LEADI G ART ICLE

Drug Safety 7 (I): 3·7, 1992 0114·5916/ 92/0001·0003/$02.50/0 © Adis International Limited. All rights reserved. DRS1530

Activated Charcoal in the Treatment of Drug Overdose An Update

Wesley Palatnick and Milton Tenenbein Department of Family Medicine and Departments of Pediatrics, Pharmacology and Medicine, University of Manitoba, and the Manitoba Poison Control Centre, Winnipeg, Manitoba, Canada

The administration of activated charcoal is a well established treatment for patients with acute poisoning. Comprehensive reviews have been published elsewhere (Cooney 1980; Neuvonen 1982). It is used both to prevent the absorption of swallowed poisons and to enhance their excretion from the bloodstream (Neuvonen & Olkkola 1988). The former is accomplished by a large single dose given soon after ingestion, while the latter involves the administration of multiple smaller doses during the early course of the poisoning. In this update we review 2 contentious issues; the optimal dose of activated charcoal and the concomitant use of cathartics. We then discuss combining charcoal with whole bowel irrigation and conclude with a discussion of the current status of single- and multiple-dose activated charcoal therapy. Specifically, a single dose of activated charcoal is being widely advocated as the sole gastrointestinal decontamination procedure for patients with poisoning, and the role of multiple-dose activated charcoal has recently been questioned.

1. Optimal Dose of Activated Charcoal There is uncertainty regarding the optimal dose of activated charcoal. Recommendations have been based on the amount of the ingestion or the patient's weight, while others favour an empiric

dose unrelated to either. Historically, the common recommendation was to administer 10 times the amount of the ingested toxin (Picchioni 1970); however, this is impractical because that information is rarely known. Basing a dose of a therapeutic agent on the patient's weight is commonly done with the intent being to maximise the therapeutic result and minimise the risk of adverse effects. However, in the case of activated charcoal this is illogical because it lacks agonistic activity. The common recommendation of 1 gjkg seems to originate from a statement made in a review article (Neuvonen 1982), but we were unable to locate any supportive data. This can lead to underdosing, particularly in young children, For example, a toddler might only receive 15g which would be insufficient to overcome competition from gastrointestinal contents. Because of mass action, large doses are needed to enhance adsorption to, and to prevent desorption from, activated charcoal. This is supported by Levy and Tsuchiya (1972) who demonstrated increased adsorption by activated charcoal with increased dose despite a constant charcoal: toxin ratio of 10 : I. Also, the I gjkg dose is rather impractical for the nurse who is requested to measure and administer a nonunit dose of charcoal. We recommend the administration of as much as possible with the limitation being patient tol-

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Drug Safety 7 (1) 1992

erance. Experience supports doses of 25 to 50g for children less than 5 years old, and 50 to l00g for older children and adults. For those patients who have ingested large gram quantities of a drug, as is often the case for paracetamol (acetaminophen) or aspirin (acetylsalicylic acid), the administration of greater amounts should be considered.

2. Concomitant Cathartic Therapy The use of cathartics with activated charcoal is a common practice and has been extensively reviewed elsewhere (Riegel et al. 1981; Shannon et al. 1986). The 2 reasons usually cited to support this practice are to counteract the constipating effects of charcoal and to hasten the elimination of the charcoal toxin complex, thus decreasing the opportunity for drug desorption. There is no evidence that single-dose charcoal has a constipating effect, with the mean time to first stool being 23.5h (Krenzelok et al. 1985). Minimising the effects of desorption by decreasing gastrointestinal transit time is an attractive hypothesis, but 5 human studies did not show decreased drug absorption when carthartics were added to charcoal (Easom et al. 1982; Mayersohn et al. 1977; McNamara et al. 1988; Neuvonen & Olkkola 1986; Sketris et al. 1982). A modest treatment effect of a 14.2% decrease in salicylate absorption when sorbitol was added to charcoal was demonstrated by Keller et al. (1990), which is of questionable clinical significance. Adverse effects, morbidity and even mortality have been associated with the use of carthartics. These include thirst, severe abdominal cramps, fluid and electrolyte abnormalities, hypermagnesaemia and iatrogenic death (Brent et al. 1989; Caldwell et al. 1987; Farley 1986; Jones et al. 1986; Keller et al. 1990; McCord & Okun 1987; McNamara et al. 1988).

