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

Charcoal hemoperfusion: Principles and differences from hemodialysis

Alex Yartsev, 02/06/2011

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.

The Charcoal Hemoperfusion Filter:

Brochure from the “Adsorba C” range by Gambro, for the Prismaflex machines

- 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.

Activated charcoal

Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6Winchester, 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.

- 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

The principle of Charcoal Hemoperfusion:

Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6Winchester, 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)

- 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–S6Winchester, 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)

- 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

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, 1965Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6Winchester, 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)

- 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!

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

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

Charcoal Hemoperfusion vs. Hemodiafiltration:

Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6Replacement of renal function by dialysis: a textbook of dialysis By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

- 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.

Complications of Charcoal Hemoperfusion

Dunea G. et al, Experience with the Yatzidis charcoal artificial kidney Trans Am Soc Artif Intern Organs 11:178, 1965Winchester, 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)

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

History of Hemoperfusion:

Muirhead et al, Resin artifical kidney J lab Clin Med 33:841 1948Schreiner et al, the role of hemodialysis in acute poisoning Arch Intern Med 102:896 1958Yatzidis et al, Treatment of severe barbiturate poisoning lancet 2: 216 1963Chang 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, 1974Replacement of renal function by dialysis: a textbook of dialysis By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

- 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 1948Schreiner et al, the role of hemodialysis in acute poisoning Arch Intern Med 102:896 1958Yatzidis et al, Treatment of severe barbiturate poisoning lancet 2: 216 1963Chang 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, 1974Replacement of renal function by dialysis: a textbook of dialysis By John Francis Maher, the 20th chapter by james F. Winchester (pp 439)

-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.

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)

Notable drugs:-Theophylline-Barbiturates-Tricyclics (incl. Carbamazepine)-Digoxin-Salicylates-Paraquat-Organophosphates

Clearance of Drugs: comparison of

conventional hemodialysis with charcoal hemoperfusion

Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6Replacement of renal function by dialysis: a textbook of dialysis By John Francis Maher, the 20th chapter by james F. Winchester (pp 439

Specialised adsorption resins

Clearance of Drugs: comparison of

conventional hemodialysis with charcoal hemoperfusion

Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6Replacement of renal function by dialysis: a textbook of dialysis By John Francis Maher, the 20th chapter by james F. Winchester (pp 439

With charcoal,at least a modest benefit

Criteria for Hemoperfusion

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)

Of note:Impairment of excretory functionSubstance is more easily extracted than excreted

Hemodialysis ineffective

WELL ESTABLISHED INDICATIONS for hemoperfusion

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 charcoal hemoperfusion in carbamazepine overdose. Clin Toxicol (Phila) 2008;46:342-3.

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

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): 87-89Greenberg 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 1984Molina, Fabian, et al; Use of charcoal hemoperfusion to reduce serum methotrexate levels in a patient with acute renal insufficiency Am J Med 82: 350, 1987Roberts et al, Lessons learnt in the pharmacokinetic analysis of the effect of haemoperfusion for acute overdose with sustained-release diltiazem AnaesthesiaVolume 63, Issue 7, pages 714–718, July 2008Eyer 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

- 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)

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.

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 orcondition which is responsible for theinduction 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)

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: 1976Cruz 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

When is hemodialysis better:

Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6

- 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.

The jury is still out:

Botella et.al. Adsorption in hemodialysis. Kidney International (2000) 58, S60–S6

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

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.

No further questions, please.

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