Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Gastrointestinal decontamination Carson R. Harris MD & Rick Kingston PharmD To cite this article: Carson R. Harris MD & Rick Kingston PharmD (1992) Gastrointestinal decontamination, Postgraduate Medicine, 92:2, 116-128, DOI: 10.1080/00325481.1992.11701420 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701420
Published online: 17 May 2016.
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-@CME credit article
Gastrointestinal decontamination Which method is best?
Carson R. Harris, MD
Rick Kingston, Pharm.D
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or C ipecacuanha plant. Syrup of ipecac is made from powdered ipecac, which contains the alkaloids emetine and cephaeline. Emetine constitutes more than 50% of the total alkaloid content and is more cardiotoxic than cephaeline. Although both alkaloids are responsible for the nausea and vomiting associated with ipecac use, cephaeline is more There is, however, a noticeable potent. Ipecac syrup has been and consistent trend in emergency available in the United States departments toward limiting use since the mid-1950s, but its use of syrup of ipecac as a first step was not widespread until 1966, in gastric emptying. Use of this when it was classified as an overagent prolongs the time patients the-counter agent. must remain in the emergency In an early repon by Robendepartment and delays the adson, 1 emesis was induced in 189 ministration of activated char(88%) of214 children within coal. Activated charcoal alone 30 minutes after administration or in combination with gastric of 20 mL of ipecac syrup and lavage is becoming the primary large volumes of water. The failchoice for emergency manageure rate after two doses is generment, and whole-bowel irrigation ally less than 3%. The emetic is gaining in popularity. effect lasts about 2 hours and Management options for poiproduces an average of three soning and overdose are listed episodes (range, one to eight) in table 1. The debate continues over a 24- to 60-minure period.2.3 about which method is best and Repeated emesis lasting longer when a particular method should than 2 hours may be caused by be used. This article reviews curanother source, such as the inrent options for decontamination gested toxin. and recommends appropriate apDespite isolated reponed cases plications. of uncomplicated Mallory-Weiss tears or pneumomediastinum ocSyrup of ipecac curring after use of ipecac syrup, Ipecac is the dried rhiwme and its therapeutic application is relaroots of the Cephaelis acuminata tively safe. During the mid-1980s,
Why has Ipecac syrup become less popular in emergency management of poisoning and overdose? When should gastric lavage, activated charcoal, cathartics, or a combination of methods be used? Which patients are candidates for whole-bowel irrigation with polyethylene glycol-electrolyte solution? Drs Harris and Kingston answer these questions and present their recommendations for each of the available management options.
Gastrointestinal decontamination is currently the most controversial area of medical toxicology. In recent years, multiple studies have attempted to reappraise emergency management of poisoning and overdose. Many of the traditional methods of gastrointestinal decontamination have been challenged as being ineffective and possibly dangerous. Yet, confusion abounds in current medical literature because of inconsistent protocols and differences in lavage technique among the various studies. Many of the studies have not involved severely poisoned patients, and it is this group that is of most concern to emergency · department physicians. In addition, consensus appears to be lacking among emergency physicians and toxicologists on the appropriate method or sequence of methods for decontaminating patients with mild or moderate poisoning.
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Illustration: C> 1992. Matt Mahurin
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A disadvantage of using ipecac syrup in
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emergency departments is that it delays initiation of activated charcoal treatment because of repeated episodes of vomiting.
Table 1. Options for Gl decontamination in cases of poisoning or overdose
Ipecac syrup Gastric lavage Activated charcoal Cathartics Whole-bowel irrigation Combination of gastric lavage and activated charcoal Multiple-dose activated charcoal Chelation Gastroscopy and/or gastrotomy
cardiotoxicity was recognized as a life-threatening complication of chronic abuse of ipecac syrup by patients with bulimia. Effons to reverse the agent's over-thecounter status were unsuccessful, and widespread education regarding the dangers of abuse appears to have reduced this particular use. Of greater concern is the inappropriate administration of ipecac syrup in patients who ( 1) do not have a gag reflex, (2) have ingested agents that cause an abrupt change in con-
118
sciousness, or (3) have ingested caustic or volatile agents. We recommend a dose of 15 mL of ipecac syrup for children aged 6 months to 7 years and 30 mL for older children and adults. If vomiting does not occur within 20 to 30 minutes, a second dose may be given. Infants younger than 12 months are not routinely treated at home. Some investigators4 have advocated use of a single 30-mL dose in pediatric patients. A disadvantage of use of ipecac syrup in emergency depanments is that it delays initiation of activated charcoal treatment because of repeated episodes of vomiting. Kulig and associates 5 noted a 2.2-hour delay in the administration of activated charcoal in patients receiving ipecac syrup. In addition, Tandberg and Murphf found that even when patients received ipecac syrup within 10 minutes after ingesting a tracer, the mean recovery rate of the swallowed tracer was only 47.1% (range, 40.1% to 54%).
Gastric lavage For decades gastric lavage has been the cornerstone of management of poisoned patients who have an altered mental status. It is routinely indicated for any patient in whom gastric decontami-
nation is mandatory and emesis cannot be safely initiated. Contraindications to its use include ingestion of strong corrosives and coingestion of sharp objects. Two recent studies7•8 have used ingested tracers to compare the effectiveness of gastric lavage with that of ipecac-induced emesis. Mean tracer recovery rates ranging from 30% to 90% have been reponed with lavage, but the techniques used in the studies varied considerably. Differences in size of orogastric tube, failure to indicate lavage fluid temperature or use of epigastric massage, and vague descriptions oflavage end point make it difficult to interpret the study results. Technique is extremely important in achieving maximum benefit with gastric lavage (table 2). Use of various techniques among physicians undoubtedly affects the procedure's efficacy. Saetta and Quinton9 demonstrated that 15 (88%) of 17 self-poisoned patients had residual intragastric solids after administration of a standardized lavage procedure. However, the investigators did not explicitly define their lavage technique or specifY whether the clear lavage return contained dissolved drug. In a study of 60 self-poisoned patients, Saetta and associates 10
01 DECONTAMINATION • VOL92/NO 2/AUGUST 1992/POSTGRAOUATE MEDICINE
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Gastric lavage is routinely indicated for any patient in whom gastric decontamination is mandatory and emesis cannot be safely initiated.
examined the possibility that ipecac-induced emesis and gastric lavage promote the movement of gastric contents into the small bowel. In the control group, which did not undergo a gastricemptying procedure, 16% of ingested radiopaque pellets were found in the small bowel; this compared with 17% of ingested pellets in the group receiving gastric lavage and 23% in the group receiving ipecac syrup. These findings indicate that the procedures cause significant extrusion of ingested substances into the small bowel, where further absorption may occur. In addition, the study revealed the inefficiency of gastric-emptying procedures: 58.5% of the total number of pellets ingested were retained in the gastrointestinal tract in the ipecac group, whereas 51.8% of the pellets were retained in the gastric lavage group. McDougal and Maelean 11 demonstrated that gastric lavage with warm fluid (46°C [114.8°F]), in combination with mechanical agitation, was the most effective method of removing medications from an artificial stomach. Compared with lavage using water at room temperature (22°C [71.6°F]), warm-water lavage and agitation reduced removal time from 68 minutes to 5.3 minutes.
Table 2. Suggested procedure for gastric lavage
1. Protect airway in lethargic or comatose patients.
2. Gently advance large-bore orogastric tube (16F to 28F in children, 36F to 40F in adults) into stomach. 3. Confirm proper placement by auscultating epigastrium while injecting air into tube. 4. Place patient in left lateral decubitus position with head lowered.
