acute overdose with sustained-release diltiazem Anaesthesia Volume 63, Issue 7, pages 714–718, July 2008 Eyer F, Felgenhauer N, Pfab R, Thürmel K, Zilker T. Treatment of severe intravenous phenytoin overdose with hemodialysis and hemoperfusion. Med Sci Monit. 2008 Dec;14(12):CS145-8. Licari, Elisa MD; Calzavacca, Paolo MD; Warrillow, Stephen J. MD; Bellomo, Rinaldo MD Life-threatening sodium valproate overdose: A comparison of two approaches to treatment. Critical Care Medicine: December 2009 - Volume 37 - Issue 12 - pp 3161-3164

20. Charcoal Hemoperfusion in Hepatic Encephalopathy • in 1972, Chang et al first reported the use of charcoal hemoperfusion in an encephalopathic woman. (She survived) • In theory, the mercaptans and ammonia are adsorbed more easily than they are dialysed • The idea is to intervene BEFORE Stage IV coma by West Haven Criteria • (i.e. before unresponsiveness, when cerebral oedema is irreversibly established) • Exactly when to intervene? • Nobody agrees. • Some useful things may also be removed.

21. Studies of Hemoperfusion in hepatic encephalopathy • From 1972 to 1985: • as methodology improved, treatment effect deteriorated Treatment effect may be owed more to cessation of the agent or condition which is responsible for the induction of the coma. Opinion of experts: • Nobody knows at what stage to start HP • Everyone seems to agree that resin rather than charcoal should be used (as not all molecules responsible for encephalopathy are removed)

22. NON-STANDARD APPLICATIONS OF HEMOPERFUSION • 1976, McEwoy et al • Psoriasis improved during dialysis. Effect was not sustained in RCT. • 1977, Wagemaker and Cade: • “dramatic” improvement in delusions and paranoid ideation in 5 out of the 6 chronic schizophrenics , attributed to the hemoperfusion removal of leucine-endorphin. • Not supported by subsequent series. • 2009, EUPHAS trial: • Significant reduction in mortality following hemoperfusion with Polymyxin-B containing column, in 64 surgical patients with severe septic shock. • Trial terminated: unethical to withhold lifesaving polymyxin. Wagemaker, Cade ; the use of hemodialysis in chronic schizophrenia. Am J Psychiatr 134: 684 1977. McEwoy et al, psoriatic clearance during hemodialysis Ulster Med J 76: 1976 Cruz DN, Antonelli M, Fumagalli R, et al. Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock: The EUPHAS Randomized Controlled Trial JAMA. 2009;301:2445-2452

23. When is hemodialysis better: • Hemodialysis is much better at correcting acidosis • Thus, hemodialysis is better at treating overdose with a substance that causes acidosis, such as ethylene glycol, methanol or salicylates • Hemodialysis is better in ethanol poisoning, because charcoal is rapidly saturated by ethanol • If a substance is equally well removed by either hemodialysis or hemoperfusion, then hemodialysis is the modality of choice, because it has fewer complications. Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6

24. The jury is still out: • PARACETAMOL: • Single trial: no evidence of survival benefit, but technically feasible • AMITRYPTILINE / NORTRIPTYLINE • Several studies, in disagreement. Not all demonstrate a survival benefit. • DIGOXIN: • Several studies, in disagreement. Not all demonstrate a survival benefit. • Benefit outweighs risk in end-stage renal failure patients • May be more relevant now that digoxin antibodies are withdrawn from the market Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6

25. Hemoperfusion is more efficient at clearing protein-bound drugs • Hemoperfusion is more efficient at clearing lipid-soluble drugs • There are specific overdoses where benefit outweighs risk • Hemodialysis is more efficient at clearing drugs with small Vd • Hemodialysis/diafiltration is much better at improving acid-base disorders and clearing small substances, and thus remains the treatment of choice for garden-variety ARF • If a substance is equally well removed by either hemodialysis or hemoperfusion, then hemodialysis is the modality of choice, because it has fewer complications. BOTTOM LINE:Hemoperfusion vs. Hemodialysis:

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