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Clinical Toxicology, 37(6), 731–751 (1999) 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 Centresand Clinical Toxicologists ABSTRACT
In preparing this Position Statement, all relevant scientific literature was identi-
fied and reviewed critically by acknowledged experts using agreed criteria.1–124
Well-conducted clinical and experimental studies were given precedence over
anecdotal case reports and abstracts were not usually considered. A draft Posi-
tion Statement was then produced and subjected to detailed peer review by an
international group of clinical toxicologists chosen by the American Academy
of Clinical Toxicology and the European Association of Poisons Centres and
Clinical Toxicologists. The Position Statement went through multiple drafts
before being approved by the Boards of the two societies.
The Position Statement includes a summary statement for ease of use and is
supported by detailed documentation which describes the scientific evidence on
which the Statement is based.
Although many studies in animals and volunteers have demonstrated that mul-
tiple-dose activated charcoal increases drug elimination significantly, this ther-
apy has not yet been shown in a controlled study in poisoned patients to reduce
morbidity and mortality. Further studies are required to establish its role and
the optimal dosage regimen of charcoal to be administered.
Based on experimental and clinical studies, multiple-dose activated charcoal
should be considered only if a patient has ingested a life-threatening amount
of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. With all
This Position Statement is endorsed by the Canadian Association of Poison Control Centres.
Copyright  1999 by Marcel Dekker, Inc.
of these drugs there are data to confirm enhanced elimination, though no con-
trolled studies have demonstrated clinical benefit.
Although volunteer studies have demonstrated that multiple-dose activated
charcoal increases the elimination of amitriptyline, dextropropoxyphene, digi-
toxin, digoxin, disopyramide, nadolol, phenylbutazone, phenytoin, piroxicam,
and sotalol, there are insufficient clinical data to support or exclude the use of
this therapy.
The use of multiple-dose charcoal in salicylate poisoning is controversial. One
animal study and 2 of 4 volunteer studies did not demonstrate increased sali-
cylate clearance with multiple-dose charcoal therapy. Data in poisoned patients
are insufficient presently to recommend the use of multiple-dose charcoal ther-
apy for salicylate poisoning.
Multiple-dose activated charcoal did not increase the elimination of astemizole,
chlorpropamide, doxepin, imipramine, meprobamate, methotrexate, pheny-
toin, sodium valproate, tobramycin, and vancomycin in experimental and/or
clinical studies.
Unless a patient has an intact or protected airway, the administration of multi-
ple-dose activated charcoal is contraindicated. It should not be used in the pres-
ence of an intestinal obstruction. The need for concurrent administration of
cathartics remains unproven and is not recommended. In particular, cathartics
should not be administered to young children because of the propensity of laxa-
tives to cause fluid and electrolyte imbalance.
In conclusion, based on experimental and clinical studies, multiple-dose acti-
vated charcoal should be considered only if a patient has ingested a life-threat-
ening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophyl-
line.
This Position Statement was drafted by JA Vale, EP Krenzelok, and GD Barceloux.
SUMMARY STATEMENT
the optimal dosage regimen of charcoal to be ad-ministered.
INTRODUCTION
• The challenge for clinicians managing poisoned patients is to identify at an early stage those who RATIONALE
are most at risk of developing serious complica-tions and who might potentially benefit, therefore, • Drugs with a prolonged elimination half-life fol- lowing overdose and small volume of distribution • Multiple-dose activated charcoal therapy involves (Ͻ1 L/kg body weight), are particularly likely to the repeated administration (more than 2 doses) of have their elimination enhanced to a clinically sig- oral activated charcoal to enhance the elimination nificant degree by multiple-dose activated char- of drugs already absorbed into the body.
• No evidence has yet been published to demon- • Multiple-dose activated charcoal is thought to pro- strate convincingly that multiple-dose activated duce its beneficial effect by interrupting the enter- charcoal reduces morbidity and mortality in poi- oenteric and, in some cases, the enterohepatic and the enterogastric circulation of drugs. In addition, • Further studies are required to establish its role and any unabsorbed drug still present in the gut will be adsorbed to activated charcoal, thereby reduc- studies in volunteers which demonstrate that the elimination of carbamazepine,41,42 dapsone,6,43 phe-nobarbital,44–47 quinine,48 and theophylline23,26,49–55is enhanced by multiple-dose activated charcoal.
ANIMAL STUDIES
• Clearance values achieved by multiple-dose acti- vated charcoal in the case of carbamazepine,89–91 In animal studies multiple-dose activated charcoal dapsone,43 and phenobarbital96,96 are comparable to has been shown to reduce the elimination half-life those produced by the more invasive techniques and increase the total body clearance of acetamin- ophen (paracetamol),1 digoxin,1 phenobarbital,2 • There is also some evidence to suggest that, con- phenytoin,3 and theophylline.1 The elimination of trary to the findings in 1 animal4 and 2 volunteer salicylate4 and valproic acid1 was not enhanced by studies,29,30 multiple-dose activated charcoal may increase the elimination of salicylate56,57; these re-sults need to be confirmed in further studies before VOLUNTEER STUDIES
• Although the elimination of digoxin was enhanced • Studies in volunteers have demonstrated that by the use of multiple-dose activated charcoal in multiple-dose activated charcoal increases the 4 experimental studies,1,8,9,10 in 3 case reports,58–60 elimination of carbamazepine,5 dapsone,6 dex- and 1 case series,61 it is unlikely that the increase tropropoxyphene,7 digitoxin,8,9 digoxin,8–10 diso- in body clearance of digoxin will be of clinical pyramide,11 nadolol,12 phenobarbital,5,13–15 phenyl- significance because of the large volume of distri- butazone,5 phenytoin,16,17 piroxicam,18 quinine,19 bution of digoxin. Moreover, severe digoxin poi- soning may be treated effectively with digoxin- • The elimination of salicylate was increased by specific antibody fragments. There is also limited multiple-dose activated charcoal in two studies,27,28 clinical evidence that multiple-dose activated char- but not in two other studies.29,30 Although a statisti- coal may increase the clearance of digitoxin.62 cally significant difference was shown, the treat- • The elimination of dapsone was increased by multiple-dose activated charcoal in volunteer and • Multiple-dose activated charcoal therapy did not increase the elimination of astemizole,31 chlor- • Although an experimental study36 did not demon- propamide,32 sodium valproate,33 tobramycin34,35 strate enhanced clearance, 2 case reports63,64 sug- gest that multiple-dose activated charcoal may in- • The elimination half-life of amitriptyline,37 but not of doxepin38 or imipramine,39 was also reduced by • Multiple-dose activated charcoal does not appear multiple-dose activated charcoal in volunteer stud- to increase the clearance of meprobamate,65,66 ies. Crome et al.40 showed a significant reduction methotrexate,67 phenytoin,68–72 tricyclic antidepres- in the area under the curve (AUC) of nortriptyline sants,73,74 and valproic acid75 in patients who have after multiple-dose activated charcoal. However, ingested or been administered these drugs.
there are good pharmacokinetic reasons to suggestthat in the case of tricyclic antidepressants, a clini- INDICATIONS
cally-significant increase in body clearance is un-likely to result from the use of such treatment, • The use of multiple-dose activated charcoal should even though the apparent half-life may be short- be considered if the patient has ingested a life- threatening amount of carbamazepine, dapsone,phenobarbital, quinine, or theophylline, and may CLINICAL STUDIES
obviate the need for invasive extracorporeal tech-niques in these cases.
• Clinical studies of multiple-dose activated char- • The ultimate decision to use multiple-dose acti- coal consist only of case series and reports.
• Studies in poisoned patients have confirmed those the physician’s clinical judgment regarding the expected outcome in a patient poisoned Relative
with carbamazepine, dapsone, phenobarbital,quinine, or theophylline; • Decreased peristalsis (decreased bowel sounds, the presence of a contraindication to the use abdominal distension, ileus) such as occurs fol- lowing overdoses of drugs with opioid or anti- the effectiveness of alternative methods of • Multiple-dose charcoal should be administered cautiously in the presence of decreased peristalsiswith careful monitoring for the development of ob- DOSAGE REGIMEN
struction and for the prevention of aspiration.