3. Combining Activated Charcoal with Whole Bowel Irrigation Whole bowel irrigation with polyethylene glycol-electrolyte lavage solution has been described as a gastrointestinal decontamination procedure for

selected poisoning patients (Tenenbein 1988). A recent in vitro study examined the effectiveness and safety of combining activated charcoal with whole bowel irrigation. It was found to be safe, as there was only a minor decrease in the osmolality of the irrigating solution after the addition of charcoal. However, combination with lower doses of activated charcoal, comparable with the amounts that would be used with multiple-dose charcoal therapy, resulted in decreased salicylic acid adsorption, probably due to competition with the polyethylene glycol for charcoal binding sites. It was concluded that a large initial charcoal dose prior to the initiation of whole bowel irrigation is appropriate; however, the combination of multiple doses of activated charcoal during whole bowel irrigation provides no additional benefit (Kirshenbaum et al. 1990b).

4. Charcoal as the Sole Intervention for Gastrointestinal Decontamination Gastrointestinal decontamination is a key aspect of poisoning management. The administration of activated charcoal alone is gaining favour as the sole intervention, replacing both gastric lavage and induced emesis. Absolute proof supporting 1 intervention over others is probably unobtainable and would not be expected from 1 study. However, when the studies are considered as a group, charcoal alone emerges as the favoured approach. Evidence can be divided into 3 categories: descriptive toxin recovery data, controlled human volunteer subtoxic ingestion studies, and large clinical outcome studies. 4.1 Descriptive Toxin Recovery Data Iron is a unique ingestant because its presence can be documented by abdominal radiographs. Radiographs taken before and after ipecac or gastric lavage have shown the relative ineffectiveness of these interventions (Tenenbein 1985, 1987). Both adherence of iron to the gastric wall and the presence of tablet concretions had been excluded. Recently, Saetta and Quinton (1991) demonstrated the

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Update on Activated Charcoal

disappointing efficacy of gastric emptying procedures in 30 emergency department overdose patients. They performed gastroscopies after ipecac-induced emesis or gastric lavage and found two-thirds of patients had residual intragastric material. These data are not especially strong but tend to discredit both ipecac and gastric lavage; however, they do not provide evidence that activated charcoal is effective. 4.2 Controlled Human Volunteer Subtoxic Ingestion Studies Recently, Saetta et al. (1991) studied gastric emptying procedures using radiopaque pellets in emergency department patients. As well as showing relative ineffectiveness, they also found that both ipecac and gastric lavage increase the rate of anterograde gastric emptying into the small bowel. This could result in earlier time to peak or higher peak drug concentrations, and it also decreases the opportunity for intragastric charcoal adsorption of the ingestant. There have been relatively few controlled human studies comparing activated charcoal with the gastric emptying procedures. In an aspirin model with interventions at I h, prevention of absorption was 30 and 44% for ipecac and charcoal, respectively (Curtis et al. 1984). In an ampicillin overdose model, also with interventions at I h, prevention of drug absorption was 32, 38 and 57% for ipecac, gastric lavage and charcoal, respectively (Tenenbein et al. 1987). The first study, like the preceding group of descriptive toxin recovery studies, discredits ipecac and lavage but does not directly support charcoal. However, its strength is that it provides objective, controlled, quantitative data. Direct support for activated charcoal is provided by the latter 2 studies, which compare charcoal with the gastric emptying procedures. 4.3 Clinical Outcome Studies Three large prospective studies have compared traditional gastric decontamination with activated charcoal alone. Clinical course and outcomes were

used to judge the effectiveness of these 2 approaches. A controlled randomised trial of 592 patients with acute overdose compared ipecac and activated charcoal with activated charcoal alone in awake patients, and gastric lavage and activated charcoal with activated charcoal alone in obtunded patients (Kulig et al. 1985). Neither the ipecac- nor the gastric lavage-treated patients fared differently from their charcoal controls. The only exception was for obtunded patients treated with gastric lavage within I h of overdose. They seemed to fare better; however, these data were not especially strong. A similar study compared ipecac and activated charcoal with activated charocal alone in 200 adults with mild to moderate overdoses (Albertson et al. 1989). It showed no differences in clinical course or outcome, but found a higher complication rate, 5.4 versus 0.9%, with combined therapy versus charcoal alone. Similarly, Merigian et al. (1990) in their study of 808 patients found no benefit from gastric emptying before administering activated charcoal but an increased incidence of pulmonary aspiration. All 3 of these controlled studies in emergency department poisoning patients failed to show benefit from induced emesis or gastric lavage. Additional findings were that combined therapy increases both the duration of the emergency department stay and the risk for complications. Thus, activated charcoal alone is emerging as the sole gastrointestinal decontamination procedure for acute poisoning patients.

