Toxicological uses of dialysis, haemoperfusion and plasmapheresis

Two past paper SAQs ask the candidates to discuss the use of extracorporeal clearance techniques in the treatment of drug overdose. Of these, Question 19.1 from the first paper of 2009 was more specific ("list the relevant physical features of hemodialysis and hemoperfusion filters" ). With such direct questions, we can almost forgive this Australian college their American spelling.  Question 29 from the second paper of 2010 was much more general ("When is dialysis utilised in toxic syndromes?" ) and the extracorporeal questions were buried under a lot of stuff about activated charcoal.

There are some good articles on this topic. Specific reading recommendations are  as follows:

• Haemodiafiltration: Bunchman et al, 2010
• Haemoperfusion: Ghannoum et al, 2014
• Plasmapheresis: Nenov et al, 2003

If one were to limit their reading to only articles which are useful for answering Question 29 from the second paper of 2010, the one most useful article would be  Holubek et al (2008). In this article, of specific interest are tables listing the most common toxins which were responsible for patients receiving various blood purification techniques. In the pre-exam state of panic, one should probably just read the LITFL entry on the toxicological uses of extracorporeal blood purification.

Use of haemodialysis and haemofiltration in toxicology

Specific features of CRRT filters which make them suitable for use

• Large surface area of the membrane increases the rate of molecule transport.
• Porosity of the membrane affects the maximum molecular weight of the transported molecules.
• The haemodialysis-specific filters offer significant resistance to flow because the membrane is formed of long tortuous channels; this increases the surface area and enhances clearance by movement along a concentration gradient.
• Ultrafiltration rate, as a function of porosity (among other factors) affects the rate of removal for larger molecules
• Dialysate flow rate affects the rate of clearance for drugs with smaller molecules
• Theoretically, adsorption on to the circuit components may play a role in the clearance of some traditionally "undialysable" drugs (Leypoldt et al, 1992). For example, the clearance of amikacin by CRRT is in part owed to adsoption on to polyacrylonitrile filter membranes.

Specific features of toxins which make them susceptible to removal by dialysis:

• Small molecule size
• Highly water soluble
• Small volume of distribution (i.e. ideally limited to circulating volume,  or the extracellular fluid)
• Large protein-unbound free fraction

Specific toxins which are susceptible to clearance by dialysis

• Barbiturates
• Lithium
• Alcohols eg. ethylene glycol, methanol
• Paraquat
• Salycilates
• Valproate
• Metformin
• Methotrexate
• It is generally accepted that extracorporeal elimination is worthwhile if it increases total body clearance by 30% or more (Pond et al, 1991)

Use of haemoperfusion in toxicology

Rationale and mechanism of clearance by haemoperfusion

• Many drugs are either highly protein bound or highly lipophilic
• These qualities make them unavailable for haemodialysis or ultrafiltration clearance, which can only access the ionised water-soluble fraction
• Adsorption can be used to clear these substances from the bloodstream
• The high surface area of resins and charcoal can compete with serum proteins for drug binding. The drugs are bound reversibly by Van der Waal forces (attractive forces between molecules not due to covalent, electrostatic or hydrogen bond interaction)
• Large surface area of resin or charcoal filter enhances adsorption by presenting a larger contact surface for the filtered blood.
• Charcoal is a "broad-spectrum" adsorption agent, whereas resins typically favour lipophilic substances.  Resin filters may also be impregnated with drug-specific antibodies
• The rate of adsorption generally depends upon the size of the granules, and the capacity of each cartridge is determined by its size (i.e. how much charcoal is inside).

However:

• Much interest in haemoperfusion was ultimately exhaused in the 1980s, and now we have lots of studies from that era to look at which do not in any way represent the current state of the art in haemoperfusion technology. Older data may not be generalisable because those machines and techniques have now become obsolete.

Specific toxins which are susceptible to clearance by haemoperfusion

• Theophylline
• Carbamazepine
• Phenytoin
• Paracetamol
• Digoxin
• Diltiazem
• Metoprolol
• Colchicine
• Promethazine
• Amanite phalloides mushroom toxin (phalloidin)

Complications of haemoperfusion

• Erratic electrolyte derangement
  • hypocalcemia
  • hypophosphatemia
  • hypoglycemia
• Coagulopathy
  • Low fibrinogen
  • Thrombocytopenia: on average the count decreases 20–50% from baseline
  • Depletion of all other coagulation factors
  • Complement activation leading to DIC
• Immune suppression
  • Low WCC
  • Depleted immunoglobulins
  • Depleted cytokines
  • Low complement
• Malnutrition due to adsortion of amino acids
• Feberile reaction to the circuit
• Charcoal embolization
• Haemolysis
• "Reverse adsorption" - redistribution of the toxin back into the bloodstream

Use of plasmapheresis in toxicology

• Toxidromes which benefit from dialysis and haemoperfusion will also benefit from plasmapheresis.
• Plasmapheresis is specifically beneficial in situations where the toxin has high plasma protein binding and a low volume of distribution (i.e. limited essentially to the circulating pool of proteins)
• If the toxin has a large volume of distribution (i.e. it is distributed widely to the tissues) several sessions of plasmapheresis will be required. In such a situation, there will be "rebound" toxicity as sequestered toxin redistributes into the bloodstream between sessions.
• Theoreticlly, drugs which might benefit from plasma exchange include the following:
  • Phalloidin
  • Amitryptilline
  • l-thyroxine
  • Verapamil
  • Diltiazem 
  • Digoxin
  • Carbamazepime
  • Theophylline
  • Mercury
  • Vanadium
• Realistically, plasmapheresis is used mostly to treat phalloid mushroom intoxications (Amanita phalloides). Plasmapheresis has been shown to decrease mortality from >20% to  4.8%. As far as raw toxin removal goes, it is at least as effective as haemoperfusion.