• The optimum dose of charcoal is unknown but it is recommended that after an initial dose of 50– COMPLICATIONS OF USE
100 g to an adult, activated charcoal should be ad-ministered at a rate of not less than 12.5 g/h or • Treatment with multiple-dose activated charcoal is equivalent. Lower doses (10–25 g) of activated relatively free from serious side-effects, although charcoal may be employed in children less than 5 transient constipation may occur if aqueous char- years of age as usually they have ingested smaller coal is administered in substantial dose, particu- overdoses and their gut lumen capacity is smaller.
larly in nonambulatory patients due to a depressed Activated charcoal should be continued until the patient’s condition and laboratory parameters, in- • Occasionally, bowel obstruction has been reported cluding plasma drug concentration, are improving.
necessitating manual evacuation or surgical inter- It may be difficult in clinical practice to administer substantial doses of activated charcoal because of • Regurgitation, with subsequent aspiration into the drug-induced vomiting such as occurs with the- lungs of gastric contents containing charcoal, or ophylline in overdose. Smaller doses (and there- direct installation of charcoal into the lungs as a fore smaller volumes) of activated charcoal admin- result of a misplaced nasogastric tube, has led istered more frequently may reduce the likelihood rarely to severe pulmonary complications and of vomiting. However, it is often necessary to give death.112,117–119 Emesis of aqueous activated char- an antiemetic intravenously to ensure satisfactory coal occurs infrequently. The incidence appears to administration of charcoal, even by a nasogastric be greater when activated charcoal is administered CO-ADMINISTRATION OF A
CATHARTIC
SUPPORTING DOCUMENTATION
INTRODUCTION
• The need for concurrent administration of a cathar- tic, such as sorbitol, remains unproven and is not Charcoal is prepared from vegetable matter, usually recommended. In particular, a cathartic should not peat, coal, wood, coconut shell, or petroleum. Charcoal be administered to young children because of the is ‘‘activated’’ by heating it at high temperature in a propensity to cause fluid and electrolyte imbal- stream of oxidizing gas (e.g., steam, carbon dioxide, air) or with an activating agent, such as phosphoric acid orzinc chloride, or by a combination of both. The processof activation creates a highly developed internal pore CONTRAINDICATIONS
structure and thereby increases the surface area from 2– Absolute
4 m2/g to an area in excess of 1500 m2/g. Medicinal acti-vated charcoal must meet BP, USP, or similar standards and have a surface area of at least 900 m2/g.
Multiple-dose activated charcoal therapy is the re- • A gastrointestinal tract not anatomically intact peated administration (more than 2 doses) of oral acti- vated charcoal with the intent of enhancing drug elimina- that the concentration there is lower than that in blood. The rate of passive diffusion depends on Multiple-dose activated charcoal is perceived as a the concentration gradient and the intestinal sur- simple, inexpensive, and safe therapy which may avoid face area, permeability, and blood flow. Under the need for more invasive procedures such as hemo- these ‘‘sink’’ conditions, a concentration gradient dialysis and hemoperfusion. While studies in volunteers is maintained and the drug passes continuously demonstrate that its administration both reduces the elim- into the gut lumen where it is adsorbed to char- ination half-life and increases drug clearance of some coal. This process has been termed ‘‘gastrointesti- drugs, most of the clinical data supporting the use of nal dialysis.’’78 Animal studies have confirmed multiple-dose activated charcoal are anecdotal case re- that activated charcoal significantly interrupts the ports. Controlled clinical studies are necessary to estab- enteroenteric circulation of phenobarbital.79 Interrupting the enterohepatic and the enterogas-tric circulation of drugs.
METHODOLOGY
In preparing this Position Statement all relevant scien- ANIMAL STUDIES
tific literature was identified by searching Medline, Tox-line, and EMBASE using the terms ‘‘activated char- Acetaminophen (Paracetamol). Acetaminophen 30
coal,’’ ‘‘multiple-dose activated charcoal,’’ and ‘‘repeat mg/kg was administered intravenously over 12 minutes dose activated charcoal.’’ The original papers were ob- with 3 other drugs (aminophylline, digoxin, valproic tained and reviewed critically by a group of clinical toxi- acid) to 7 pigs with an indwelling gastrostomy tube.1 Ac- cologists chosen by the 2 sponsoring Societies. A draft tivated charcoal 25 g with sorbitol (48 g) was adminis- Position Statement was produced which went through tered as the initial intervention at time zero and an aque- multiple drafts before being approved by the Boards of ous slurry of activated charcoal (25 g) was administered at 2, 4, 6, 12, 18, 24, and 30 hours via the gastrostomytube. The mean acetaminophen half-life was reduced sig- RATIONALE
nificantly (p Ͻ 0.01) from 1.7 Ϯ (SD) 0.2 hours to 1.4 Ϯ0.3 hours and significantly increased (p Ͻ 0.01) the clear- Drugs with a prolonged elimination half-life following ance from 4.57 Ϯ 0.54 mL/min/kg to 5.41 Ϯ 0.63 mL/ overdose are likely to have their elimination enhanced by multiple-dose activated charcoal.1,76 Other relevant phar- Aspirin. In a crossover study, 6 fasted pigs received
macokinetic factors include volume of distribution (Ͻ1 aspirin 300 mg/kg intravenously followed by no treat- L/kg body weight), pKa, and protein binding. If multiple- ment or activated charcoal 1 g/kg every hour for 6 doses dose activated charcoal therapy is initiated during a [the first dose contained sorbitol (70%) 4 mL/kg] via a drug’s distributive phase, particularly if it is long, it may gastrostomy tube.4 There were no statistical differences have a considerable pharmacokinetic effect by inter- between the control and treatment arms. Mean peak se- rupting drug distribution into tissues.1 In addition, if a rum salicylate concentrations were 474 Ϯ 62 mg/L and major route of elimination is no longer available due to 484 Ϯ 3.9 mg/L, respectively (p ϭ 0.74), and the AUC the onset of organ failure, this treatment has the potential over 6 hours was 171,000 Ϯ 24,000 mg ⋅ min/L in the to make a contribution to total body clearance of the drug control group and 188,000 Ϯ 18,000 mg ⋅ min/L in the ingested which is clinically beneficial.
Digoxin. Seven female pigs were administered di-
goxin 30 µg/kg intravenously together with 3 other drugs MECHANISMS OF ACTION
(aminophylline, digoxin, valproic acid).1 Activated char-coal (25 g) with sorbitol (48 g) was administered as the Multiple-dose activated charcoal is thought to produce initial intervention at time zero and an aqueous slurry of activated charcoal (25 g) was administered at 2, 4, 6, 12, Binding any drug which diffuses from the circula- 18, 24, and 30 hours via an indwelling gastrostomy tube.
tion into the gut lumen.77 After absorption, a drug The half-life was reduced significantly (p Ͻ 0.001) from will reenter the gut by passive diffusion provided a mean of 64.8 Ϯ (SD) 23.7 hours to 17.2 Ϯ 5.6 hours.
Clearance was increased from 2.33 Ϯ 0.85 mL/min/kg nophylline) 8.9 mg/kg intravenously over 12 minutes to to 7.05 Ϯ 1.42 mL/min/kg (p Ͻ 0.001).
7 pigs that were also coadministered digoxin, acetamino- Phenobarbital (Phenobarbitone). Arimori and Na-
phen, and valproic acid. Activated charcoal (25 g) with kano2 administered phenobarbital 10 mg/kg body weight sorbitol (48 g) was administered as the initial intervention intravenously to 5 fasted Wistar strain male rats. Acti- at time zero and an aqueous slurry of activated charcoal vated charcoal 300 mg was given orally at time zero and (25 g) was administered at 2, 4, 6, 12, 18, 24, and 30 then in a dose of 150 mg at 1, 2, 3, 4, and 6 hours after hours via a gastrostomy tube after the initiation of the dosing. The mean phenobarbital elimination half-life was aminophylline infusion. The mean (ϮSD) theophylline reduced significantly (p Ͻ 0.05) from 8.52 Ϯ (SEM) 0.62 half-life was reduced from 9.4 Ϯ 2.0 to 3.5 Ϯ 2.3 (p Ͻ hours to 5.71 Ϯ 0.35 hours and the mean total body clear- 0.01) hours and the AUC from 168.9 Ϯ 34.3 mg/h/L to ance of phenobarbital was increased significantly (p Ͻ 0.01) from 50.2 Ϯ (SEM) 2.73 mL/kg/h to 77.0 Ϯ 1.21 Valproic acid. Valproic acid was administered intra-
mL/kg/h. There was a significant (p Ͻ 0.01) reduction venously over 12 minutes with 3 other drugs (acetamino- in the mean AUC of 64% from 184.2 Ϯ 9.56 mcg ⋅ h/ phen, aminophylline, digoxin) to 7 pigs with an indwell- ing gastrostomy tube.1 Activated charcoal (25 g) with Phenytoin. A reduction in the elimination half-life of
sorbitol (48 g) was administered as the initial intervention phenytoin by multiple-dose activated charcoal was re- at time zero and an aqueous slurry of activated charcoal ported by Arimori and Nakano.3 Five fasted Wistar strain (25 g) was administered at 2, 4, 6, 12, 18, 24, and 30 rats were treated with activated charcoal 300 mg at time hours via the gastrostomy tube, but did not reduce sig- zero and 150 mg at 1, 2, 3, 4, and 6 hours after the admin- nificantly the half-life and AUC or increase the clearance istration of a single intravenous dose of phenytoin 10 mg/ kg or 50 mg/kg body weight. There were no statisticaldifferences between any parameters at 10 mg/kg. Themean elimination half-life at the 50 mg/kg dose fell sig- VOLUNTEER STUDIES
nificantly (p Ͻ 0.05) from 6.2 Ϯ (SEM) 0.73 hours to4.77 Ϯ 0.43 hours and the total body clearance increased Aspirin. Barone et al.27 gave activated charcoal 50 g
significantly (p Ͻ 0.01) from 0.16 Ϯ (SEM) 0.01 L/kg/ to 10 fasted volunteers at 1, 5, and 9 hours after the ad- h to 0.22 Ϯ 0.01 L/kg/h. The AUC was reduced signifi- ministration of aspirin 1944 mg. There was a statistically cantly (p Ͻ 0.01) from 311.2 Ϯ 19.3 mcg ⋅ h/mL to significant reduction (p Ͻ 0.01) in the mean % recovery of total salicylate from the urine (49.2 Ϯ 12.48%) com- Theophylline. Arimori and Nakano2 administered
pared to controls [91.0 Ϯ (SD) 6.12%]; serum sali- aminophylline 10 mg/kg body weight intravenously to 5 cylate concentrations were not measured.