5. Aspirate stomach contents using warm tap water in adults and warm saline solution in children. Instill lavage aliquots of 200 to 300 ml (10 ml/kg in children), then allow to drain into collection container. 6. Massage upper left quadrant during procedure when drug concretions are possible. 7. Continue procedure until lavage fluid is clear. Instill additional1 to 2 L for greater margin of safety. Adapted from Bryson PO. Comprehensive review in toxicology. 2d ed. Rockville, MD: Aspen, 1989:21-2.
An additional benefit of warm lavage fluid is that it decreases peristalsis, which reduces movement of the ingested substance beyond the pylorus during the procedure. Recent calls for the elimination of gastric lavage are somewhat premature. The number of severely poisoned patients studied thus far is obviously insufficient to warrant the conclusion that these patients do not benefit from removal (or partial removal)
of unabsorbed toxins. Physicians need to rely on their clinical judgment in determining which patients may benefit from gastric lavage rather than another procedure.
Activated charcoal Activated charcoal has been used as an antidote since the 1830s. The charcoal is produced by destructive distillation of various organic materials, most commonly wood pulp, and is then treated at
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Activated charcoal used alone or in
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combination with gastric lavage has become increasingly popular in the last 10 years.
Table 3. Agents with minimal or no adsorption by activated charcoal Alkali
Boric acid Chlorpropamide (Diabinese) Cyanide DDT
Ethanol Ferrous sulfate Isopropanol Lithium Methanol Methyl carbamate Mineral acids Potassium hydroxide Sodium hydroxide Sodium metasilicate
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high temperatures with steam, carbon dioxide, or strong acids to increase its adsorptive capacity. 12 Traditionally, activated charcoal was used as an adjunct to lavage and ipecac syrup. However, activated charcoal used alone or in combination with gastric lavage has become increasingly popular in the last 10 years. In some European countries, activated charcoal is used in homes and hospitals as first-line treatment for acute poisoning. Data from the last several years have shown that ipecac syrup and gastric lavage have limited effectiveness even when used early in the course of treatment. In addition, most adults who overdose typically arrive in the emergency department several hours after ingestion. These facts prompted investigators in the United States to reexamine the standards for gastric decontamination. In a prospective study of 592 patients with drug overdose, Kulig and colleagues5 concluded that a satisfactory outcome can be attained without routine gastric emptying. The investigators found that activated charcoal and supportive care were sufficient in most cases. Other studies 13• 15 have also shown that patients presenting with mild to moderate over-
dose may be treated with activated charcoal alone without increasing morbidity. In these studies, gastric emptying essentially yielded no benefit when done before administration of activated charcoal. Unfortunately, these studies included only a small number of patients with potentially lethal ingestions. For this reason, gastricemptying techniques should not be abandoned until further investigations involving large samples of patients with severe poisoning (with tricyclic antidepressants, digoxin [Lanoxicaps, Lanoxin], lithium) have been completed. In addition, some substances are poorly adsorbed by activated charcoal (table 3), and some agents cause abrupt changes in mental status; other methods may be more effective in removing these agents. All of these factors need to be considered before gastric-emptying procedures (specifically, gastric lavage) are discontinued. It has been suggested that activated charcoal significantly adsorbs oral acetylcysteine (Mucomyst) in patients with acetaminophen overdose, thereby reducing the antidote's effectiveness. However, this assumption has been challenged in several studies.IG.I7
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Multiple dosing with activated charcoal decreases absorption and blood levels of certain drugs.
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Multiple-dose activated charcoal Use of multiple doses of activated charcoal is an alternative that has stimulated the interest of clinicians and researchers. Multiple dosing decreases both absorption and blood levels of certain drugs.' 8 This method appears to be effective in enhancing elimination of drugs that undergo enterohepatic recirculation or in promoting drug exsorption from the systemic circulation into the intestinal lumen, or both.' 9 Thus, patients receive "gastrointestinal dialysis." Of 28 drugs studied thus far, 26 have shown varying degrees of increased elimination with multiple-dose activated charcoal. A partial list of these agents is presented in table 4. The multiple-dose regimen consists of an initial dose of 50 to 100 g followed by maintenance doses of 30 to 50 g every 2 to 6 hours with or without administration of a cathartic agent. When a cathartic is given with subsequent doses of activated charcoal, patients should be closely monitored for excessive fluid loss and electrolyte disturbances. To minimize this complication, use of charcoal and cathartics may be alternated with aqueous solutions of activated charcoal. Because patient sam-
pling in this area of poison management has been relatively small, further studies are needed to prove its effect on patient outcome.
Table 4. Agents demonstrating increased elimination with multiple-dose activated charcoal therapy
Cathartics
Carbamazepine (Epitol, Tegretol)
Cathartics (ie, purgatives, or laxatives) have long been promoted as adjunctive therapy for poisoning. The rationale for their use is that they may promote intestinal evacuation, but there has been little documentation in the literature to support their use in poison management. Five classes of cathartics are currently available: bulk-forming agents, stimulants or irritants, softeners, saline and osmotic agents, and lubricants. The saline and osmotic agents are the most common cathartics and are the only agents advocated as adjunctive therapy for poisoning. Magnesium sulfate, magnesium citrate, sodium sulfate, sorbitol, and hypertonic phosphate solutions are generally used. In the early 1980s, commercial preparations of activated charcoal containing sorbitol as a diluent became available, and these products have gained widespread use. Sorbitol makes activated charcoal more palatable and provides a bacteriostatic environment during storage.
Digitoxin (Crystodigin) Glutethimide (Doriden) Meprobamate (Equanil, Miltown) Nadolol (Corgard) Phencyclidine HCI Phenobarbital (Luminal Sodium) Phenylbutazone (Azolid, Butazolidin) Phenytoin (Dilantin) Piroxicam (Feldene) Propoxyphene (Darvon, Dolene) Salicylates Theophylline Tricyclic antidepressants
Adverse effects from use of cathartics are primarily related to dehydration and electrolyte imbalances. These complications usually result from repeated administration of an agent. Hyper-
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Whole-bowel irrigation is indicated in patients who have ingested agents that are not adsorbed by activated charcoal.
ministered through a nasogastric tube at the same rate. The end point of treatment is a dear effluent, which may take 2 to 6 hours to obtain. There is some debate about whether the appearance of a dear effluent is an adequate gauge of the procedure's effective-
ness.
Carson R. Harris, MD Rick Kingston, PhannD Dr Harris (left) is senior staff physician, emergency medicine department, and interim medical director, Minnesota Regional Poison Center, St Paul-Ramsey Medical Center, St Paul. Dr Kingston (right) is senior clinical toxicologist, Minnesota Regional Poison Center.
magnesemia, hypocalcemia, hyperphosphatemia, and hypokalemia have been reponed. Although sorbitol is still used in commercial brands of activated charcoal, the use of other cathartics is declining.
