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. The Charcoal Hemoperfusion Filter:
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.
Brochure from the “Adsorba C” range by Gambro, for the Prismaflex machines

4. Activated charcoal 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
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 p. 300.

5. The principle of Charcoal Hemoperfusion:
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
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 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 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. Preventing the clotting of the filter
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!
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 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. Diffusion from blood to charcoal
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
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 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 qualities
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
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 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. Charcoal Hemoperfusion vs. Hemodiafiltration:
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.
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. Complications of Charcoal Hemoperfusion
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
Dunea G. et al, Experience with the Yatzidis charcoal artificial kidney Trans Am Soc Artif 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 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. History of Hemoperfusion:
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
Muirhead et al, Resin artifical kidney J lab Clin Med 33:
Schreiner et al, the role of hemodialysis in acute poisoning Arch Intern Med 102:
Yatzidis et al, Treatment of severe barbiturate poisoning lancet 2:
Chang et al, Serum middle molecule levels in uremia during long term intermittent hemopefusion with ACAD (coated charcoal) microcapsule artficial kidney Trans Am Soc Irtif int 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. History of Hemoperfusion:
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.
Muirhead et al, Resin artifical kidney J lab Clin Med 33:
Schreiner et al, the role of hemodialysis in acute poisoning Arch Intern Med 102:
Yatzidis et al, Treatment of severe barbiturate poisoning lancet 2:
Chang et al, Serum middle molecule levels in uremia during long term intermittent hemopefusion with ACAD (coated charcoal) microcapsule artficial kidney Trans Am Soc Irtif int 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. Hemoperfusion in Overdose
Notable drugs:
Theophylline
Barbiturates
Tricyclics (incl. Carbamazepine)
Digoxin
Salicylates
Paraquat
Organophosphates
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
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 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 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 charcoal hemoperfusion in carbamazepine overdose. Clin Toxicol (Phila) 2008;46:342-3.

19. LESS WELL ETABLISHED APPLICATIONS of hemoperfusion
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)
Parish RC, Treatment of Amanita mushroom poisoning: a review. Vet Hum Toxicol. 1986 Aug;28(4):
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 , 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 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 Volume 37 - Issue 12 - pp

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:
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:

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:
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. BOTTOM LINE: Hemoperfusion vs. Hemodialysis:
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.

26. No further questions, please.