fasted Wistar strain rats. Activated charcoal 300 mg was Kirshenbaum et al.28 investigated the effect of multi- given orally at time zero and then 150 mg was adminis- ple-dose charcoal therapy in 10 volunteers who were tered at 1, 2, 3, and 4 hours postdosing with aminophyl- given aspirin 2880 mg (29–59 mg/kg body weight) orally line. The mean elimination half-life was reduced signifi- which produced a mean peak serum salicylate concentra- cantly (p Ͻ 0.05) from 4.63 Ϯ (SEM) 0.49 hours to tion of 192 Ϯ (SD) 27.6 mg/L. During the treatment 2.84 Ϯ 0.20 hours and the mean total body clearance of phase, between 4 and 10 hours postingestion, each re- theophylline was increased significantly (p Ͻ 0.05) from ceived activated charcoal 25 g every 2 hours (total dose 66.7 Ϯ (SEM) 9.03 mL/kg/hour to 101.2 Ϯ 9.77 mL/ 100 g). A significant reduction (p Ͻ 0.05) in the AUC kg/h. There was a significant (p Ͻ 0.02) reduction in the of 9% was observed in the treatment phase, with an 18% mean AUC from 138.1 Ϯ 17.5 mcg ⋅ h/mL to 88.0 Ϯ reduction (p Ͻ 0.01) in total urinary excretion of sali- cylate. While concluding that the ‘‘modest’’ effect of Aminophylline was administered intravenously to 5 multiple-dose charcoal on salicylate clearance suggested dogs in doses of 50–100 mg/kg followed by duodenal it was ‘‘of questionable value’’ in the treatment of acute administration of activated charcoal 45–50 g every hour salicylate poisoning, the authors acknowledged that the for 7 hours (8 doses).80 Although mean AUC values were observed benefit would be potentially greater in severely reduced in the charcoal-treated group, no statistical anal- intoxicated patients in whom the plasma concentrations ysis was undertaken and the results are therefore uninter- would be significantly higher and the salicylate half-life substantially longer than in this study.
Chyka et al.1 administered theophylline (as ami- The administration of activated charcoal 25 g 4 hours after aspirin dosing (1300 mg orally) to 6 fasted adult administered every 6 hours for 8 doses. It should be noted volunteers, followed by 3 further doses of charcoal 10 g that in the control phase, volunteers received activated every 2 hours, did not result in a significant reduction in charcoal 50 g 5 minutes after dextropropoxyphene dos- half-life or AUC.29 Peak serum salicylate concentrations ing. The mean elimination half-life of dextropropoxy- phene was reduced significantly (p Ͻ 0.05) from 31.1 Ϯ Mayer et al.30 administered aspirin 2880 mg (33–44 (SEM) 4.2 hours to 21.2 Ϯ 3.1 hours and the mean elimi- mg/kg body weight) to 9 volunteers and 4 hours later nation half-life of norpropoxyphene was reduced signifi- activated charcoal 25 g was given and repeated every 2 cantly (p Ͻ 0.001) from 34.4 Ϯ (SEM) 2.5 hours to 19.8 hours for 4 doses. Following charcoal treatment, no sig- nificant difference was observed in the mean peak serum Digitoxin and digoxin. Park et al.8 gave 6 adult vol-
salicylate concentrations: 160 Ϯ (SD) 17 mg/L in the unteers intravenous infusions of digoxin (0.75 mg/70 kg control group and 150 Ϯ 24 mg/L in the charcoal group.
body weight) or digitoxin (1 mg/70 kg body weight) fol- No significant differences in the AUCs were observed.
lowed either by water alone or activated charcoal (20 g Astemizole. Laine et al.31 demonstrated that activated
immediately, then 20 g every 4 hours for 36 hours; a charcoal (12 g) administered twice daily (from 6 hours further 20 g dose was administered 48 hours postinfu- onwards) to 7 volunteers for 8 days did not alter the sion). The serum digoxin half-life was decreased signifi- rate of elimination or AUC (0–192 hours) of astemizole cantly (p Ͻ 0.05) from 23.1 Ϯ (SEM) 1.7 hours to 17.0 Ϯ 1.5 hours but the increase in digoxin clearance was Carbamazepine. In a randomized crossover study in
not statistically significant (p Ͼ 0.1). The half-life of 5 fasted volunteers given carbamazepine 400 mg orally, digitoxin was decreased significantly (p Ͻ 0.01) from Neuvonen and Elonen5 found the mean elimination half- 110.6 Ϯ 11.0 hours to 51.1 Ϯ 4.5 hours and digitoxin life was reduced significantly (p Ͻ 0.05) from 32 Ϯ clearance was increased significantly (p Ͻ 0.001) from (SEM) 3.4 hours to 17.6 Ϯ 2.4 hours following multiple- 0.24 Ϯ 0.01 to 0.47 Ϯ 0.04 L/h. The authors also re- dose charcoal therapy (50 g at 10 hours postdosing; 17 ported a reduction in the digoxin elimination half-life g at 14, 24, 36, and 48 hours postdosing). The mean total from 93.3 to 29.3 hours in a volunteer with chronic renal body clearance was also increased significantly (p Ͻ failure; the total body clearance of digoxin increased 0.05) from 22.0 Ϯ (SEM) 1.9 mL/min to 40.0 Ϯ 2.7 mL/ Reissell and Manninen9 found that during mainte- Chlorpropamide. Neuvonen and Ka¨rkka¨inen32 dem-
nance therapy with digoxin or digitoxin in 6 individuals onstrated that the half-life of chlorpropamide was not re- aged 60–74 years, the administration of activated char- duced significantly by the use of multiple-dose activated coal 6 g a day significantly decreased (p Ͻ 0.001) the charcoal (50 g at 6 hours followed by 12.5 g every 6 mean plasma digoxin concentration by 31.2% and re- hours for 8 hours) following the administration of chlor- duced significantly (p Ͻ 0.05) the mean serum digitoxin propamide 250 mg orally to 6 volunteers.
Dapsone. Neuvonen et al.6 administered dapsone 500
Activated charcoal (225 g over 40 hours) was given mg to 5 volunteers over 4 days (100 mg daily for 3 days to 10 healthy volunteers after the intravenous administra- and 100 mg twice daily on day 4) in a randomized cross- tion of digoxin 10 µg/kg. Charcoal increased signifi- over study. Ten hours after the last dose, subjects were cantly (p Ͻ 0.005) the total body clearance of digoxin given charcoal 50 g, then 17 g every 12 hours for an from 12.2 Ϯ (SD) 2.0 L/h to 18.0 Ϯ 2.9 L/h and the additional 4 doses. The dapsone elimination half-life was terminal half-life was reduced significantly (p Ͻ 0.005) reduced significantly (p Ͻ 0.01) from 20.5 Ϯ (SEM) 2.0 from 36.5 Ϯ (SD) 11.8 hours to 21.5 Ϯ 6.5 hours.10 hours during the control period to 10.8 Ϯ 0.4 hours after Disopyramide. Arimori et al.11 administered activated
charcoal. The half-life of the metabolite monoacetyldap- charcoal (40 g at 4 hours and 20 g at 6, 8, and 12 hours) sone was also reduced significantly (p Ͻ 0.001) during to 6 volunteers after they had been given disopyramide 200 mg orally. The mean elimination half-life was de- Dextropropoxyphene. Ka¨rkka¨inen and Neuvonen7
creased significantly (p Ͻ 0.05) from 6.09 Ϯ (SEM) 0.48 found that the elimination half-lives of dextropropoxy- hours to 4.11 Ϯ 0.45 hours and the total body clearance phene and its metabolite, norpropoxyphene, were re- increased significantly (p Ͻ 0.01) from 0.113 Ϯ (SEM) duced in 6 volunteers given activated charcoal 50 g 6 0.017 L/h/kg to 0.138 Ϯ 0.019 L/h/kg.
hours after the oral administration of dextropropoxy- Nadolol. The elimination half-life of oral nadolol 80
phene 130 mg; further doses of charcoal (12.5 g) were mg in 8 adult volunteers was reduced significantly (p Ͻ 0.05) from 17.3 Ϯ (SEM) 1.7 hours to 11.8 Ϯ 1.6 hours 18.87 Ϯ 14.70 hours and the mean (ϮSD) phenobarbital by small doses (500 mg at 3 and 4 hours after dosing and clearance was increased significantly (p Ͻ 0.0005) from then 250 mg hourly for a further 8 hours) of activated 2.79 Ϯ 9.69 mL/kg/h (control group) to 19.95 Ϯ 11.5 Phenobarbital (Phenobarbitone). Neuvonen and
Phenylbutazone. Multiple-dose activated charcoal
Elonen5 gave 5 fasted volunteers activated charcoal 50 g (50 g 10 hours postdosing; 17 g at 14, 24, 36, and 48 at 10 hours and 17 g at 24, 36, and 48 hours after the hours postdosing) reduced significantly (p Ͻ 0.05) the oral administration of phenobarbital 200 mg and found mean elimination half-life of phenylbutazone from that the mean phenobarbital elimination half-life was re- 51.5 Ϯ (SEM) 7.6 hours to 36.7 Ϯ 4.1 hours after the duced significantly (p Ͻ 0.05) from 110 Ϯ (SEM) 23 oral administration of phenylbutazone 200 mg.5 The to- hours to 19.8 Ϯ 1.0 hours. The total phenobarbital clear- tal phenylbutazone clearance was also increased signifi- ance was increased significantly (p Ͻ 0.05) from 4.6 Ϯ cantly (p Ͻ 0.05) from 1.5 Ϯ (SEM) 0.16 mL/min to (SEM) 0.9 mL/min to 23.0 Ϯ 3.0 mL/min.