Whole-bowel irrigation Recently, whole-bowel irrigation with polyethylene glycolelectrolyte solution (CoLyte, OCL) has been suggested as an option for gastrointestinal decontamination. The technique was first performed in the United
Kingdom using normal saline solution. However, use of normal saline solution had to be abandoned because patients experienced electrolyte abnormalities. During irrigation with polyethylene glycol-electrolyte solution, no fluids are absorbed or secreted across the gastrointestinal epithelium. For the procedure to be effective and to reduce abdominal discomfort, adults must ingest the solution at a rate of 2 Llhr (500 mL/hr in children); alternatively, the solution may be ad-
Patients may experience nausea and bloating during the procedure. These side effects can be averred by pretreatment with 10 to 20 mg of metodopramide (Reglan) given intravenously. Use of ipecac syrup with whole-bowel irrigation should be avoided, but activated charcoal may be administered before the procedure. Whole-bowel irrigation has been found to be safe and effective in the management of acute overdoses of such agents as ampicillin, iron, lithium, and entericcoated or sustained-release medications. It has also been used in decontamination of patients attempting to conceal packets of controlled substances (eg, cocaine).20 Patients who have ingested large amounts of agents that are poorly adsorbed or not adsorbed by activated charcoal are candidates for whole-bowel irrigation.
Combination therapy Attempts to improve the efficiency of gastrointestinal decon-
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tamination have included a combination of activated charcoal and lavage techniques. Unfortunately, study protocols have not closely reflected clinical practice, which usually involves a greater delay before initiation of treatment. In a study in animal models by Burton and colleagues/' activated charcoal administered before and after gastric lavage proved to be more effective than activated charcoal alone in reducing salicylate absorption. However, activated charcoal alone is superior to whole-bowel irrigation and activated charcoal used together. 22 '23 Because activated charcoal adsorbs drugs in seconds, it ideally should be given before lavage is performed, thereby decreasing the chance of drugcharcoal desorption farther down in the intestinal tract.
Conclusions The primary controversy in poison management concerns the use of activated charcoal alone versus gastric lavage or ipecac syrup before activated charcoal. Multiple studies have shown that a relatively small amount of gastric contents is removed with gastric lavage or ipecac syrup. However, a universally standardized lavage
method has not been used in these studies. The importance of lavage fluid temperature, abdominal massage, and positioning of the patient during the procedure has not been thoroughly evaluated. Other factors, such as diameter of the orogastric tube and size of aliquot, may play a role in obtaining optimum decontamination with gastric lavage. Further studies are needed using a standardized protocol in large samples of poisoned patients. Caution is advised with the use of activated charcoal alone, because not all substances are adsorbed by this agent and other methods may prove more effective. Gastric lavage may
force unabsorbed agents into the duodenum and small intestine, where they may be further absorbed and theoretically may cause the patient's condition to worsen. Positioning the patient on the left side with head lowered at about a 30-degree angle could minimize extrusion into the small intestine. lUll Earn credit on this article.
~ See CME Qui~
Address for correspondence: Carson R. Harris, MD, Emergency Medicine Department, St Paul-Ramsey Medical Center, 640 Jackson St, St Paul, MN 55101.
References 1. Robertson WO. Syrup of ipecac: a slow or fast emetic? Am J Dis Child 1962; I 03(Feb): 136-9 2. MacLean WC Jr. A comparison of ipecac syrup and apomorphine in rhe immediate rrearmenr of ingestion of poisons. J Pediarr 1973; 82(1):121-4 3. Rauber AP, Maroncelli RD. The duration of emetic effect of ipecac: duration and frequency of vomiting. (Absrr) Ver Hum Toxicol 1982; 24(Aug 4):281 4. Krenzelok EP, Dean BS. Effectiveness of 15-mL versus 30-mL doses of syrup of ipecac in children. Clin Pharm 1987;6(9):715-7 5. Kulig K, Bar-Or D, Cantrill SV, et al. Management of acutely poisoned patients withour gastric emptying. Ann Emerg Med 1985; 14(6):562-7 6. Tandberg D, Murphy LC. The knee-chest position does nor improve rhe efficacy of ipecac-
induced emesis. Am J Emerg Med 1989;7(3): 267-70 7. Tandberg D, Diven BG, McLeod.JW, Ipecac-induced emesis versus gasrric lavage: a controlled study in normal adults. Am J Emerg Med 1986;4(3):205-9
8. Auerbach PS, Osterloh J, Braun 0, et al. Efficacy of gastric emptying: gastric lavage versus emesis induced wirh ipecac. Ann Emerg Med 1986; 15(6):692-8 9. SaettaJP, Quinton DN. Residual gastric content after gastric lavage and ipecacuanhainduced emesis in self-poisoned patients: an endoscopic study. J R Soc Med 1991;84(1):35-8 10. SaettaJP, March S, Gaunt ME, et al. Gastric emptying procedures in the self-poisoned patient: are we forcing gastric content beyond rhe pylorus? J R Soc Med 1991 ;84(5):274-6 11. McDougal CB, Maclean MA. Modifications in rhe technique of gastric lavage. Ann
continued on page 128
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lheo-24® (theophylline anhydrous) Extended-releasecapsules 100,200, & 300 mg
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The following is a brief summary only. Before prescribing, consult complete prescribing information in product labeling orPOR.
INDICATIONS AND USAGE Theo·24 is indicated for relief and/or prevention of symptoms from asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema. CONTRAINDICATION& Theo-24 is contraindicated in patients with a history of hypersensitivity to theophylline. It is also contraindicated in patients with active peptic ulcer disease and in patients with underlying seizure disorders (unless receiving appropriate anticon· vulsant medication). WARNINGS Serum levels above 20 mcg/ml are rarely found after appropriate administration of the recommended doses. However, in individuals in whom theophylline plasma clearance is reduced for any reason, even conventional doses may result in increased serum levels and potential toxicity. Reduced theophylline clearance has been documented in the following readily identifiable groups: (1) patients with impaired liver function; (2) patients over 55 years of age, particularly mates and those with chronic tung disease; (3) patients with cardiac failure from any cause; (4) patients with sustained high fever; (5) infants under 1 year of age; and (6) patients tak1ng certain drugs (see Precautions: Drug/Drug interactiCms). Frequently, such patients have markedly prolonged theophylline serum levels following discontinuation of the drug. Reduction of dosage and laboratory monitoring is especially appropriate in the above individuals. Serious side effects such as ventricular arrhythmias, convulsions, or even death may appear as the first sign of toxicity without any previous warning. Less serious signs of theophylline toxicity (ie, nausea and restlessness) may occur frequently when initiating therapy, but are usually transient; when such signs are persistent during maintenance therapy, they are often associated with serum concentrations above 20 meg/mi. Serious toxicity is not reliably preceded by less severe side effects. A serum concentration measurement is the most reliable method of predicting potentially life-threatening toxicity. Many patients who require theophylline may exhibit tachycardia due to their underlymg disease process so that the cause/ effect relationship to elevated serum theophylline concentrations may not be recognized. Theophylline products may cause arrhythmia and/or worsen preexisting arrhythmtas. Any significant change in rate and/or rhythm warrants monitoring and further Investigation. Halothane anesthesia in the presence of theophylline may produce sinus tachycardia or ventricular arrhythmias. Studies in laboratory animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of necrosts of the myocardium) when theophylline and beta agonists were administered concomitantly. The significance of these findings when applied to humans is unknown. PRECAUTIONS General: On the average, theophylline's half-life is shorter in cigarette and marijuana smokers than in nonsmokers, but smokers can have half-lives as long as nonsmokers. Theophylline should not be administered concomitantly