5. Multiple-Dose Activated Charcoal Therapy The goal of single-dose charcoal is to prevent absorption of toxin and thereby limit body burden and toxicity. The goals of multiple-dose charcoal therapy include the above as well as increasing the elimination of systemically absorbed toxin. That mUltiple doses of charcoal enhance the rate of elimination of absorbed drugs was first reported by Neuvonen and Elonen (1980) and was later confirmed for phenobarbital (Berg et al. 1982) and

Drug Safety 7 (1) 1992

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theophylline (Berlinger et at 1983). These reports along with Levy's landmark editorial (1982) have had a major effect on the management of poisoning. Multiple-dose charcoal therapy is seen as an inexpensive, noninvasive and comparatively safe procedure which can be used in any . hospital. Its use has been widely promoted and extensively reviewed in the literature (Derlet & Albertson 1986; Jones et al. 1987; Katona et al. 1987; Neuvonen & Olkkola 1988; Park et al. 1986; Pond 1986). However, its role has recently been questioned because there is no evidence that patients benefit from this intervention and because of reports of complications from its use (Tenenbein 1991). The chief mechanism for increased drug clearance due to multiple dose charcoal therapy is believed to be enhancement of back diffusion of drug from the bloodstream into the gut lumen. Drugs in the non-protein-bound, nonionic state can passively diffuse from the circulation into the gastrointestinal lumen. This process is favoured by a concentration gradient and the large surface area of the intestine. Activated charcoal facilitates the process by binding drug in the intestinal lumen, effectively reducing its concentration to zero, which maintains the concentration gradient. In effect, the gut epithelium acts as a semipermeable dialysis membrane, for which Levy (1982) coined the term 'gastrointestinal dialysis'. Other mechanisms for increased drug clearance include the interruption of enterohepatic and enterogastric drug circulations. However, these circulations do not occur with all drugs and the absolute amount of drug passing through these pathways is quite small. Therefore it is unlikely that interruption of internal drug ciculations plays a very important role (Kirshenbaum et al. 1990a). Although it was initially felt to be relatively safe, the increased use of multiple-dose charocal therapy has been accompanied by a number of case reports of morbidity and mortality. These include nausea and vomiting, particularly in theophylline poisoning (Sessler 1987; Sessler et al. 1985), fatal pulmonary aspirations of charcoal (Benson et al. 1989; Harsch 1986; Menzies et al. 1988; Rau et al. 1988),

and charcoal-induced bowel obstructions (Ray et al. 1988; Watson et a1. 1986). The use of repeated cathartic therapy, often recommended when using multiple-dose charcoal, is not without risk. Reported adverse effects include symptomatic hypermagnesaemia (Jones et a1. 1986), significant electrolyte disturbances and dehydration (Caldwell et a1. 1987; Farley 1986; McCord & Okun 1987) and 1 iatrogenic death (Brent et a1. 1989). Data from controlled studies indicate that multiple-dose charcoal therapy enhances the clearance of phenobarbital (Berg et a1. 1982), theophylline (Berlinger et a1. 1983) and phenytoin (Mauro et al. 1987), but not salicylates (Ho et a1. 1989; Kirshenbaum et a1. 1990a) and imipramine (Goldberg et a1. 1985). There are conflicting data for digoxin (Lalonde et al. 1985; Park et al. 1985). There is, however, no evidence of patient benefit from this intervention, as shown, for example, in a small controlled study of phenobarbital overdose patients (Pond et a1. 1984). Clearly, multiple-dose charcoal therapy should not be used in all patients with poisoning but should only be considered for selected clinical situations. Whether it should be used at all requires additional investigation.