Six volunteers were given activated charcoal 40 g at Phenytoin. The effect of multiple-dose activated char-
time zero and 20 g at 6, 12, 18, 24, 30, 42, and 66 hours coal on the elimination of intravenously administered following the intravenous administration of phenobarbi- phenytoin was studied in 7 fasting volunteers by Mauro tal 200 mg.13 The mean phenobarbital half-life was re- et al.16 Each participant received phenytoin 15 mg/kg in- duced significantly (p Ͻ 0.01) from 110 Ϯ (SEM) 8 hours travenously over 60 minutes which produced a mean Cmax to 45 Ϯ 6 hours, the mean total body clearance of pheno- of approximately 22 mg/L. At the end of the phenytoin barbital was increased significantly (p Ͻ 0.01) from infusion, activated charcoal 60 g with sorbitol was given 4.4 Ϯ 0.2 to 12.0 Ϯ 1.6 mL/kg/h, and the nonrenal clear- followed by 30 g (with random sobitol administration) at ance of phenobarbital was increased from 52 to 80% of 2, 4, 8, 12, 24, 30, 36, and 48 hours (total dose 300 g over 48 hours). Charcoal significantly reduced (p Ͻ 0.001) the In another study14 the effects of charcoal alone and mean phenytoin elimination half-life from 44.5 Ϯ (SD) a charcoal-sorbitol mixture on phenobarbital elimination were investigated in 6 men. Following the intravenous In another study,17 8 fasted volunteers received phe- administration of phenobarbital 200 mg/70 kg over 1 nytoin 15 mg/kg intravenously over 1 hour followed by hour, either activated charcoal 105 g or activated charcoal charcoal 140 g over 10 hours (40 g at end of the infusion; 105 g with sorbitol was given over a 36-hour period (30 20 g at 2, 4, 6, 8, and 10 hours after the infusion). Half g at end of dosing; 15 g at 6, 12, 18, 24, and 36 hours of the subjects received sorbitol in their loading dose and after dosing). The mean phenobarbital elimination half- with every other dose of activated charcoal. Administra- life (T1/2 3–60h) fell significantly (p Ͻ 0.05) from 72 Ϯ (SD) tion of activated charcoal led to a significant increase 7 hours (control) to 36 Ϯ 4 hours (charcoal alone), and (p ϭ 0.008) in mean phenytoin clearance from 15.3 Ϯ 30 Ϯ 4 hours (charcoal-sorbitol). However, there was no 3.8 mL/min/1.73m2 to 20.9 Ϯ 5.2 mL/min/1.73m2.
significant difference in the terminal elimination half-life There was a nonsignificant decrease in half-life from in each group: 102 Ϯ 19 hours (control), 119 Ϯ 22 hours 25.5 Ϯ 9.8 hours to 23.6 Ϯ 15.9 hours after charcoal.
(charcoal alone), and 116 Ϯ 25 hours (charcoal-sorbitol).
The addition of sorbitol to the treatment regimen did not The apparent mean systemic clearance of phenobarbital increased significantly (but no p value was included) Piroxicam. In a study with a randomized crossover
from 0.0895 Ϯ 0.019 mL/min (control) to 0.141 Ϯ 0.029 design and 6 volunteers, Laufen and Leitold18 studied the mL/min/kg (charcoal alone) and 0.146 Ϯ 0.036 mL/min/ use of multiple-dose activated charcoal following the ad- ministration of piroxicam 20 mg by either the oral or rec- Frenia et al.15 administered phenobarbital 5 mg/kg tal route. In the oral drug administration phase, activated to 10 volunteers. Each volunteer received 6 doses of charcoal 50 g was administered at 10 hours postingestion activated charcoal: 50 g with sorbitol (50 g of 70%) 30 followed by doses of 20–30 g for a total of 70 g every minutes after phenobarbital and five 25 g doses at 4.5, 24 hours up to 58 hours after piroxicam ingestion. The 8.5, 12.5, 16.5, and 20.5 hours; and a dose of sorbitol elimination half-life was reduced significantly (p Ͻ 0.05) (25 g of 70%) was administered at 12.5 and 24.5 hours.
from a mean (ϮSD) of 40.2 Ϯ 10.0 hours (control group) The mean (ϮSD) phenobarbital half-life was reduced to 19.6 Ϯ 5.9 hours (charcoal group). The mean apparent significantly (p ϭ 0.005) from 148.1 Ϯ 332.1 hours to total clearance increased significantly (p Ͻ 0.05) from 3.46 Ϯ 1.33 mL/min to 5.66 Ϯ 1.41 mL/min. In the rec- weight) administered to 5 volunteers was investigated by tal administration phase, activated charcoal 30 g was ad- Berlinger et al.21 Activated charcoal 40 g was given at ministered at 2 hours after drug delivery and 20–30 g time zero and 20 g at 2, 4, 6, 9, and 12 hours after comple- was given at varying intervals for a total of 70 g every 24 tion of the theophylline infusion. Treatment with acti- hours. The elimination half-life was reduced significantly vated charcoal significantly decreased (p Ͻ 0.05) the from a mean (ϮSD) of 40.7 Ϯ 12.6 hours in the control mean elimination half-life from 6.4 Ϯ (SEM) 1.2 hours group to 21.6 Ϯ 6.4 hours in the charcoal group. There to 3.3Ϯ0.4 hours. The AUC in the charcoal group was was also a significant (p Ͻ 0.05) increase in the mean 42 Ϯ 4 mg ⋅ h/L compared to 78 Ϯ 14 mg ⋅ h/L in con- (ϮSD) apparent total clearance from 3.65 Ϯ 1.19 mL/ Mahutte et al.23 administered an infusion of amino- Quinine. The effect of multiple-dose activated char-
phylline 8 mg/kg to 7 volunteers. Each then received acti- coal on quinine elimination was studied following a ther- vated charcoal 30 g at time zero and at 2, 4, and 6 hours.
apeutic (600 mg) dose of quinine bisulphate to 7 adult A significant reduction (p Ͻ 0.001) in the mean theophyl- fasted volunteers.19 Activated charcoal 50 g was adminis- line elimination half-life from 10.2 Ϯ (SD) 2.1 hours to tered 4 hours after quinine dosing and 3 further doses 4.6 Ϯ 1.3 hours was observed. The total body clearance were given over the next 12 hours. Activated charcoal of theophylline was also increased significantly (p Ͻ significantly lowered (p Ͻ 0.001) the quinine elimination 0.001) by charcoal administration from 35.6 Ϯ (SD) half-life from 8.23 Ϯ (SD) 0.57 to 4.55 Ϯ 0.15 hours and the clearance was significantly increased (p Ͻ 0.001) The effect of different regimens of multiple-dose acti- from 11.8 Ϯ (SD) 1.23 L/h to 18.4 Ϯ 2.8 L/h.
vated charcoal on the elimination of aminophylline 6 mg/ Sotalol. The mean elimination half-life of sotalol was
kg given by infusion over 1 hour in 6 volunteers was decreased significantly (p Ͻ 0.01) from 9.4 Ϯ (SEM) 0.4 investigated by Park et al.24 A significant reduction (p Ͻ hours to 7.6 Ϯ 0.3 hours by the administration of acti- 0.01) in the mean theophylline elimination half-life from vated charcoal (50 g at 6 hours, then 12.5 g every 6 hours 9.1 Ϯ (SEM) 0.7 hours was achieved either with charcoal for 8 doses) to 7 fasted adult volunteers who had received 20 g every 2 hours for 6 doses (4.3 Ϯ 0.4 hours) or 10 g every hour for 6 doses (4.3 Ϯ 0.2 hours). Park et al.25 Theophylline. The effect of activated charcoal on the-
also gave 8 volunteers aminophylline 5–6 mg/kg intrave- ophylline kinetics when a sustained-release preparation nously over 60 minutes. Immediately on discontinuing was administered orally to 20 children in a dose of 10 the aminophylline infusions, the volunteers received acti- mg/kg was studied by Lim et al.81 Five children given vated charcoal either 5 g or 20 g every 2 hours for 6 activated charcoal 1 g/kg body weight (maximum 60 g) doses. The 20 g regimen produced a significant reduction at 6, 9, and 12 hours postdosing had a 20.65% nonsig- (p Ͻ 0.01) in the halflife [4.9 Ϯ (SEM) 0.2 hours] com- nificant reduction in the AUC compared to controls.