With other xanthlnes. Use with caution in patients with hypoxemia, hypertension, or those with a history of peptic ulcer. Theophyttlne may occasionally act as a local irritant to the gastrointestinal tract when administered orally, although gastrointestinal symptoms are more commonly centrally mediated and associated with serum drug concentrations over 20 meg/mi. Information for patients: Patients should be instructed to take this medication in the morning, at approximately the same time each day, and not to exceed the prescribed dose. Patients who require a relatively high dose of theophylline (1e, a dose equal to or greater than 900 mg or 13 mg/kg, which· ever tsless) should be informed of important considerations relating to time of drug administration and meal content (see Precautions: Drug/ Food interactions; and Dosage and Administration). As with any controlled-release theophylline product the patient should alert the physician if symptoms occur repeatedly, especially near the end of a dosing intervaL . Laboratory taata: Serum levels should be monitored periodically to determine the theophylline level associated with observed clinical response and as the method of prediCting toxicity. For such measurements, the serum sample should be obtained at the time of peak concentrations, approximately 12 hours after administration of a morning dose. It is important that the patient has not missed or taken additional doses during the previous 72 hqurs and that dosing Intervals have been reasonably cons1stent. Dose adjustment based on measurements when these 1nstructions have not been followed may result in toxicity (see Dosage and Administration). Drug Interaction• Drug/Drug interactions: Toxic synergism has been documented with ephedrine and may occur with other sympathomimetic bronchodllators. Halothane anesthesia in the presence of theophylline may produce sinus tachycardia or ventricular arrhythmias. In addition, the following drug interactions have been demonstrated with theophylline: Uthlum carbonate Increased renal excretion of lithium Allopurinol (hi-dose) Increased serum theophylline levels Clmetldlne Increased serum theophylline levels Erythromycin, troleandomycin Increased serum theophylline levels Oral contraceptive steroids Increased serum theophylline levels Ciprofloxacin Increased serum theophylline levels Propranolol Increased serum theophylline levels Phenytoin Decreased theophylline and phenytoin serum levels Carbamazepine Decreased serum theophylline levels Phenobarbital Decreased serum theophylline levels Alfampin Decreased serum theophylline levels Drug/Food interactions: Taking Theo-241ess than one hour before a high-fat-content meal, such as 8 oz whole milk, 2 fried eggs, 2 bacon Strips, 2 oz hashed brown potatoes, and 2 slices of buttered toast (about 985 calories, Including approximately 71 g of fat) may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state. In some cases (especially with doses of 900 mg or more taken less than one hour before a high-fat-content meal) serum theophylline levels may exceed the 20 mcg/mllevel, above which theophylline toxicity is more likely to occur. Drug !Laboratory test interactions: Currently available analytical methods, including high pressure liquid chromatography and immunoassay techniques, for measuring serum theophylline levels are specific. Metabolites and other drugs generally do not affect the results. Other new analytical methods are In use. The physician should be aware of the laboratory method used and whether other drugs wtll interfere with the assay for theophylline. Cerclnogeneala, mutagenaala, end Impairment of fertility: long-term carcmogenicity studies have not been performed with theophylline. Theophylline has been shown to be mutagenic in Eschen·chia coli and other lower organisms (Euglena gracilis and Ophiostoma multiannulatum). Chromosome-breaking activity was detected in human cell cultures at concentrations of theophylline up to 50 times the therapeutic serum concentration in humans. Theophylline was not mutagenic in the dominant lethal assay in male mice g1ven theophylline intraperitoneally in doses up to 30 times the maximum daily human oral OOse. Studies to determine the etlect on fertility have not been performed with theophylline. Pregnancy: Pregnancy Category C. limited animal studtes have shown teratogenic activity of theophylline in mice and rats. There are no adequate and well-controlled stud1es in pregnant women. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the latus. Nuralng mothere: Theophylline is distributed mto breast milk and may causa Irritability or other signs of toxicity in nursing infants. Because of the potential for serious adverse reactions in nursing infants from theophylline, a decision should be made whether to discontinue nurs1ng or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric use: Safety and effectiveness in children under 12 years of age have not been established with this product. ADVERSE REACnONS The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. The most consistent adverse reactions are usually due to overdosage. Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea. Central nervous system: headaches, irritability, restlessness, insomnia, reflex hyperexcitability, muscle twitching, clonic and tonic generalized convulsions. Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, ventricular arrhythmias. Respiratory: tachypnea. Renal: potentiation of diuresis. Other: alopecia, hyperglycemia, inappropriate ADH (antidiuretic hormone) syndrome, rash. HOW SUPPLIED Theo-24 (theophylline anhydrous) rs supplied in controlled-release capsules containing 100, 200, or 300 mg of anhydrous theophylline. Caution: Federal law prohibits dispensing without prescription. 8/14/89 References: 1. Tinkelman DG, Miller E, Janky DG et al, A comparative trial of the clin1cal efficacy and pharmacokinetics of 12-hour and 24-hourcontrolled release theophylline preparations m patients with chronic asthma. Ann Allergy 55: 571-576, 1985. 2. Dockhorn AJ, Green AW, Green E, Assessing the efficacy and safety of q.d. theophylline therapy: A multicenter study. Ann Allergy 55: 658-664, 1985.
Emerg Med 1981;10(10):514-7 12. Howland MA. Antidotes in depth: activated charcoal. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et a!, eds. Goldfrank's toxicologic emergencies. 4th ed. East Norwalk, CT: Appleton & Lange, 1990:129-33 13. Albertson TE, Derlet RW, Foulke GE, et al. Superiority of activated charcoal alone compared with ipecac and activated charcoal in the ueatment of acute toxic ingestions. Ann Emerg Med 1989;18(1):56-9 14. Merigian KS, Woodard M, Hedges JR, et al. Prospective evaluation of gastric emptying in the self-poisoned patient. Am J Emerg Med 1990;8(6):479-83 15. Neuvonen PJ, Vartiainen M, Tokola 0. Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Eur J Clin Pharmacol 1983;24(4) :55 7-62 16. Ekins BR, Ford DC, Thompson MI, et al. The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med 1987;5(6):483-7 17. Renzi FP, Donovan.JW; Martin TG, et al. Concomitant use of activated charcoal and N-acetylcysteine. Ann Emerg Med 1985;14(6): 568-72 18. Katona BG, Siegel EG, Cluxton RJ Jr. The new black magic: activated charcoal and new therapeutic uses. JEmerg Med 1987;5(1): 9-18 19. McLuckie A, Forbes AM, Dett KF. Role of repeated doses of oral activated charcoal in the treatment of acute intoxications. Anaesth Intensive Care 1990;18(3):375-84 20. Hollman RS, Smilkstein MJ, Goldfrank LR. Whole bowel irrigation and the cocaine body-packer: a new approach to a common problem. Am J Emerg Med 1990;8(6):523-7 21. Burton BT, Bayer MJ, Barron L, et al. Comparison of activated charcoal and gastric lavage in the prevention of aspirin absorption. J Emerg Med 1984; 1(5) :411-6 22. Rosenberg PJ, Livingstone OJ, McLellan BA. Effect of whole-bowel irrigation on the antidotal efficacy of oral activated charcoal. Ann EmergMed 1988;17(7):681-3 23. Hoffman RS, Chiang WK, Howland MA, et al. Theophylline desorption from activated charcoal caused by whole bowel irrigation solution. J Toxicol Clin Toxicol1991;29(2): 191-201
128 Manufactured lor Whitby Pharmaceuticals, Inc. Richmond, VA 23220, by G.D. Searle & Co. Chicago. ll60680
Gl DECONTAMINATION
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Gastrointestinal decontamination Carson R. Harris MD & Rick Kingston PharmD To cite this article: Carson R. Harris MD & Rick Kingston PharmD (1992) Gastrointestinal decontamination, Postgraduate Medicine, 92:2, 116-128, DOI: 10.1080/00325481.1992.11701420 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701420
Published online: 17 May 2016.
