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
- Â 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
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%Â Â (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.
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