pared to the 5 g regimen (6.3 Ϯ 0.5 hours). The AUC Minton and Henry82 administered 3 sustained-release was also reduced significantly (p Ͻ 0.01) from 88.9 Ϯ theophylline 200 mg tablets to 10 fasted volunteers. Acti- 8.4 (5 g regimen) mg/L/h to 67.7 Ϯ 3.6 mg/L/h (20 g vated charcoal 50 g was given at 6 hours, with 2 further 25 g doses at 10 hours and 14 hours. The AUC of theoph- In another study,26 6 subjects with cirrhosis were given ylline in the control group was 152.8 Ϯ (SD) 1.44 mg/ multiple-dose activated charcoal (40 g at time zero and L/h and in the charcoal group was 65.3 Ϯ 1.33 mg/L/ 20 g at 2, 4, 6, 9, and 12 hours) following an infusion of h. No statistical calculations were undertaken.
aminophylline 6 mg/kg over 1 hour. The mean theophyl- Goldberg et al.83 demonstrated that the addition of sor- line half-life during treatment was reduced significantly bitol to charcoal significantly reduced (p Ͻ 0.01) the (p Ͻ 0.05) from 12.7 Ϯ (SEM) 4.0 hours to 4.0 Ϯ 0.7 AUC [85.5 Ϯ (SEM) 10.0 mg/h/L] when compared to multiple-dose charcoal alone (113 Ϯ 5.7 mg/h/L) and Five fasted volunteers received an infusion of amino- controls (304.6 Ϯ 18.8 mg/h/L). In this study, charcoal, phylline 8 mg/kg over 1 hour followed by various acti- with or without sorbitol, was administered at 6, 7, 8, 10, vated charcoal regimens: 12.5 g every hour for 8 hours; and 12 hours after administration of slow release theoph- 25 g every 2 hours for 8 hours; 50 g every 4 hours for 8 hours.22 Each dosage regimen was preceded by activated The effect of multiple-dose charcoal on the kinetics charcoal 50 g and each subject received a total of 150 g.
of an intravenous dose of aminophylline (6 mg/kg body The mean theophylline elimination half-life was reduced significantly (p Ͻ 0.05) for each charcoal regimen com- Crome et al.40 administered 4 separate doses of acti- pared to controls, but there was no significant difference vated charcoal 5 g to 6 volunteers 30, 120, 240, and 360 between the treatment groups. Similarly, the mean AUC minutes after they had been given nortriptyline 75 mg for each charcoal regimen was significantly lower (p Ͻ orally. There was a mean 72% (range 62–78%) reduction 0.05) than controls, although there was no significant dif- (p Ͻ 0.01) in peak nortriptyline concentrations and a sig- ference between the charcoal regimens.
nificant reduction (mean 70%; range 58–76%; p Ͻ 0.01) Tobramycin. Davis et al.34 administered tobramycin
in AUC0–48 h compared to control after multiple doses of 2.5 mg/kg intravenously over 30 minutes to 6 volunteers.
charcoal. When only a single dose of activated charcoal Activated charcoal 50 g was given prior to tobramycin 5 g was administered 30 minutes after nortriptyline, there administration and subsequent doses of 15 g were admin- was a mean 58% (range 30–81%) reduction in peak istered at 2, 4, and 6 hours. There was no difference in plasma nortriptyline concentrations and a mean 55% the mean values for total body clearance of tobramycin (range 32–67%) reduction in AUC0–48 h. The difference in peak nortriptyline concentrations and AUC0–48 h after Multiple-dose activated charcoal (10 g 2 hours prior single- and multiple-dose charcoal therapy was also sig- to dosing, 10 g at zero time, and 10 g at 2, 6, and 8 hours after dosing) had no effect on the elimination of tobra- Valproic Acid. Following the oral administration of
mycin 1.5 mg/kg administered intravenously in 5 volun- sodium valproate 300 mg to 7 volunteers, multiple-dose activated charcoal 20 g was administered at 4 hours; 10 Tricyclic Antidepressants. Ka¨rkka¨inen and Neuvo-
g was given at 8, 12, 24, and 32 hours.33 Activated char- nen37 studied the impact of activated charcoal on the elim- coal did not significantly change the half-life of sodium ination of amitriptyline 75 mg administered orally to 6 valproate which was 20.0 Ϯ (SD) 6.8 hours in the control fasted volunteers. Activated charcoal 50 g was given 6 group and 22 Ϯ 9.2 hours in the charcoal group. The hours after amitriptyline dosing and further doses (12.5 AUC0–48 h after activated charcoal was 408.0 Ϯ (SD)114.5 g) of charcoal were administered at 12, 18, 24, 30, 36, mg/L/h which was not significantly different from con- 42, 48, and 54 hours. Charcoal shortened significantly (p Ͻ 0.05) the elimination half-life of amitriptyline from Vancomycin. Davis et al.36 investigated the role of
27.4 Ϯ (SEM) 4.8 hours (control) to 21.1 Ϯ 3.3 hours multiple-dose activated charcoal after the administration (charcoal group). The AUC0–72 h was also reduced sig- of vancomycin 1 g intravenously to 6 volunteers. Acti- nificantly (p Ͻ 0.05) in the charcoal group.
vated charcoal 50 g was administered before the infusion In a further study, 8 volunteers were given doxepin followed by 15 g doses at 2, 4, 6, and 8 hours after the 50 mg orally and then received activated charcoal 15 g start of the vancomycin infusion. Multiple-dose activated 3 hours later, followed by charcoal 10 g at 6, 9, 12, and charcoal therapy did not enhance vancomycin clearance.
24 hours after dosing.38 The half-life in the activated char-coal group [16.2 Ϯ (SEM) 2.3 hours] was not signifi-cantly different from the control group (17.9 Ϯ 4.3 hours) CLINICAL STUDIES
and the clearance of doxepin in the activated charcoalgroup [1.23 Ϯ (SEM) 0.31L/h/kg] was not significantly Clinical studies of multiple-dose activated charcoal different from the control group (0.93 Ϯ 0.03 L/h/kg).
consist only of case series and case reports.
The effect of multiple-dose activated charcoal on the Aspirin. Hillman and Prescott56 described 5 patients
elimination of imipramine was studied in a randomized with salicylate poisoning whose peak plasma salicylate crossover trial.39 Four fasted volunteers received imipra- concentrations were 425–655 mg/L. In 2 cases where the mine 12.5 mg/70 kg intravenously over 1 hour followed salicylate concentration exceeded 500 mg/L, alkaline di- by either water or 180 g activated charcoal over 24 hours uresis was employed initially. All patients received mul- (20 g at 0, 2, 4, 6, 9, 12, 16, 20, and 24 hours after dosing).
tiple-dose activated charcoal (75 g, then 50 g every 4 There was no significant difference (p Ͼ 0.05) in imipra- hours) until their symptoms resolved. However, the char- mine half-life in controls [9.0 Ϯ (SEM) 0.8 hours] com- coal preparation administered (Medicoal) contains sub- pared to the charcoal treated group (10.9 Ϯ 1.6 hours) stantial amounts of sodium bicarbonate and all patients or in clearance values in the control group (992.2 Ϯ 138.3 developed an alkaline urine (personal communication) mL/min/70 kg) and in the charcoal treated group which may have further increased salicylate elimination.
In a control group (selection criteria were not stated) of 6 patients with mild salicylate poisoning who were Table 1
treated with oral fluids alone, the mean elimination half- Comparison of Elimination Techniques in life was 27 hours, whereas the mean half-life in the treat- In 7 patients, all of whom had salicylate concentra- Half-life
Clearance
tions greater than 500 mg/L and who received no other Elimination
(mL/min)
therapy, Vale57 found the elimination half-life to be 9.7 Ϯ (SD) 3.0 hours after each received at least 12.5 g/h acti- vated charcoal. However, no control data were included Conclusion. One animal study and 2 of 4 volunteer
studies did not demonstrate increased salicylate clearancewith multiple-dose charcoal therapy. Data in poisonedpatients are insufficient to recommend the use of charcoaltherapy.
terms of total body clearance, multiple-dose charcoal is Carbamazepine. After multiple-dose activated char-
comparable to charcoal hemoperfusion (Table 1). How- coal (mean total dose 203 Ϯ 58 g), the mean elimination ever, a reduction in morbidity has not yet been demon- half-life in 15 patients poisoned with carbamazepine was 8.6 Ϯ (SD) 2.4 hours and the mean total body clearance Dapsone. Neuvonen et al.6 described 2 patients with
was 113 Ϯ (SD) 44 mL/min,41 whereas in 2 other series dapsone poisoning. One received activated charcoal 20 of patients treated only with supportive measures,84,85 the g every 6 hours on days 5 and 6 postingestion, with a mean elimination half-life was approximately 19 hours reduction in the elimination half-life from 88 to 13.5 [19.0 Ϯ (SD) 6.9 hours84 and 18.9 Ϯ (SD) 9.8 hours85].
hours. The second patient received charcoal 20 g every Montoya-Cabrera et al.42 administered multiple-dose 6 hours only on the third day postoverdose. A reduction activated charcoal (1 g/kg every 4 hours) to 8 patients in the dapsone elimination half-life from 33 to 11 hours (mean total dose 386 Ϯ 72 g). The mean (ϮSD) carbama- approximately was observed. Workers from the same zepine half-life was 9.5 Ϯ 1.9 hours and the mean (ϮSD) unit43 reported a further 3 patients with dapsone poison- total body clearance was 105.13 Ϯ 20.4 mL/min/kg.