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-@CME credit article
Gastrointestinal decontamination Which method is best?
Carson R. Harris, MD
Rick Kingston, Pharm.D
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or C ipecacuanha plant. Syrup of ipecac is made from powdered ipecac, which contains the alkaloids emetine and cephaeline. Emetine constitutes more than 50% of the total alkaloid content and is more cardiotoxic than cephaeline. Although both alkaloids are responsible for the nausea and vomiting associated with ipecac use, cephaeline is more There is, however, a noticeable potent. Ipecac syrup has been and consistent trend in emergency available in the United States departments toward limiting use since the mid-1950s, but its use of syrup of ipecac as a first step was not widespread until 1966, in gastric emptying. Use of this when it was classified as an overagent prolongs the time patients the-counter agent. must remain in the emergency In an early repon by Robendepartment and delays the adson, 1 emesis was induced in 189 ministration of activated char(88%) of214 children within coal. Activated charcoal alone 30 minutes after administration or in combination with gastric of 20 mL of ipecac syrup and lavage is becoming the primary large volumes of water. The failchoice for emergency manageure rate after two doses is generment, and whole-bowel irrigation ally less than 3%. The emetic is gaining in popularity. effect lasts about 2 hours and Management options for poiproduces an average of three soning and overdose are listed episodes (range, one to eight) in table 1. The debate continues over a 24- to 60-minure period.2.3 about which method is best and Repeated emesis lasting longer when a particular method should than 2 hours may be caused by be used. This article reviews curanother source, such as the inrent options for decontamination gested toxin. and recommends appropriate apDespite isolated reponed cases plications. of uncomplicated Mallory-Weiss tears or pneumomediastinum ocSyrup of ipecac curring after use of ipecac syrup, Ipecac is the dried rhiwme and its therapeutic application is relaroots of the Cephaelis acuminata tively safe. During the mid-1980s,
Why has Ipecac syrup become less popular in emergency management of poisoning and overdose? When should gastric lavage, activated charcoal, cathartics, or a combination of methods be used? Which patients are candidates for whole-bowel irrigation with polyethylene glycol-electrolyte solution? Drs Harris and Kingston answer these questions and present their recommendations for each of the available management options.
Gastrointestinal decontamination is currently the most controversial area of medical toxicology. In recent years, multiple studies have attempted to reappraise emergency management of poisoning and overdose. Many of the traditional methods of gastrointestinal decontamination have been challenged as being ineffective and possibly dangerous. Yet, confusion abounds in current medical literature because of inconsistent protocols and differences in lavage technique among the various studies. Many of the studies have not involved severely poisoned patients, and it is this group that is of most concern to emergency · department physicians. In addition, consensus appears to be lacking among emergency physicians and toxicologists on the appropriate method or sequence of methods for decontaminating patients with mild or moderate poisoning.
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Illustration: C> 1992. Matt Mahurin
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A disadvantage of using ipecac syrup in
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emergency departments is that it delays initiation of activated charcoal treatment because of repeated episodes of vomiting.
Table 1. Options for Gl decontamination in cases of poisoning or overdose
Ipecac syrup Gastric lavage Activated charcoal Cathartics Whole-bowel irrigation Combination of gastric lavage and activated charcoal Multiple-dose activated charcoal Chelation Gastroscopy and/or gastrotomy
cardiotoxicity was recognized as a life-threatening complication of chronic abuse of ipecac syrup by patients with bulimia. Effons to reverse the agent's over-thecounter status were unsuccessful, and widespread education regarding the dangers of abuse appears to have reduced this particular use. Of greater concern is the inappropriate administration of ipecac syrup in patients who ( 1) do not have a gag reflex, (2) have ingested agents that cause an abrupt change in con-
118
sciousness, or (3) have ingested caustic or volatile agents. We recommend a dose of 15 mL of ipecac syrup for children aged 6 months to 7 years and 30 mL for older children and adults. If vomiting does not occur within 20 to 30 minutes, a second dose may be given. Infants younger than 12 months are not routinely treated at home. Some investigators4 have advocated use of a single 30-mL dose in pediatric patients. A disadvantage of use of ipecac syrup in emergency depanments is that it delays initiation of activated charcoal treatment because of repeated episodes of vomiting. Kulig and associates 5 noted a 2.2-hour delay in the administration of activated charcoal in patients receiving ipecac syrup. In addition, Tandberg and Murphf found that even when patients received ipecac syrup within 10 minutes after ingesting a tracer, the mean recovery rate of the swallowed tracer was only 47.1% (range, 40.1% to 54%).
Gastric lavage For decades gastric lavage has been the cornerstone of management of poisoned patients who have an altered mental status. It is routinely indicated for any patient in whom gastric decontami-
nation is mandatory and emesis cannot be safely initiated. Contraindications to its use include ingestion of strong corrosives and coingestion of sharp objects. Two recent studies7•8 have used ingested tracers to compare the effectiveness of gastric lavage with that of ipecac-induced emesis. Mean tracer recovery rates ranging from 30% to 90% have been reponed with lavage, but the techniques used in the studies varied considerably. Differences in size of orogastric tube, failure to indicate lavage fluid temperature or use of epigastric massage, and vague descriptions oflavage end point make it difficult to interpret the study results. Technique is extremely important in achieving maximum benefit with gastric lavage (table 2). Use of various techniques among physicians undoubtedly affects the procedure's efficacy. Saetta and Quinton9 demonstrated that 15 (88%) of 17 self-poisoned patients had residual intragastric solids after administration of a standardized lavage procedure. However, the investigators did not explicitly define their lavage technique or specifY whether the clear lavage return contained dissolved drug. In a study of 60 self-poisoned patients, Saetta and associates 10
01 DECONTAMINATION • VOL92/NO 2/AUGUST 1992/POSTGRAOUATE MEDICINE
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Gastric lavage is routinely indicated for any patient in whom gastric decontamination is mandatory and emesis cannot be safely initiated.
examined the possibility that ipecac-induced emesis and gastric lavage promote the movement of gastric contents into the small bowel. In the control group, which did not undergo a gastricemptying procedure, 16% of ingested radiopaque pellets were found in the small bowel; this compared with 17% of ingested pellets in the group receiving gastric lavage and 23% in the group receiving ipecac syrup. These findings indicate that the procedures cause significant extrusion of ingested substances into the small bowel, where further absorption may occur. In addition, the study revealed the inefficiency of gastric-emptying procedures: 58.5% of the total number of pellets ingested were retained in the gastrointestinal tract in the ipecac group, whereas 51.8% of the pellets were retained in the gastric lavage group. McDougal and Maelean 11 demonstrated that gastric lavage with warm fluid (46°C [114.8°F]), in combination with mechanical agitation, was the most effective method of removing medications from an artificial stomach. Compared with lavage using water at room temperature (22°C [71.6°F]), warm-water lavage and agitation reduced removal time from 68 minutes to 5.3 minutes.
Table 2. Suggested procedure for gastric lavage
1. Protect airway in lethargic or comatose patients.
2. Gently advance large-bore orogastric tube (16F to 28F in children, 36F to 40F in adults) into stomach. 3. Confirm proper placement by auscultating epigastrium while injecting air into tube. 4. Place patient in left lateral decubitus position with head lowered.
