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Three Part Question

In [adults who have taken a tricyclic antidepressant overdose] is [activated charcoal] effective at [reducing drug absorption and reducing complication rates]?

Clinical Scenario

A 25 year old woman attends the emergency department having taken an overdose of amitriptyline. You wonder whether she will benefit from treatment with activated charcoal.

Search Strategy

Ovid Medline 1950 – 2008 May Week 3. 67 papers
Embase 1980 – 2008 Week 22: 125 papers (no additional papers found)

(exp Antidepressive Agents, Tricyclic/ OR tricyclic.mp. OR amitriptyline.mp. OR exp Amitriptyline/ OR desipramine.mp. OR exp Desipramine/ OR clomipramine.mp. OR exp Clomipramine/ OR doxepin.mp. OR exp Doxepin/ OR dothiepin.mp. OR exp Dothiepin/ OR imipramine.mp. OR exp Imipramine/ OR lofepramine.mp. OR exp Lofepramine/ OR nortriptyline.mp. OR exp Nortriptyline/ OR trimipramine.mp. OR exp Trimipramine/) AND (exp Overdose/ OR exp Poisoning/ OR overdose.mp.) AND (exp Charcoal/ OR charcoal.mp.) limit to humans and English language

Search Outcome

67 papers were identified in Medline and 125 in Embase. Eight were relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Crome P et al 1977 UK	Health volunteers given 75mg nortriptyline. 10g medicoal at 30 min	Experimental	Plasma nortriptyline level	60% decreased	Small dose of TCA.
Crome P et al 1983 UK	48 patients with suspected TCA overdose. All had gastric lavage. 10g medicoal vs nothing	PRCT	Plasma TCA concentration	No difference in rate of fall noted	Small numbers with complications. Small charcoal dose. 18 patents excluded.
			Clinical signs	No significant difference
Karkkainen S and Neuvonen PJ 1986	6 healthy volunteers. Each took 75mg amitriptyline. 50g charcoal within 5 min	Experimental	Plasma TCA absorption	Decreased by 99%	Small dose of TCA. Unrealistic time to charcoal.
Hulten BA et al 1988 Multinational	77 patients over 14 years old with TCA overdose. All had gastric lavage. 20g charcoal vs nothing	PRCT	Clinical signs	No significant difference	Control group differed from charcoal group at baseline.
			Plasma TCA concentration	No significant difference in peak or half-life
Dawling et al 1978 England	6 fasted healthy volunteers given 75mg nortriptyline, allocated to four groups on different occasions: (1) No treatment (2) 10g Medicoal after 30min (3) 10g Medicoal after 2h (4) 10g Medicoal after 4h	Experimental, volunteer study, crossover design	Mean reduction in peak plasma nortriptyline concentrations	77% in group (2), 37% in group (3), 19% in group (4) (p<0.001)	Conducted in fasted volunteers Small dose of notrtiptyline
			Mean reduction in plasma nortriptyline availability (area under time-concentration curve)	74% in group (2), 37.5% in group (3), 13% in group (4). (p<0.001)
Hedges et al 1986 United States	9 patients with TCA overdose who clinically required hospitalisation All patients had gastric lavage and charcoal, the timing and dosing of which were performed at the treating physician’s discretion	Prospective observational cohort	Correlation between estimated plasma amitriptyline concentration half-life and time to charcoal	Directly proportional (r=0.78, p<0.05)	Small numbers No data on time to gastric lavage 5 patients received a second dose of charcoal, which may have affected the results Dose of charcoal not standardised
			Correlation between estimated plasma amitriptyline concentration half-life and dose of charcoal	Weak inverse correlation (r=0.44, p=0.25)
Schenin et al 1985 Finland	8 healthy volunteers given 50mg doxepin followed by 15g activated charcoal after 30min.	Experimental volunteer study	Peak serum doxepin concentration	Reduced by 70%	Volunteer study, small numbers Small dose of TCA and charcoal
			Total doxepin availability	Reduced by 49%
			Apparent elimination half-life of doxepin and its metaboilte	Prolonged by 350 and 140% respectively following single dose charcoal
Bosse et al 1995 United States	51 patients presenting to the ED with TCA overdose. Block randomisation to three groups: (1) 50g charcoal, 10oz magnesium citrate (2) Gastriclavage followed by 50g charcoal and 10oz magnesium citrate (3) 25g charcoal, gastric lavage, followed by 25g charcoal and 10oz magnesium citrate	PRCT	Mean serum TCA levels	No significant differences (p=0.797)	Block randomisation No sample size calculation – unknown power
			Seizures	No significant difference (p=1.000)
			Wide QRS (>0.1s)	No significant difference (p=0.472)
			Hypotension (90 systolic)	No significant difference (p=0.874)
			Sinus tachycardia (rate >100)	No significant difference (p=0.280)
			Ventricular dysrhythmias	None in any group
			Median GCS	Mean 8.5 in group 1; 8 in group 2; 12 in group 3 (p=0.242)
			Mean length of stay in hospitalised patients	No significant difference (p=0.473)
			Mean length of ICU stay	No significant difference (p=0.436)
			Mean duration of sinus tachycardia	No significant difference (p=0.594)
			Incidence of aspiration	15.7% of patients aspirated (no difference between groups, p=0.501)