ing. The initial dapsone concentrations measured be- The role of multiple-dose charcoal in carbamazepine tween 16–47 hours after ingestion were 28.0, 23.6, and poisoning was questioned by Wason et al.86 who reported 17.5 mg/L, respectively. Oral activated charcoal 20 g ev- on its use in 2 children with acute and 2 (1 with 2 epi- ery 6 hours was administered for 1 to 2 days beginning sodes of poisoning) with acute-on-chronic carbamazep- 2 to 4 days postingestion. The mean dapsone elimination ine intoxication. The peak carbamazepine concentrations half-life was reduced from 77 Ϯ (SEM) 23 hours to in this study were between 22.4 and 60.0 mg/L. The mean elimination half-life of carbamazepine was 23.3 Conclusion. Volunteer studies demonstrate that mul-
hours (1 case) without charcoal, 10.17 hours (p Ͻ 0.05) tiple-dose activated charcoal increases dapsone elimina- when activated charcoal 30–50 g was given (2 episodes tion. Clinical data support this conclusion and the elimi- of poisoning), and 7.21 hours (p Ͻ 0.05) when more than nation half-life achieved by charcoal is comparable to charcoal 50 g was used (3 episodes of poisoning). The that (10.4 Ϯ 1.7 hours) during hemodialysis.43 However, authors reported no benefit from multiple-dose charcoal it has not been demonstrated that methemoglobinemia in terms of time to complete recovery despite the effect and hemolytic anemia are less likely to result after the on the plasma half-life of the drug. However, this conclu- sion has been criticized by Vale and Heath87 who stated Digitoxin. Pond et al.62 advocated the use of multiple-
that the study was too small to test reliably the hypothesis dose activated charcoal in digitoxin poisoning, based on that there exists a relationship between the dose of acti- their experience of a patient with a peak plasma digitoxin vated charcoal and time to recovery.
concentration of 264 µg/L who received activated char- Conclusion. There is good evidence from animal and
coal 50 g initially, then 60 g (with magnesium citrate 250 volunteer studies and from poisoned patients that the total mL) every 8 hours for 72 hours. Following charcoal, the body clearance of carbamazepine is enhanced signifi- digitoxin half-life was 18 hours compared to a half-life cantly by multiple-dose activated charcoal therapy. In of 162 hours after discontinuation of charcoal.
Conclusion. Volunteer studies and 1 case report sug-
ceived oral activated charcoal 50 g every 4 to 6 hours for gest that the clearance of digitoxin may be increased by 5 doses after an initial loading dose (75 g in 1 patient).
multiple-dose activated charcoal, though clinical benefit The elimination half-lives for meprobamate were 4.4 has yet to be demonstrated. However, in severe cases of poisoning, digoxin-specific antibody fragments should be Three patients with meprobamate poisoning were treated with multiple-dose activated charcoal.66 Peak me- Digoxin. Boldy et al.58 described a 69-year-old man
probamate concentrations were 221 mg/L, 91 mg/L, and who had ingested a digoxin overdose and had a plasma 80.5 mg/L, respectively and all patients initially required digoxin concentration of 8.3 µg/L, 14.5 hours postinges- mechanical ventilation. With charcoal therapy, the elimi- tion. He received activated charcoal 100 g over 1 hour, nation half-lives for meprobamate were 4.0, 4.5, and 5.0 then 50 g every 4 hours for a further 7 doses. The plasma digoxin concentration fell to 1.0 µg/L over the ensuing Conclusion. Reports of meprobamate poisoning man-
48 hours with a terminal elimination half-life of 14 hours.
aged without multiple-dose charcoal suggest an elimina- Lake et al.59 reported a 71-year-old woman with tion half-life of about 13 hours92 and thus charcoal ther- chronic renal failure and digoxin toxicity (peak plasma apy may be effective in increasing drug elimination concentration 9 µg/L) who was treated with activated though there are no volunteer studies to confirm this.
charcoal 50 g followed by 25 g every 6 hours for 8 doses.
Methotrexate. Serum methotrexate concentrations
The digoxin elimination half-lives calculated before, dur- were estimated after a 6-hour infusion of 1 g/m2 metho- ing, and after charcoal therapy were 7.3, 1.4, and 6.3 trexate had been administered to 7 patients.67 Each re- ceived activated charcoal 25 g at 12, 18, 24, 36, and 48 Critchley and Critchley 60 described a 66-year-old hours after the infusion. The elimination half-life in the male with an 8-year history of chronic renal failure who charcoal treated group was reduced, but not significantly, was suffering from digoxin toxicity (severe bradycardia from 8.46 Ϯ (SEM) 0.47 hours (controls) to 7.6 Ϯ 0.44 and hypotension). The patient’s serum digoxin concen- tration failed to decrease over 4 days despite the use of Conclusion. This single study does not support the
daily hemodialysis. On day 4, multiple-dose activated clinical use of multiple-dose activated charcoal after charcoal therapy was instituted (50 g every 6 hours for 48 hours). The serum digoxin concentration decreased Phenobarbital (Phenobarbitone). Goldberg and
from 2.1 µg/L to 0.8 µg/L within 48 hours. A second Berlinger44 gave multiple-dose activated charcoal to 2 pa- course of activated charcoal (50 g every 6 hours for 72 tients poisoned with phenobarbital. The first patient (se- hours) was instituted from admission day 9 to 12, re- rum phenobarbital concentration 141 mg/L) received ac- sulting in a decrease in the digoxin concentration from tivated charcoal 40 g (with sodium sulfate 20 g) on 0.8 µg/L to 0.4 µg/L. During each course of activated admission and activated charcoal 40 g (with magnesium charcoal therapy, there was a precipitous reduction in the citrate 60 mL) every 4 hours for 5 additional doses. The serum half-life of digoxin, but precise half-lives were not second patient (serum concentration 107 mg/L) was given activated charcoal 30 g (and sodium sulfate 30 g) Multiple-dose activated charcoal (dose not stated) in- 6 hours after admission and this dose was continued ev- creased the mean digoxin clearance in 23 patients to 98 Ϯ ery 6 hours for a total of 6 doses. The phenobarbital elim- (SD) 34 mL/min (mean clearance in 16 nontreated pa- ination half-lives in these 2 patients were approximately tients 55 Ϯ 17 mL/min) and decreased the digoxin elimi- nation half-life from 68 Ϯ (SD) 19 hours to 36 Ϯ 14 A randomized study of 10 comatose patients who re- hours (control group); all patients had plasma digoxin quired endotracheal intubation and mechanical ventila- tion was reported by Pond et al.45 The control group (n ϭ Conclusion. The elimination half-life of digoxin was
5) who received only a single dose of activated charcoal decreased by the use of multiple-dose activated charcoal (mean plasma phenobarbital concentration 121 Ϯ 31 in animal and volunteer studies, in 2 case reports and 1 mg/L) and the treatment group (n ϭ 5) who received case series. However, in severe cases of poisoning, di- multiple doses of activated charcoal (mean plasma phe- goxin-specific antibody fragments should be considered.
nobarbital concentration 132 Ϯ 36 mg/L) both received Meprobamate. Hassan65 described a further 2 pa-
activated charcoal 50 g with magnesium citrate 250 mL tients with meprobamate poisoning whose peak plasma on presentation and, in addition, patients in the treatment concentrations were 320 mg/L and 240 mg/L. Each re- group were given activated charcoal 17 g together with sorbitol 70 mL (70%) every 4 hours until they had recov- Table 2
ered sufficiently to be extubated. Although the mean Comparison of Elimination Techniques in elimination half-life of phenobarbital was shortened (36 Ϯ (SD) 13 hours) significantly (p Ͻ 0.01) in the mul-tiple-dose charcoal treatment group when compared to Clearance
the single-dose charcoal group (93 Ϯ 52 hours), the Elimination
(mL/min)
length of time that the patients in each group required mechanical ventilation did not differ significantly and nor did the time spent in hospital. This trial has been criti- cized as being too small and having unevenly matched In another series,46 charcoal, in larger doses and given without cathartic, not only greatly enhanced the elim- ination of phenobarbital, but also decreased the timeto recovery. Six patients with moderate to severe pheno-barbital intoxication (mean peak plasma phenobarbital year-old, hepatitis B–positive, chronic alcohol abuser re- concentration 139.2 Ϯ 76.8 mg/L) were treated with re- ceiving both phenobarbital and phenytoin long-term for peated oral doses of activated charcoal 50 g (in 3 cases epilepsy. Twenty-four hours before admission his plasma the charcoal employed contained sodium bicarbonate) phenytoin concentration was 34 mg/L and on admission following an initial dose of 50 to 150 g (total dose 225– 47 mg/L, at which time features of phenytoin toxicity 500 g). During and for up to 12 hours after treatment were present. He received activated charcoal 50 g with with activated charcoal, the mean phenobarbital half-life sorbitol 96 g every 6 hours for 4 doses. The phenytoin was 11.7 Ϯ 3.5 hours. The mean total body clearance of concentration decreased to 20 mg/L approximately 44 the drug during and up to 12 hours after administration hours after admission. Since it is likely that this patient of charcoal was 84 Ϯ 34 mL/min. It is possible that in had taken an acute overdose of phenytoin and had in- the 3 patients receiving sodium bicarbonate, renal clear- duced hepatic enzymes, the benefit of multiple-dose acti- ance of phenobarbital may have been enhanced. It should vated charcoal is difficult to determine.