5. Aspirate stomach contents using warm tap water in adults and warm saline solution in children. Instill lavage aliquots of 200 to 300 ml (10 ml/kg in children), then allow to drain into collection container. 6. Massage upper left quadrant during procedure when drug concretions are possible. 7. Continue procedure until lavage fluid is clear. Instill additional1 to 2 L for greater margin of safety. Adapted from Bryson PO. Comprehensive review in toxicology. 2d ed. Rockville, MD: Aspen, 1989:21-2.
An additional benefit of warm lavage fluid is that it decreases peristalsis, which reduces movement of the ingested substance beyond the pylorus during the procedure. Recent calls for the elimination of gastric lavage are somewhat premature. The number of severely poisoned patients studied thus far is obviously insufficient to warrant the conclusion that these patients do not benefit from removal (or partial removal)
of unabsorbed toxins. Physicians need to rely on their clinical judgment in determining which patients may benefit from gastric lavage rather than another procedure.
Activated charcoal Activated charcoal has been used as an antidote since the 1830s. The charcoal is produced by destructive distillation of various organic materials, most commonly wood pulp, and is then treated at
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Activated charcoal used alone or in
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combination with gastric lavage has become increasingly popular in the last 10 years.
Table 3. Agents with minimal or no adsorption by activated charcoal Alkali
Boric acid Chlorpropamide (Diabinese) Cyanide DDT
Ethanol Ferrous sulfate Isopropanol Lithium Methanol Methyl carbamate Mineral acids Potassium hydroxide Sodium hydroxide Sodium metasilicate
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high temperatures with steam, carbon dioxide, or strong acids to increase its adsorptive capacity. 12 Traditionally, activated charcoal was used as an adjunct to lavage and ipecac syrup. However, activated charcoal used alone or in combination with gastric lavage has become increasingly popular in the last 10 years. In some European countries, activated charcoal is used in homes and hospitals as first-line treatment for acute poisoning. Data from the last several years have shown that ipecac syrup and gastric lavage have limited effectiveness even when used early in the course of treatment. In addition, most adults who overdose typically arrive in the emergency department several hours after ingestion. These facts prompted investigators in the United States to reexamine the standards for gastric decontamination. In a prospective study of 592 patients with drug overdose, Kulig and colleagues5 concluded that a satisfactory outcome can be attained without routine gastric emptying. The investigators found that activated charcoal and supportive care were sufficient in most cases. Other studies 13• 15 have also shown that patients presenting with mild to moderate over-
dose may be treated with activated charcoal alone without increasing morbidity. In these studies, gastric emptying essentially yielded no benefit when done before administration of activated charcoal. Unfortunately, these studies included only a small number of patients with potentially lethal ingestions. For this reason, gastricemptying techniques should not be abandoned until further investigations involving large samples of patients with severe poisoning (with tricyclic antidepressants, digoxin [Lanoxicaps, Lanoxin], lithium) have been completed. In addition, some substances are poorly adsorbed by activated charcoal (table 3), and some agents cause abrupt changes in mental status; other methods may be more effective in removing these agents. All of these factors need to be considered before gastric-emptying procedures (specifically, gastric lavage) are discontinued. It has been suggested that activated charcoal significantly adsorbs oral acetylcysteine (Mucomyst) in patients with acetaminophen overdose, thereby reducing the antidote's effectiveness. However, this assumption has been challenged in several studies.IG.I7
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Multiple dosing with activated charcoal decreases absorption and blood levels of certain drugs.
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Multiple-dose activated charcoal Use of multiple doses of activated charcoal is an alternative that has stimulated the interest of clinicians and researchers. Multiple dosing decreases both absorption and blood levels of certain drugs.' 8 This method appears to be effective in enhancing elimination of drugs that undergo enterohepatic recirculation or in promoting drug exsorption from the systemic circulation into the intestinal lumen, or both.' 9 Thus, patients receive "gastrointestinal dialysis." Of 28 drugs studied thus far, 26 have shown varying degrees of increased elimination with multiple-dose activated charcoal. A partial list of these agents is presented in table 4. The multiple-dose regimen consists of an initial dose of 50 to 100 g followed by maintenance doses of 30 to 50 g every 2 to 6 hours with or without administration of a cathartic agent. When a cathartic is given with subsequent doses of activated charcoal, patients should be closely monitored for excessive fluid loss and electrolyte disturbances. To minimize this complication, use of charcoal and cathartics may be alternated with aqueous solutions of activated charcoal. Because patient sam-
pling in this area of poison management has been relatively small, further studies are needed to prove its effect on patient outcome.
Table 4. Agents demonstrating increased elimination with multiple-dose activated charcoal therapy
Cathartics
Carbamazepine (Epitol, Tegretol)
Cathartics (ie, purgatives, or laxatives) have long been promoted as adjunctive therapy for poisoning. The rationale for their use is that they may promote intestinal evacuation, but there has been little documentation in the literature to support their use in poison management. Five classes of cathartics are currently available: bulk-forming agents, stimulants or irritants, softeners, saline and osmotic agents, and lubricants. The saline and osmotic agents are the most common cathartics and are the only agents advocated as adjunctive therapy for poisoning. Magnesium sulfate, magnesium citrate, sodium sulfate, sorbitol, and hypertonic phosphate solutions are generally used. In the early 1980s, commercial preparations of activated charcoal containing sorbitol as a diluent became available, and these products have gained widespread use. Sorbitol makes activated charcoal more palatable and provides a bacteriostatic environment during storage.
Digitoxin (Crystodigin) Glutethimide (Doriden) Meprobamate (Equanil, Miltown) Nadolol (Corgard) Phencyclidine HCI Phenobarbital (Luminal Sodium) Phenylbutazone (Azolid, Butazolidin) Phenytoin (Dilantin) Piroxicam (Feldene) Propoxyphene (Darvon, Dolene) Salicylates Theophylline Tricyclic antidepressants
Adverse effects from use of cathartics are primarily related to dehydration and electrolyte imbalances. These complications usually result from repeated administration of an agent. Hyper-
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Whole-bowel irrigation is indicated in patients who have ingested agents that are not adsorbed by activated charcoal.
ministered through a nasogastric tube at the same rate. The end point of treatment is a dear effluent, which may take 2 to 6 hours to obtain. There is some debate about whether the appearance of a dear effluent is an adequate gauge of the procedure's effective-
ness.
Carson R. Harris, MD Rick Kingston, PhannD Dr Harris (left) is senior staff physician, emergency medicine department, and interim medical director, Minnesota Regional Poison Center, St Paul-Ramsey Medical Center, St Paul. Dr Kingston (right) is senior clinical toxicologist, Minnesota Regional Poison Center.
magnesemia, hypocalcemia, hyperphosphatemia, and hypokalemia have been reponed. Although sorbitol is still used in commercial brands of activated charcoal, the use of other cathartics is declining.