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Update on Activated Charcoal

Oerlet RW, Albertson TE. Activated charcoal- past, present and future. Western Journal of Medicine 145: 493-496, 1986 Easom JM, Caraccio TR, Lovejoy Jr FH. Evaluation of activated charcoal and magnesium citrate in the prevention of aspirin absorption in humans. Clinical Pharmacy I: 154-156, 1982 Farley T A. Severe hypernatremic dehydration after use of activated charcoal-sorbitol suspension. Journal of Pediatrics 109: 719-722, 1986 Goldberg MJ, Park GO, Spector R, Fischer U, Feldman RD. Lack of effect of oral activated charcoal on imipramine clearance. Oinical Pharmacology and Therapeutics 38: 350-353, 1985 Goldberg MJ, Spector R, Park GO, Roberts RJ. An approach to the management of the poisoned patient. Archives of Internal Medicine 146: 1381-1385, 1986 Harsch HH. Aspiration of activated charcoal. New England Journal of Medicine 314: 318, 1986 Ho JL, Tierney Mg, Dickinson GE. An evaluation of the effect of repeated doses of activated charcoal on salicylate elimination. Journal of Clinical Pharmacology 29: 366-369, 1989 Jones J, Heiselman 0, Dougherty J, Eddy E. Cathartic induced magnesium toxicity during overdose management. Annals of Emergency Medicine 15: 1214-1218, 1986 Jones J, McMullen MJ, Dougherty J, Cannon L. Repetitive doses of activated charcoal in the treatment of poisoning. American Journal of Emergency Medicine 5: 305-310,1987 Katona BG, Siegel EG, Cluxton Jr RJ. The new black magic: activated charcoal and new therapeutic uses. Journal of Emergency Medicine 5: 9-18, 1987 Keller RE, Schwab RA, Krenzelok EP. Contribution of sorbitol combined with activated charcoal in prevention of salicylate absorption. Annals of Emergency Medicine 19: 654-656, 1990 Kirshenbaum LA, Mathews SC, Sitar OS, Tenenbein M. Does multiple-dose charcoal therapy enhance salicylate excretion? Archives ofinterval Medicine 150: 1281-1283, 1990a Kirshenbaum LA, Sitar OS, Tenenbein M. Interaction between whole bowel irrigation solution and activated charcoal: implications for the treatment of toxic ingestions. Annals of Emergency Medicine 19: 1129-1132, 1990b Krenzelok EP, Keller R, Stewart RD. Gastrointestinal transit times of cathartics combined with charcoal. Annals of Emergency Medicine 14: 1152-1155, 1985 Kulig K, Bar-Or 0, Cantrill SV, Rosen P, Rumack BH. Management of acutely poisoned patients without gastric emptying. Annals of Emergency Medicine 14: 562-567, 1985 Lalonde RL, Oeshpande R, Hamilton PP, Mclean WM, Greenway DC. A~celeration of digoxin clearance by activated charcoal. Clinical Pharmacology and Therapeutics 37: 367-371, 1985 Levy G. Gastrointestinal clearance of drugs with activated charcoal. New England Journal of Medicine 307: 676-678, 1982 Levy G, Tsuchiya T. Effect of activated charcoal on aspirin absorption in man. Clinical Pharmacology and Therapeutics 13: 317-322,1972 Mauro LS, Mauro VF, Brown DL, Somani P. Enhancement of phenytoin elimination by multiple-dose activated charcoal. Annals of Emergency Medicine 16: 1132-1135, 1987 Mayersohn M, Perrier 0, Picchioni AL. Evaluation of charcoal mixture as an antidote for oral aspirin overdose. Clinical Toxicology II: 561-567, 1977 McCord MM, Okun AL. Toxicity of sorbitol-charcoal suspension. Journal of Pediatrics III: 307-308, 1987 McNamara R, Aaron CK, Gemborys M, Davidheiser S. Sorbitol catharsis does not enhance efficacy of charcoal in a simulated acetaminophen overdose. Annals of Emergency Medicine 17: 243-246, 1988 Menzies DO, Busuttil A, Precott LF. Fatal pulmonary aspiration of activated charcoal. British Medical Journal 297: 459-460, 1988 Merigian KS, Woodard M, Hedges Jr, Stuebing R, Rashkin Me. Prospective evaluation of gastric emptying in the self poisoned patient. American Journal of Emergency Medicine 8: 479-483, 1990 Neuvonen PJ. Clinical pharmacokinetics or oral activated char-