be noted that only one third of the patients in this series Ros and Black70 described a 17-year-old epileptic were receiving long-term anticonvulsant therapy, in con- whose serum phenytoin concentration at admission was trast to 100% of patients in the study reported by Pond 56 mg/L, rising to 69 mg/L after 24 hours. He was then treated with 9 doses of activated charcoal 30 g every 4 The administration of 6 doses of activated charcoal hours. Thirty-eight hours after the first dose of charcoal, (0.7 g/kg) to a severely brain-damaged neonate (weight the serum phenytoin concentration had fallen to 22 mg/ 2.6 kg), treated with intravenous phenobarbital (50 mg/ L. When charcoal was discontinued, the serum phenytoin kg), decreased the serum phenobarbital half-life from a concentration increased to 33 mg/L, then slowly declined.
calculated 250 hours to 22 hours, enabling earlier initia- Weichbrodt and Elliott71 reported a 38-year-old woman on long-term phenytoin therapy who was treated Conclusion. There is good evidence from animal and
with multiple-dose activated charcoal after an overdose volunteer studies and from poisoned patients that the total of phenytoin 10–15 g. She received an initial dose of body clearance of phenobarbital is enhanced significantly activated charcoal 30 g at 7 hours postoverdose, followed by multiple-dose activated charcoal therapy. In terms of by 30 g every 6 hours for 4.5 days commencing some total body clearance, multiple dose charcoal is compara- 30 hours after overdose (magnesium citrate 180 mL was ble to other elimination techniques such as hemodialysis co-administered with each dose). Her peak serum pheny- toin concentration (52 mg/L) was reached within 42.5 Phenytoin. A 21-year-old woman presented 9 hours
hours and the phenytoin concentration fell to within the after allegedly ingesting phenytoin 20 g and was treated therapeutic range 6 days postoverdose.
with 3 doses (amount not stated) of activated charcoal A further case of chronic phenytoin intoxication in a every 2 hours (time after overdose not stated). The phe- patient with severe liver disease was reported by Weidle nytoin concentration fell from 41 mg/L on admission to et al.72 Seven days after commencing phenytoin 300 mg twice daily, the patient became agitated and incoherent Howard et al.69 reported the clinical course of a 36- and the serum phenytoin concentration was found to be 44.4 mg/L. Phenytoin was discontinued and 2 days later Following a medical error,50 a patient with a peak the- (phenytoin concentration 45.2 mg/L) she was com- ophylline concentration of 42.5 mg/L was treated with menced on a multiple-dose charcoal regimen of 30 g ev- multiple-dose activated charcoal 15 g every 2 hours for ery 4 hours. After 10 doses of charcoal, the serum pheny- 4 doses and the elimination half-life was reduced from toin concentration was 11.4 mg/L. The authors estimated that the clearance had been increased by approximately A 23-year-old woman attempted suicide by ingesting theophylline and terbutaline tablets.51 The peak (on ad- Conclusion. Although there is some evidence from
mission) serum theophylline concentration was 111.4 animal and volunteer studies that multiple-dose activated mg/L. Treatment with multiple-dose activated charcoal charcoal may enhance phenytoin elimination, the 5 anec- 50 g every 6 hours led to a reduction in the theophylline dotal case reports published to date do not confirm that this therapeutic approach is of clinical benefit.
Two adolescents with serum theophylline concentra- Quinine. In 5 symptomatic patients with acute quinine
tions greater than 100 mg/L were treated with a continu- poisoning, the mean elimination half-life was 8.1 Ϯ (SD) ous nasogastric infusion of activated charcoal at a maxi- 1.1 hours after each had been administered activated mum rate of 50 g/h.52 During the first 20 hours of charcoal 50 g every 4 hours.48 This should be compared to charcoal therapy, the elimination half-life of theophylline a half-life of approximately 26 hours in poisoned patients was estimated as 7.7 and 13.5 hours, respectively, de- creasing subsequently to 2.6 and 3.2 hours.
Conclusion. A volunteer study has demonstrated that
Sessler et al.53 reported 14 cases of theophylline poi- quinine elimination is enhanced significantly by multiple- soning, 10 of whom were treated with activated charcoal.
dose activated charcoal and a single clinical study has Although several patients vomited charcoal, the mean confirmed this observation, even though the relatively theophylline half-life during charcoal therapy was 5.6 Ϯ large volume of distribution (Ͼ1–2.7 L/kg) and high pro- tein binding (70–90%) do not favor the use of charcoal A further 5 cases, including one reported previously therapy. Further studies are required to demonstrate that by Amitai et al.49 of theophylline poisoning due to medi- the serious sequelae encountered in quinine poisoning are cal error in infants under 7 months old, were reported by reduced or even abolished by charcoal therapy.
Shannon et al.54 Multiple-dose activated charcoal re- Theophylline Poisoning. Mahutte et al.23 reported a
sulted in an elimination half-life of 8.3 Ϯ (SD) 4.7 hours 72-year-old man with theophylline poisoning (admission concentration 31 mg/L) in whom 4 doses of activated Conclusion. Patients poisoned severely with theoph-
charcoal 30 g every 2 hours reduced the pretreatment ylline are invariably vomiting repeatedly which makes half-life from 34.4 to 5.7 hours. Workers from the same administration of charcoal problematic, even via a nasog- unit subsequently described 4 further patients [mean Ϯ astric tube. In these circumstances the use of an anti- (SD) pretreatment theophylline concentrations were emetic intravenously should be considered. Studies in an- 37.1 Ϯ 11.25 mg/L] in whom multiple-dose charcoal re- imals and volunteers confirm that the elimination of duced the mean serum theophylline half-life from theophylline is enhanced by multiple-dose activated char- 23.30 Ϯ (SD) 7.95 hours to 8.0 Ϯ 3.95 hours.55 coal. Case reports also suggest that theophylline elimina- Five patients with moderate theophylline poisoning tion is increased by this means although further studies who were treated with multiple-dose charcoal were re- are required to demonstrate that morbidity is reduced by ported by Radomski et al.26 The mean serum theophylline half-life (ϮSEM) was 4.9 Ϯ 0.8 hours with peak serum Tricyclic Antidepressants. Swartz and Sherman73 ad-
theophylline concentrations ranging from 32–59 mg/L.
ministered activated charcoal to 3 patients poisoned with Amitai et al.49 reported 2 patients (a 34-year-old amitriptyline. The first patient received 2 doses (50 g at woman and a 5-month-old infant) with theophylline poi- 2 hours and 25 g at 10 hours postoverdose) of activated soning (peak plasma concentrations 100 mg/L and 97 charcoal, the second patient received 3 doses (50 g at 2 mg/L, respectively). With activated charcoal 15 g hourly hours, 25 g at 6 hours, and 25 g at 23 hours postover- for 9 doses commencing 14 hours after overdose, the dose), and the third patient received 4 doses (40 g at 1 adult patient’s theophylline elimination half-life fell to hour, 20 g at 4 hours, 20 g at 9 hours, and 20 g at 21 3.7 hours. The infant received 3 doses of activated char- hours postoverdose) of activated charcoal. Although the coal: 10 g at 4.5 hours, 5 g at 8 hours, and 2.5 g at 11 authors concluded that charcoal ‘‘greatly accelerated tri- hours postoverdose. The initial elimination half-life of 19 cyclic elimination,’’ this cannot be supported from the hours decreased to 2.4 hours after charcoal.
Three patients poisoned with dothiepin received acti- cedure are experienced in its use both to reassure the con- vated charcoal 100–200 g following overdose.74 The scious patient and to reduce the risk of complications in mean elimination half-life was 12.1 Ϯ (SD) 1.3 hours, which is not substantially different from cases treated A patient should be told that large and repeated doses of activated charcoal need to be given and that its admin- Conclusion. A variable effect on the elimination half-
istration may lead to a faster recovery. If appropriate, the life of amitriptyline, doxepin, and imipramine has been patient should be informed that the treatment is to be reported in volunteer studies. However, it would not be given via a nasogastric tube. Such an approach is manda- expected from the very large volume of distribution of tory if the patient is unconscious but may also be neces- tricyclic antidepressants that their elimination would be sary if the individual is nauseated or vomiting.