Whole-bowel irrigation Recently, whole-bowel irrigation with polyethylene glycolelectrolyte solution (CoLyte, OCL) has been suggested as an option for gastrointestinal decontamination. The technique was first performed in the United
Kingdom using normal saline solution. However, use of normal saline solution had to be abandoned because patients experienced electrolyte abnormalities. During irrigation with polyethylene glycol-electrolyte solution, no fluids are absorbed or secreted across the gastrointestinal epithelium. For the procedure to be effective and to reduce abdominal discomfort, adults must ingest the solution at a rate of 2 Llhr (500 mL/hr in children); alternatively, the solution may be ad-
Patients may experience nausea and bloating during the procedure. These side effects can be averred by pretreatment with 10 to 20 mg of metodopramide (Reglan) given intravenously. Use of ipecac syrup with whole-bowel irrigation should be avoided, but activated charcoal may be administered before the procedure. Whole-bowel irrigation has been found to be safe and effective in the management of acute overdoses of such agents as ampicillin, iron, lithium, and entericcoated or sustained-release medications. It has also been used in decontamination of patients attempting to conceal packets of controlled substances (eg, cocaine).20 Patients who have ingested large amounts of agents that are poorly adsorbed or not adsorbed by activated charcoal are candidates for whole-bowel irrigation.
Combination therapy Attempts to improve the efficiency of gastrointestinal decon-
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tamination have included a combination of activated charcoal and lavage techniques. Unfortunately, study protocols have not closely reflected clinical practice, which usually involves a greater delay before initiation of treatment. In a study in animal models by Burton and colleagues/' activated charcoal administered before and after gastric lavage proved to be more effective than activated charcoal alone in reducing salicylate absorption. However, activated charcoal alone is superior to whole-bowel irrigation and activated charcoal used together. 22 '23 Because activated charcoal adsorbs drugs in seconds, it ideally should be given before lavage is performed, thereby decreasing the chance of drugcharcoal desorption farther down in the intestinal tract.
Conclusions The primary controversy in poison management concerns the use of activated charcoal alone versus gastric lavage or ipecac syrup before activated charcoal. Multiple studies have shown that a relatively small amount of gastric contents is removed with gastric lavage or ipecac syrup. However, a universally standardized lavage
method has not been used in these studies. The importance of lavage fluid temperature, abdominal massage, and positioning of the patient during the procedure has not been thoroughly evaluated. Other factors, such as diameter of the orogastric tube and size of aliquot, may play a role in obtaining optimum decontamination with gastric lavage. Further studies are needed using a standardized protocol in large samples of poisoned patients. Caution is advised with the use of activated charcoal alone, because not all substances are adsorbed by this agent and other methods may prove more effective. Gastric lavage may
force unabsorbed agents into the duodenum and small intestine, where they may be further absorbed and theoretically may cause the patient's condition to worsen. Positioning the patient on the left side with head lowered at about a 30-degree angle could minimize extrusion into the small intestine. lUll Earn credit on this article.
~ See CME Qui~
Address for correspondence: Carson R. Harris, MD, Emergency Medicine Department, St Paul-Ramsey Medical Center, 640 Jackson St, St Paul, MN 55101.
References 1. Robertson WO. Syrup of ipecac: a slow or fast emetic? Am J Dis Child 1962; I 03(Feb): 136-9 2. MacLean WC Jr. A comparison of ipecac syrup and apomorphine in rhe immediate rrearmenr of ingestion of poisons. J Pediarr 1973; 82(1):121-4 3. Rauber AP, Maroncelli RD. The duration of emetic effect of ipecac: duration and frequency of vomiting. (Absrr) Ver Hum Toxicol 1982; 24(Aug 4):281 4. Krenzelok EP, Dean BS. Effectiveness of 15-mL versus 30-mL doses of syrup of ipecac in children. Clin Pharm 1987;6(9):715-7 5. Kulig K, Bar-Or D, Cantrill SV, et al. Management of acutely poisoned patients withour gastric emptying. Ann Emerg Med 1985; 14(6):562-7 6. Tandberg D, Murphy LC. The knee-chest position does nor improve rhe efficacy of ipecac-
induced emesis. Am J Emerg Med 1989;7(3): 267-70 7. Tandberg D, Diven BG, McLeod.JW, Ipecac-induced emesis versus gasrric lavage: a controlled study in normal adults. Am J Emerg Med 1986;4(3):205-9
8. Auerbach PS, Osterloh J, Braun 0, et al. Efficacy of gastric emptying: gastric lavage versus emesis induced wirh ipecac. Ann Emerg Med 1986; 15(6):692-8 9. SaettaJP, Quinton DN. Residual gastric content after gastric lavage and ipecacuanhainduced emesis in self-poisoned patients: an endoscopic study. J R Soc Med 1991;84(1):35-8 10. SaettaJP, March S, Gaunt ME, et al. Gastric emptying procedures in the self-poisoned patient: are we forcing gastric content beyond rhe pylorus? J R Soc Med 1991 ;84(5):274-6 11. McDougal CB, Maclean MA. Modifications in rhe technique of gastric lavage. Ann
continued on page 128
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lheo-24® (theophylline anhydrous) Extended-releasecapsules 100,200, & 300 mg
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The following is a brief summary only. Before prescribing, consult complete prescribing information in product labeling orPOR.
INDICATIONS AND USAGE Theo·24 is indicated for relief and/or prevention of symptoms from asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema. CONTRAINDICATION& Theo-24 is contraindicated in patients with a history of hypersensitivity to theophylline. It is also contraindicated in patients with active peptic ulcer disease and in patients with underlying seizure disorders (unless receiving appropriate anticon· vulsant medication). WARNINGS Serum levels above 20 mcg/ml are rarely found after appropriate administration of the recommended doses. However, in individuals in whom theophylline plasma clearance is reduced for any reason, even conventional doses may result in increased serum levels and potential toxicity. Reduced theophylline clearance has been documented in the following readily identifiable groups: (1) patients with impaired liver function; (2) patients over 55 years of age, particularly mates and those with chronic tung disease; (3) patients with cardiac failure from any cause; (4) patients with sustained high fever; (5) infants under 1 year of age; and (6) patients tak1ng certain drugs (see Precautions: Drug/Drug interactiCms). Frequently, such patients have markedly prolonged theophylline serum levels following discontinuation of the drug. Reduction of dosage and laboratory monitoring is especially appropriate in the above individuals. Serious side effects such as ventricular arrhythmias, convulsions, or even death may appear as the first sign of toxicity without any previous warning. Less serious signs of theophylline toxicity (ie, nausea and restlessness) may occur frequently when initiating therapy, but are usually transient; when such signs are persistent during maintenance therapy, they are often associated with serum concentrations above 20 meg/mi. Serious toxicity is not reliably preceded by less severe side effects. A serum concentration measurement is the most reliable method of predicting potentially life-threatening toxicity. Many patients who require theophylline may exhibit tachycardia due to their underlymg disease process so that the cause/ effect relationship to elevated serum theophylline concentrations may not be recognized. Theophylline products may cause arrhythmia and/or worsen preexisting arrhythmtas. Any significant change in rate and/or rhythm warrants monitoring and further Investigation. Halothane anesthesia in the presence of theophylline may produce sinus tachycardia or ventricular arrhythmias. Studies in laboratory animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of necrosts of the myocardium) when theophylline and beta agonists were administered concomitantly. The significance of these findings when applied to humans is unknown. PRECAUTIONS General: On the