Enhanced Elimination

Reviewed and revised 21 November 2016

OVERVIEW

Definition

• enhanced elimination techniques serve to increase the rate of removal of an agent from the body with the aim of reducing the severity and duration of clinical intoxication.

Types

• multiple dose activated charcoal (MDAC)
• urinary alkalinisation
• extracorporeal elmination (e.g. hemodialysis, hemofiltration,  hemoperfusion, plasmapheresis and exchange transfusion)

REQUIREMENTS

Enhanced elimination techniques are only indicated for poisonings when the following requirements are met:

• Severe toxicity
• Poor outcome despite good supportive care/antidote administration
• Slow endogenous rates of elimination
• Suitable pharmacokinetic properties
• benefit exceeds risks
• will not distract from other priorities (e.g. resuscitation, supportive care, decontamination and antidotal therapy)

MULTIPLE DOSE ACTIVATED CHARCOAL

Rationale

• Interruption of entero-hepatic circulation
  • requires biliary excretion leading to charcoal adsorption in the small intestine
• Gastrointestinal dialysis
  • drug passes down concentration gradient across gut mucosa from intravascular space where it is adsorbed by intraluminal activated charcoal
  • only if relatively small molecule, lipid soluble, has a small volume of distribution and low protein binding

Indications

• carbamazepine (most common)
• dapsone
• phenobarbitone
• quinine
• theophyline (hemodialysis is more important)

Contraindications

• Decreased level of consciousness, or anticipated decreased level of consciousness without prior airway protection
• Bowel obstruction

Technique

• Give an initial dose of activated charcoal 50 g (adults) or 1 g/kg (children) PO
• Give repeat doses of 25 g (0.5 g/kg in children) every two hours
• In the intubated patient, activated charcoal is given via oro- or naso-gastric tube after tube placement has been confirmed on chest X-ray
• Check for bowel sounds prior to administration of each dose
• Cease further administration if bowel sounds are inaudible
• Reconsider the indications and clinical end-points for therapy every six hours. Multiple-dose activated charcoal should rarely be required beyond six hours.

Complications

• Vomiting (30%)
• Charcoal aspiration, especially if there is decreased mental status or seizures
• Constipation
• Charcoal bezoar formation, bowel obstruction, bowel perforation (rare)
• Corneal abrasion
• Distraction of attending staff from resuscitation and supportive care priorities

URINARY ALKALINISATION

Rationale

•  alkaline urine pH promotes the ionisation of highly acidic drugs
• this prevents reabsorption across the renal tubular epithelium thus promoting excretion in the urine
• To be effective the drug must be filtered at the glomerulus, have a small volume of distribution and be a weak acid

Indications

• phenobarbitone
• salicylates

Contraindications

• Fluid overload

Technique

• Correct hypokalaemia if present
• Given 1-2 mmol/kg sodium bicarbonate IV bolus
• Commence infusion of 150 mmol sodium bicarbonate in 1000 mL 5% dextrose at 250 mL/hr
• 20 mmol of potassium chloride may be added to infusion to maintain normokalaemia
• Follow serum bicarbonate and potassium at least every 4 hours
• Regularly dipstick urine and aim for urinary pH >7.5
• Continue until clinical and laboratory evidence of toxicity is resolving

Complications

• Alkalaemia (usually well-tolerated)
• Hypokalaemia
• Hypocalcaemia (not usually clinically significant)

EXTRACORPOREAL ELIMINATION

Rationale

• Hemodialysis effectively enhances elimination of any drug that:
  • is a small molecule
  • has a small volume of distribution
  • rapid redistribution from tissues and plasma
  • slow endogenous elimination
• Continuous renal replacement therapy (CRRT) has lower drug clearance per unit of time but slow continuous removal may be preferred when:
  • hemodynamically unstable (unable to tolerate rapid solute and fluid loss)
  • highly protein/ tissue bound toxicant with large volume of distribution
  • substances with very long plasma half-lives
  • substances prone to “rebound” phenomenon (e.g. lithium)
• CRRT may be used as adjuvant therapy with IHD or hemoperfusion
• Hemoperfusion is traditionally used for highly protein-bound agents, but is now rarely used due to:
  • high cost and poor availability of charcoal cartridges
  • systemic adverse effects
  • rarity of theophyline overdoses
  • increased effectiveness of modern haemodialysis filters