If a patient has ingested a drug in overdose which in- Valproic Acid. A 26-month-old infant ingested a min-
duces nausea and vomiting, the administration of acti- imum of 4.5 g enteric-coated valproic acid. On arrival at vated charcoal, particularly if it contains sorbitol, may hospital, activated charcoal 20 g was administered (no produce emesis. In these circumstances it is appropriate detectable valproic acid in the serum) and following a to administer an antiemetic intravenously to ensure com- marked clinical deterioration (serum valproic acid 315 pliance. Alternatively, smaller, more frequent doses of mg/L), gastric infusion of 3 g/h activated charcoal was charcoal may be used but are not always retained.
given from 9 hours to 25 hours postoverdose.75 The elimi- The dose of administered charcoal is probably of nation half-life was 4.8 hours, which is shorter than the greater importance than the surface area of the char- 23 hours reported by Dupuis et al.100 coal.101 In a study involving 6 volunteers, activated char- Conclusion. The elimination of sodium valproate was
coal 20 g, given every 2 hours, produced a significantly not enhanced in animal and volunteer studies by the use greater reduction in the half-life of theophylline than 5 of multiple-dose charcoal therapy. It is possible that at g every 2 hours.24 In addition, administering the same higher plasma drug concentrations, when more free drug total dose of activated charcoal (120 g over 12 hours) in is likely to be present, such therapy could have greater hourly doses rather than less frequently resulted in a fur- benefit. Further studies are needed to confirm this.
ther reduction in half-life. Ilkhanipour et al.22 have also Vancomycin. A 17-day-old neonate was administered
confirmed that activated charcoal 12.5 g every hour (total vancomycin 500 mg intravenously. Multiple-dose acti- dose 150 g over 12 hours) produced the greatest reduction vated charcoal 1 g/kg was administered 5 hours later and in theophylline elimination half-life. Moreover, the more continued every 4 hours for 12 doses.64 The half-life of frequent administration of smaller doses of activated vancomycin was calculated to be 9.4 hours.
charcoal tends to prevent regurgitation which commonly A 47-day-old premature neonate received an overdose occurs when large doses are given. There is some evi- of vancomycin as a result of medical error. Exchange dence that a continuous gastric infusion of charcoal, at transfusion did not change the measured serum vancomy- least after a large initial dose (50–100 g), may offer ad- cin concentration. Multiple doses of activated charcoal 1 g/kg were administered through a nasogastric tube every Clinical experience suggests that, after an initial dose 4 hours (9 doses in all) beginning 5 hours after exchange of 50–100 g given to an adult, charcoal may be adminis- transfusion. The calculated half-life prior to and after tered hourly, every 2 hours, or every 4 hours at a dose charcoal therapy was 35 hours and 12 hours, respectively.
equivalent to 12.5 g/h. In children, lower doses (10–25 g) During therapy the serum vancomycin concentration fell of charcoal may be employed because smaller overdoses have usually been ingested and the capacity of the gut Conclusion. The elimination of vancomycin was not
increased by multiple-dose activated charcoal in a volun-teer study. The apparent greater benefit of this treatmentin 2 case reports is suggestive of benefit but further stud- CO-ADMINISTRATION OF A
ies are required to confirm efficacy.
CATHARTIC
The role of cathartics, such as sorbitol, mannitol and DOSAGE REGIMEN
sodium, and magnesium sulfate, remains controversial.
They are often given at the same time as activated char- If multiple-dose activated charcoal is considered ap- coal in order to increase palatability. Sorbitol sweetens propriate, it is essential that the staff undertaking the pro- the mixture but palatability is not relevant if administra- tion is via a nasogastric tube. Some studies (but not oth- ther case of small bowel obstruction has been reported ers) suggest that the co-administration of a cathartic may in a patient poisoned with amitriptyline who required a not only reduce drug adsorption to charcoal but, paradox- laparotomy 5 days after admission to remove a charcoal ically, increase absorption by increasing the volume of bezoar in the distal ileum; activated charcoal 30–60 g intestinal fluid.102 Furthermore, mannitol and sorbitol de- had been given every 4 to 6 hours for 5 days.107 lay gastric emptying in man,103 thereby reducing the Atkinson et al.108 have described a 24-year-old patient amount of charcoal available to adsorb the drug in the intoxicated with barbiturates and benzodiazepines who small bowel. More recent evidence, however, indicates required a limited right hemicolectomy after he devel- that in man the co-administration of a cathartic to char- oped small bowel obstruction due to a large bolus of in- coal may further hasten the elimination of phenobarbital14 spissated charcoal in the caecum. A total of 125 g of acti- and of a slow-release theophylline preparation,83 although vated charcoal was administered over 18 hours.
the combined use of sorbitol and charcoal was not with- A rectal ulcer with massive hemorrhage followed the out adverse effects. Two of the 9 volunteers in the latter administration of activated charcoal 50 g with magne- study developed liquid stools, severe abdominal cramps, sium sulfate 50 g in a 1000 mL slurry every 4 to 6 hours nausea, sweating, and hypotension. However, Al-Shareef for 50 hours to a patient with organophosphorus insecti- et al.104 did not demonstrate an additional benefit from cide poisoning.109 Bloody stools did not occur until 10 the use of a sorbitol-charcoal formulation in the manage- days after she had ingested fenitrothion and passed hard ment of theophylline poisoning. Cathartics theoretically decrease the risk of constipation and hence small bowel Goulbourne and Cisek110 have reported the develop- obstruction if very large doses of activated charcoal are ment of gastrointestinal obstruction 5 days after a patient poisoned with theophylline was given activated charcoal The need for a cathartic as part of a multiple-dose acti- 350 g. The patient underwent laparotomy with lysis of vated charcoal regimen remains unproven and many clin- low-grade adhesions at the ileo-caecal region, for which ical toxicologists have not found it necessary to employ an ileotransverse colostomy was performed. On opening cathartics in clinical practice. While the use of sorbitol the bowel, several charcoal clumps were removed mea- produces a more rapid onset of catharsis without the de- velopment of hypermagnesemia associated with the use An obstructing charcoal mass (120 g) was found at of magnesium containing cathartics, it too has well recog- the site of an intestinal perforation in a 39-year-old fe- nized complications. It is probable that the increased male who was receiving maintenance methadone and morbidity from its use will outweigh any potential benefit who had ingested a modest overdose of amitriptyline.111 (see Position Statement on Cathartics105) and therefore the Apart from lethargy, she was asymptomatic but was pre- concurrent administration of a cathartic is not recom- scribed activated charcoal 50 g every 4 hours; she de- mended. In particular, cathartics should not be adminis- clined more than 100 g. Four days later after 2 enemas, tered to young children because of the propensity of laxa- tives to cause fluid and electrolyte imbalance.
Respiratory Complications
COMPLICATIONS OF USE
In some reports it is unclear whether the respiratory complications described were due to the well recognized The administration of multiple-dose activated char- consequences of aspiration of gastric contents into the coal rarely produces clinically-important side-effects.
lung or the aspiration of activated charcoal specifically.
Black stools and mild transient constipation are well rec- In one instance the presence of povidone in the charcoal ognized but constipation is not usually severe enough to formulation was thought to be the major factor.112 require treatment, even if a cathartic has not been co- Severe airway obstruction has been reported in one infant given charcoal after vomiting was induced bysyrup of ipecac.113 Accidental administration of activated Gastrointestinal Complications
charcoal into the lung produced an adult respiratory dis-tress syndrome but the patient recovered and was dis- An adult patient treated for carbamazepine poisoning charged home 14 days later.114 Even if recovery results, with activated charcoal 240 g and magnesium citrate 600 cerebral anoxic damage may have occurred.115 Bronchio- mL developed an ileus which resolved with the adminis- litis obliterans has followed aspiration of activated char- tration of additional doses of magnesium citrate.106 A fur- Six cases of fatal pulmonary aspiration of charcoal activated charcoal on digoxin and digitoxin clearance.
have been reported,112,117–119 but in 1 case112 this was prob- Drug Intell Clin Pharm 1985;19:937–941.
ably due to the povidone in the formulation rather than Reissell P, Manninen V. Effect of administration of acti- vated charcoal and fibre on absorption, excretion andsteady state blood levels of digoxin and digitoxin. Evi-dence for intestinal secretion of the glycosides. Acta Fluid, Electrolyte, and Acid-Base Abnormalities
Med Scand 1982;668(Suppl):88–90.
Lalonde RL, Deshpande R, Hamilton PP, McLean WM, The co-administration of cathartics may produce hy- Greenway DC. Acceleration of digoxin clearance by ac- pernatremia,120–122 hypokalemia, hypermagnesemia,123–124 tivated charcoal. Clin Pharmacol Ther 1985;37:367–
and metabolic acidosis, particularly in infants.
Arimori K, Kawano H, Nakano M. Gastrointestinal di-alysis of disopyramide in healthy subjects. Int J Clin ACKNOWLEDGEMENTS
Pharmacol Ther Toxicol 1989;27:280–284.
Du Souich P, Caille´ G, Larochelle P. Enhancement ofnadolol elimination by activated charcoal and antibiot- The AACT and EAPCCT gratefully acknowledge the con- ics. Clin Pharmacol Ther 1983;33:585–590.
tributions of Jeffrey Brent, Albert Jaeger, Michael McGuigan, Berg MJ, Berlinger WG, Goldberg MJ, Spector R, John- Jan Meulenbelt, and Milton Tenenbein who reviewed the final son GF. Acceleration of the body clearance of phenobar- draft Statement. The Societies are also grateful for the assis- bital by oral activated charcoal. N Engl J Med 1982; tance of the following members of the UK National Poisons 307:642–644.
Information Service (Birmingham Centre) in the production of Berg MJ, Rose JQ, Wurster DE, Rahman S, Fincham this Position Statement: Sally Bradberry, Sarah Cage, Marie RW, Schottelius DD. Effect of charcoal and sorbitol- Dodd, Wayne Harrison, Giselle Jones, Barbara Reeves, and charcoal suspension on the elimination of intravenous phenobarbital. Ther Drug Monit 1987;9:41–47.
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Source: http://www.aacvpr.aactox.org/documents/positionpapers/MultipleDoseActivatedCharcoal.pdf