average, theophylline's half-life is shorter in cigarette and marijuana smokers than in nonsmokers, but smokers can have half-lives as long as nonsmokers. Theophylline should not be administered concomitantly With other xanthlnes. Use with caution in patients with hypoxemia, hypertension, or those with a history of peptic ulcer. Theophyttlne may occasionally act as a local irritant to the gastrointestinal tract when administered orally, although gastrointestinal symptoms are more commonly centrally mediated and associated with serum drug concentrations over 20 meg/mi. Information for patients: Patients should be instructed to take this medication in the morning, at approximately the same time each day, and not to exceed the prescribed dose. Patients who require a relatively high dose of theophylline (1e, a dose equal to or greater than 900 mg or 13 mg/kg, which· ever tsless) should be informed of important considerations relating to time of drug administration and meal content (see Precautions: Drug/ Food interactions; and Dosage and Administration). As with any controlled-release theophylline product the patient should alert the physician if symptoms occur repeatedly, especially near the end of a dosing intervaL . Laboratory taata: Serum levels should be monitored periodically to determine the theophylline level associated with observed clinical response and as the method of prediCting toxicity. For such measurements, the serum sample should be obtained at the time of peak concentrations, approximately 12 hours after administration of a morning dose. It is important that the patient has not missed or taken additional doses during the previous 72 hqurs and that dosing Intervals have been reasonably cons1stent. Dose adjustment based on measurements when these 1nstructions have not been followed may result in toxicity (see Dosage and Administration). Drug Interaction• Drug/Drug interactions: Toxic synergism has been documented with ephedrine and may occur with other sympathomimetic bronchodllators. Halothane anesthesia in the presence of theophylline may produce sinus tachycardia or ventricular arrhythmias. In addition, the following drug interactions have been demonstrated with theophylline: Uthlum carbonate Increased renal excretion of lithium Allopurinol (hi-dose) Increased serum theophylline levels Clmetldlne Increased serum theophylline levels Erythromycin, troleandomycin Increased serum theophylline levels Oral contraceptive steroids Increased serum theophylline levels Ciprofloxacin Increased serum theophylline levels Propranolol Increased serum theophylline levels Phenytoin Decreased theophylline and phenytoin serum levels Carbamazepine Decreased serum theophylline levels Phenobarbital Decreased serum theophylline levels Alfampin Decreased serum theophylline levels Drug/Food interactions: Taking Theo-241ess than one hour before a high-fat-content meal, such as 8 oz whole milk, 2 fried eggs, 2 bacon Strips, 2 oz hashed brown potatoes, and 2 slices of buttered toast (about 985 calories, Including approximately 71 g of fat) may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state. In some cases (especially with doses of 900 mg or more taken less than one hour before a high-fat-content meal) serum theophylline levels may exceed the 20 mcg/mllevel, above which theophylline toxicity is more likely to occur. Drug !Laboratory test interactions: Currently available analytical methods, including high pressure liquid chromatography and immunoassay techniques, for measuring serum theophylline levels are specific. Metabolites and other drugs generally do not affect the results. Other new analytical methods are In use. The physician should be aware of the laboratory method used and whether other drugs wtll interfere with the assay for theophylline. Cerclnogeneala, mutagenaala, end Impairment of fertility: long-term carcmogenicity studies have not been performed with theophylline. Theophylline has been shown to be mutagenic in Eschen·chia coli and other lower organisms (Euglena gracilis and Ophiostoma multiannulatum). Chromosome-breaking activity was detected in human cell cultures at concentrations of theophylline up to 50 times the therapeutic serum concentration in humans. Theophylline was not mutagenic in the dominant lethal assay in male mice g1ven theophylline intraperitoneally in doses up to 30 times the maximum daily human oral OOse. Studies to determine the etlect on fertility have not been performed with theophylline. Pregnancy: Pregnancy Category C. limited animal studtes have shown teratogenic activity of theophylline in mice and rats. There are no adequate and well-controlled stud1es in pregnant women. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the latus. Nuralng mothere: Theophylline is distributed mto breast milk and may causa Irritability or other signs of toxicity in nursing infants. Because of the potential for serious adverse reactions in nursing infants from theophylline, a decision should be made whether to discontinue nurs1ng or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric use: Safety and effectiveness in children under 12 years of age have not been established with this product. ADVERSE REACnONS The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. The most consistent adverse reactions are usually due to overdosage. Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea. Central nervous system: headaches, irritability, restlessness, insomnia, reflex hyperexcitability, muscle twitching, clonic and tonic generalized convulsions. Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, ventricular arrhythmias. Respiratory: tachypnea. Renal: potentiation of diuresis. Other: alopecia, hyperglycemia, inappropriate ADH (antidiuretic hormone) syndrome, rash. HOW SUPPLIED Theo-24 (theophylline anhydrous) rs supplied in controlled-release capsules containing 100, 200, or 300 mg of anhydrous theophylline. Caution: Federal law prohibits dispensing without prescription. 8/14/89 References: 1. Tinkelman DG, Miller E, Janky DG et al, A comparative trial of the clin1cal efficacy and pharmacokinetics of 12-hour and 24-hourcontrolled release theophylline preparations m patients with chronic asthma. Ann Allergy 55: 571-576, 1985. 2. Dockhorn AJ, Green AW, Green E, Assessing the efficacy and safety of q.d. theophylline therapy: A multicenter study. Ann Allergy 55: 658-664, 1985.
Emerg Med 1981;10(10):514-7 12. Howland MA. Antidotes in depth: activated charcoal. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et a!, eds. Goldfrank's toxicologic emergencies. 4th ed. East Norwalk, CT: Appleton & Lange, 1990:129-33 13. Albertson TE, Derlet RW, Foulke GE, et al. Superiority of activated charcoal alone compared with ipecac and activated charcoal in the ueatment of acute toxic ingestions. Ann Emerg Med 1989;18(1):56-9 14. Merigian KS, Woodard M, Hedges JR, et al. Prospective evaluation of gastric emptying in the self-poisoned patient. Am J Emerg Med 1990;8(6):479-83 15. Neuvonen PJ, Vartiainen M, Tokola 0. Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Eur J Clin Pharmacol 1983;24(4) :55 7-62 16. Ekins BR, Ford DC, Thompson MI, et al. The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med 1987;5(6):483-7 17. Renzi FP, Donovan.JW; Martin TG, et al. Concomitant use of activated charcoal and N-acetylcysteine. Ann Emerg Med 1985;14(6): 568-72 18. Katona BG, Siegel EG, Cluxton RJ Jr. The new black magic: activated charcoal and new therapeutic uses. JEmerg Med 1987;5(1): 9-18 19. McLuckie A, Forbes AM, Dett KF. Role of repeated doses of oral activated charcoal in the treatment of acute intoxications. Anaesth Intensive Care 1990;18(3):375-84 20. Hollman RS, Smilkstein MJ, Goldfrank LR. Whole bowel irrigation and the cocaine body-packer: a new approach to a common problem. Am J Emerg Med 1990;8(6):523-7 21. Burton BT, Bayer MJ, Barron L, et al. Comparison of activated charcoal and gastric lavage in the prevention of aspirin absorption. J Emerg Med 1984; 1(5) :411-6 22. Rosenberg PJ, Livingstone OJ, McLellan BA. Effect of whole-bowel irrigation on the antidotal efficacy of oral activated charcoal. Ann EmergMed 1988;17(7):681-3 23. Hoffman RS, Chiang WK, Howland MA, et al. Theophylline desorption from activated charcoal caused by whole bowel irrigation solution. J Toxicol Clin Toxicol1991;29(2): 191-201
128 Manufactured lor Whitby Pharmaceuticals, Inc. Richmond, VA 23220, by G.D. Searle & Co. Chicago. ll60680
Gl DECONTAMINATION