Comment(s)

Experimental volunteer studies have consistently shown that administration of activated charcoal to patients who have ingested TCA within 1 hour leads to a reduction in TCA absorption and biovavailability. However, it is not possible to extrapolate these results to the clinical situation of patients with TCA overdose. Larger doses of TCA may lead to delayed gastric emptying, which may alter the observed effects of activated charcoal. Further, the risk of pulmonary aspiration may be increased. One small observational study demonstrated that time to charcoal administration was directly correlated with estimated plasma TCA half-life (Hedges JR, Otten EJ, Schroeder TJ, & Tasset JJ 1987). However, the study involved small numbers and had significant weaknesses, meaning that it is difficult to interpret the results. Three randomised controlled trials of charcoal have been reported (Bosse GM, Barefoot JA, Pfiefer MP, & Rodgers GC 1995;Hedges JR, Otten EJ, Schroeder TJ, & Tasset JJ 1987;Hulten BA, Adams R, & Askenasi R 1988). None of these trials were able to demonstrate a significant improvement in clinical outcome following charcoal administration. Further, in one study of 51 patients 15.7% of patients aspirated (Bosse GM, Barefoot JA, Pfiefer MP, & Rodgers GC 1995). As pulmonary aspiration is a significant risk in patients with TCA overdose and a well-described complication of activated charcoal administration, caution should be exercised before prescribing activated charcoal in this patient group (Dorrington CL et al. 2003;Elliott CG et al. 1989;Givens T, Holloway M, & Wason S 1992;Harris CR 1992;Isbister GK et al. 2004;Rajamani S & Allen P 2004).

Editor Comment

Updated June 4, 2008 by Rick Body

Clinical Bottom Line

There is no clinical evidence that activated charcoal is of benefit in patients with TCA overdose. Experimental data suggest that drug absorption may be reduced. Activated charcoal may be considered within 1 hour of significant drug overdose but the potential for pulmonary aspiration should be strongly considered before use.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Crome P, Dawling S, Braithwaite RA et al. Effect of activated charcoal on the absorption of nortriptyline. Lancet 1977;2(8050):1203-5.
2. Crome P, Adams R, Ali C et al. Activated charcoal in tricyclic antidepressant poisoning: pilot controlled clinical trial. Human Toxicol 1983;2(2):205-9.
3. Karkkainen S and Neuvonen PJ. Pharmacokinetics of amitriptyline influenced by oral charcoal and urinary pH. Int J Clin Pharmacol 1986;24(6):326-32.
4. Hulten BA, Adams R, Askenasi R et al. Activated charcoal in tricyclic antidepressant poisoning. Human Toxicol 1988;7(4):307-10.
5. Dawling S, Crome P, Braithwaite R. Effect of delayed administration of activated charcoal on nortriptyline absorption European Journal of Clinical Pharmacology 1978; 14: 445-7
6. Hedges JR, Otten EJ, Schroeder TJ, Tasset JJ. Correlatoin of initial amitriptyline concentration reduction with activated charcoal therapy in overdose patients. American Journal of Emergency Medicine 1987; 5: 48-51
7. Scheinin M, Virtanen R, Iisalo E. Effects of single and repeated doses of activated charcoal on the pharmokinetics of doxepin International Journal of Clinical Pharmacology, Therapy & Toxicology 1985; 24(6):326-332
8. Elliott CG, Colby TV, Kelly TM, Hicks HG. Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96(3): 672-4
9. Rajamani S; Allen P Accidental charcoal aspiration J Bronchol 2004; 11: 130-1
10. Dorrington CL, Johnson DW, Brant R The Multiple Dose Activated Charcoal Study Group. The frequency of copmlications associated with the use of multiple-dose activated charcoal Annals of Emergency Medicine 2003; 41(3):370-377
11. Bosse GM, Barefoot JA, Pfiefer MP, Rodgers GC. Comparison of three methods of gut decontamination in tricyclic antidepressant overdose. Journal of Emergency Medicine 1995; 13(2): 203-9
12. Givens T, Holloway M, Wason S Pulmonary aspiration of activated charcoal: a complication of its misuse in overdose management. Pediatric Emergency Care 1992; 8(3):137-140.
13. Harris CR Accidental administration of activated charcoal into the lung: aspiration by proxy. Annals of Emergency Medicine 1992; 22:1470-1473.
14. Isbister GK, Downes F, Sibbritt Di, Dawson AH, Whyte IM. Aspiration pneumonitis in an overdose population: Frequency, predictors and outcomes Critical Care Medicine 2004; 32:88-93