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coal in acute intoxications. Clinical Pharmacokinetics 7: 465489, 1982 Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. European Journal of Clinical Pharmacology 17: 51-57, 1980 Neuvonen PJ, Olkkola KT. Effect of purgatives on antidotal efficacy of oral activated charcoal. Human Toxicology 5: 255263, 1986 Neuvonen PJ, Olkkola KT. Oral activated charcoal in the treatment of intoxications: role of single and repeated doses. Medical Toxicology 3: 33-58, 1988 Park GO, Goldberg MJ, Spector R, Johnson GF, Feldman RD, et al. The effects of activated charcoal on digoxin and digitoxin clearance. Drug Intelligence and Oinical Pharmacy 19: 937941, 1985 Park GO, Spector R, Goldberg MJ, Johnson GF. Expanded role of charcoal therapy in the poisoned and overdosed patient. Archives of Internal Medicine 146: 969-973, 1986 Picchioni AL. Activated charcoal: a neglected antidote. Pediatric clinics of North America 17: 535-543, 1870 Pond SM. Role of repeated oral doses of activated charcoal in clinical toxicology. Medical Toxicology I: 341, 1986 Pond SM, Olson KR, Osterloh JD, Tong TG. Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. Journal of the American Medical Association 251: 3104-3108, 1984 Rau NR, Nagaraj MV, Prakash PS, Nelli P. Fatal pulmonary aspiration of activated charcoal. British Medical Journal 297: 918-919, 1988 Ray MJ, Padin R, Condie JD, Halls JM. Charcoal bezoar: small bowel obstruction secondary to amitriptyline overdose therapy. Digestive Diseases and Sciences 33: 106-107, 1988 Riegel JM, Becker CEo Use of cathartics in toxic ingestions. Annals of Emergency Medicine 10: 254-258, 1981 Saetta JP, March S, Gaunt ME, Quinton ON. Gastric emptying procedures in the self-poisoned patient: are we forcing gastric content beyond the pylorus? Journal of the Royal Society of Medicine 84: 274-276, 1991 Saetta JP, Quinton ON. Residual gastric content after gastric lavage and ipecacuanha-induced emesis in self-poisoned patients: An endoscopic study. Journal of the Royal Society of Medicine 84: 35-38, 1991 Sessler CN. Poor tolerance of oral activated charcoal with theophylline overdose. American Journal of Emergency Medicine 5: 492-495, 1987 Sessler CN. Glauser FL, Cooper KR. Treatment of theophylline toxicity with oral activated charcoal. Chest 87: 325-329, 1985 Shannon M, Fish SS, Lovejoy Jr FH. Cathartics and laxatives: do they still have a place in management of the poisoned patient? Medical Toxicology I: 247-252, 1986 Sketris IS, Mowry JB, Czajka PA, Anderson WH, Stafford DT. saline catharsis: effect on aspiration bioavailability in combination with activated charcoal. Journal of Clinical Pharmacology 22: 59-64, 1982 Tenenbein M. Inefficacy of gastric emptying procedures. Journal of Emergency Medicine 3: 133-136, 1985 Tenenbein M. Whole bowel irrigation in iron poisoning. Journal of Pediatrics III: 142-145, 1987 Tenenbein M. Whole bowel irrigation as a gastrointestinal decontamination procedure after acute poisoning. Medical Toxicology 3: 77-84, 1988 Tenenbein M. Multiple doses of activated charcoal - time for reappraisal? Annals of Emergency Medicine 20: 529-531,1991 Tenenbein M, Cohen Sitar OS. Efficacy ofipecac-induced emesis, orogastric lavage and activated charcoal for acute drug over-· dose. Annals of Emergency Medicine 16: 838-841, 1987 Watson WA, Cremer KF, Chapman JA. Gastrointestinal obstruction associated with multiple activated charcoal. Journal of Emergency Medicine 4: 401-407, 1986 Correspondence and reprints: Dr Milton Tenenbein. 840 Sherbrook Street, Winnipeg, Manitoba R3A lSI, Canada.