Indications for hemodialysis/ hemofiltration

• carbamazepine (if MDAC is inadequate or infeasible)
• lithium
  • IHD removes lithium faster but rebound is a significant problem and can be addressed effectively with CRRT
• potassium
• metformin lactic acidosis
• methotrexate (if acute renal failure or leucovorin is not available)
  • prone to rebound
• paraquat (within 2 hours of ingestion)
• salicylates
• theophyline
  • RRT should be continued until clinical improvement and a plasma level < 20 mg/L is obtained. Rebound may occur
• toxic alcohols
  • intermittent hemodialysis is preferred
  • methanol: RRT should be continued until the serum methanol concentration is < 25 mg/dL and the anion-gap metabolic acidosis and osmolal gap are normal. Rebound may occur up to 36 hours.
  • ethylene glycol: RRT should be continued until the ethylene glycol level is <20 mg/dL and metabolic acidosis or other signs of systemic toxicity have been resolved. Rebound may occur up to 24 hours.
  • RRT effectively removes isopropanol and acetone, although it is usually unnecessary except in severe cases (prolonged coma, myocardial depression, renal failure).
• valproate
  • at supratherapeutic drug level plasma proteins become saturated, and the fraction of unbound drug increases substantially and becomes dialyzable

Traditional indications for hemoperfusion (now rarely performed or available)

• antiepileptics including carbamazepine and valproate (high-efficiency hemodialysis is as effective)
• theophylline

Complications

• see Continuous Renal Replacement Therapy (CRRT) Circuits

Other considerations

• extracorporeal techniques for enhanced elimination may still be useful for drugs that are highly bound to plasma proteins (Ghannoum et al, 2011) if:
  • protein binding sites are saturated in a massive overdose (e.g. valproate overdose)
  • the drug has a low association constant (i.e. low affinity) for plasma proteins (e.g. phenytoin)
• in general, extracorporeal techniques are only considered if they increase endogenous clearnace by >30%  (Ghannoum et al, 2011)
  • thus some drugs are not considered “dialysable” because they are efficiently cleared endogenously (e.g. cocaine)
  • extracorporeal drug removal may be extended to these drugs when endogenous clearance is impaired (e.g. due to renal impairment)
• extracorporeal removal if drugs with high volumes of distribution may be useful when:
  • rapid redistribution of drug from tissue compartments
  • started early while there is ongoing absorption, so that the drug has incompletely distruted to “deep” compartments
• much of the literature on extracorporeal removal of drugs does not reflect current practice, due to the existence of modern high efficiency dialysis/ haemofiltration membranes and vascaths (Ghannoum et al, 2011)

Evidence

• there are no RCTs comparing extracorporeal removal techniques versus supportive care only for poisoning
• observational studies are prone to confounding by indication (e.g. severity of illness affects choice of therapy)
• case studies, correctly perfromed can provide useful pharmacokinetic data, but are prone to publication bias and lack of controls

EXCHANGE TRANSFUSION

Indications

• methaemoglobinaemia (when refractory to other treatments, or other treatments are unavailable)

References and Links

LITFL

• CCC — Continuous Renal Replacement Therapy (CRRT) Circuits
• CCC — Indications, timing and patient selection for RRT (includes toxicology indications)

Journal articles

• Garlich FM, Goldfarb DS. Have advances in extracorporeal removal techniques changed the indications for their use in poisonings? Adv Chronic Kidney Dis. 2011 May;18(3):172-9. doi: 10.1053/j.ackd.2011.01.009. Review. PubMed PMID: 21531323.
• Ghannoum M, Nolin TD, Lavergne V, Hoffman RS; EXTRIP workgroup. Blood purification in toxicology: nephrology’s ugly duckling. Adv Chronic Kidney Dis. 2011 May;18(3):160-6. doi: 10.1053/j.ackd.2011.01.008. PMID: 21531321. [free full text pdf]
• Holubek WJ, Hoffman RS, Goldfarb DS, Nelson LS. Use of hemodialysis and hemoperfusion in poisoned patients. Kidney Int. 2008 Nov;74(10):1327-34. doi: 10.1038/ki.2008.462. Epub 2008 Sep 17. PMID: 18800032.
• Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1999;37(6):731-51. Review. PMID: 10584586.
• Proudfoot AT, Krenzelok EP, Vale JA. Position Paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42(1):1-26. Review. PMID: 15083932.
• Winchester JF, Harbord NB. Intoxications amenable to extracorporeal removal. Adv Chronic Kidney Dis. 2011 May;18(3):167-71. doi: 10.1053/j.ackd.2010.10.007. PMID: 21531322.