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Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning

MICHELE ZELL KANTER
issatisfied with the unavailability of cysteamine, Prescott and Matthew1 rst suggested using acetylcysteine as an antidote for acetaminophen-induced hepatotoxicity in 1974. In 1977, Prescott et al.2 described the treatment of 15 patients with acetaminophen poisoning with i.v. acetylcysteine using a sterile 20% aqueous solution, suggesting that oral administration may improve the drugs efcacy, since most of the dose should pass through the liver. Thus the debate began of whether acetylcysteine should be administered orally or intravenously and continues to this day. The debate was fueled by the marketing approval by the Food and Drug Administration in early 2004 of Acetadote (Cumberland Pharmaceuticals, Nashville, TN), an i.v. acetylcysteine preparation. Clinicians now have a choice of using a premade i.v. acetylcysteine product, compounding an i.v. product from an oral acetylcysteine preparation, or administering the oral form that has been used for over 25 years. Deciding on the most appropriate formulation for an individual patient can be difcult, and many factors, including efcacy, safety, and cost, need to be considered before choosing a specic product. This article reviews the issues that should be considered

Purpose. The efficacy, safety, and cost issues that should be considered when deciding on the appropriate route of acetylcysteine for the treatment of patients with acetaminophen poisoning are reviewed. Summary. Oral and i.v. acetylcysteine appear to be equally eective when given within 810 hours of acetaminophen overdose. Anaphylactoid reactions to i.v. acetylcysteine have generally been reported in 36% of acetaminophen-poisoned patients. Dosing errors and hyponatremia have occurred in pediatric patients receiving i.v. acetylcysteine. Several investigators found an increased rate of anaphylactoid reactions in patients treated with i.v. acetylcysteine whose pretreatment serum acetaminophen levels were nontoxic. Compounding i.v. acetylcysteine from the oral preparation is less expensive than using premade i.v. solution. State pharmacy laws dictate whether extemporaneous compounding of acetylcysteine from the oral formulation is allowed. Oral acetylcysteine administration has resulted in minimal anaphylactoid reactions and is safer than i.v. acetylcysteine. Oral therapy should preferentially be considered in patients with asthma or atopic histories. The most im-

portant factors to consider when selecting the route of acetylcysteine administration include individual susceptibility, the severity of acetaminophen toxicity, and the time interval between acetaminophen ingestion and initiation of acetylcysteine therapy. Conclusion. Oral acetylcysteine administered within 810 hours of acetaminophen overdose prevents liver toxicity in the majority of patients who tolerate it and have no contraindications to therapy. I.V. acetylcysteine should be administered when patients are treated more than 10 hours postingestion of acetaminophen overdose or have underlying conditions preventing oral treatment. Anaphylactoid reactions are rare and occur more frequently in patients treated with the i.v. preparation. Index terms: Acetaminophen; Acetylcysteine; Allergies; Analgesics and antipyretics; Anaphylaxis; Antidotes; Blood levels; Contraindications; Costs; Dosage; Dosage schedules; Drug administration routes; Drugs, adverse reactions; Liver diseases; Pediatrics; Pharmacoeconomics; Placental transfer; Poisoning; Pregnancy; Protocols; Toxicity Am J Health-Syst Pharm. 2006; 63:1821-7

when deciding on the appropriate route of acetylcysteine for treating acetaminophen-poisoned patients. Mechanism of action About 4% of acetaminophen is

metabolized to N-acetyl-p-benzoquinoneimine (NAPQI) via the cytochrome P-450 (CYP) isoenzyme mixed-function oxidase system.3 This potentially toxic intermediate conjugates with glutathione, forming the nontoxic metabolites cysteine and

MICHELE ZELL KANTER, PHARM.D., is Coordinator, Toxikon Consortium, Section of Clinical Toxicology, Division of Occupational Medicine, Cook County Hospital, 1900 West Polk Street, Suite 500, Chicago, IL 60612 (nkanter@aol.com).

Copyright 2006, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/06/1001-1821$06.00. DOI 10.2146/ajhp060050

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mercapturic acid conjugates. In the overdose setting, a greater percentage of acetaminophen is metabolized by CYP, and glutathione becomes depleted, resulting in the formation of more NAPQI. NAPQIs presence causes hepatic centrilobular necrosis. Acetylcysteine prevents NAPQI from binding to hepatocytes, thereby preventing liver toxicity.4-6 Acetylcysteine as an antidote Prescott et al.7 and Smilkstein and colleagues8 published landmark papers demonstrating the efcacy of i.v. and oral acetylcysteine, respectively, in patients with acetaminophen poisoning. Prescott et al.7 found that the administration of acetylcysteine 300 mg/kg i.v. over 20 hours (using a loading dose of 150 mg/kg infused over 15 minutes, followed by 50 mg/ kg over 4 hours and then 100 mg/kg over 16 hours) prevented liver toxicity in all patients with acetaminophen poisoning who received treatment within 8 hours of the overdose. Smilkstein et al.8 conducted a large prospective study of oral acetylcysteine for acetaminophen overdose. A loading dose of 140 mg/kg was given, followed 4 hours later by 70 mg/kg every 4 hours for 17 doses. They found the 72-hour oral acetylcysteine regimen to be as effective as Prescott et al.s7 20-hour i.v. protocol and speculated that oral acetylcysteine may have greater efcacy than i.v. therapy when treatment is delayed beyond 10 hours. Prescott9 recently speculated that oral acetylcysteine was more efcacious in patients who sought treatment more than 10 hours after overdose because the dosage of the oral preparation was higher and the regimen was continued for a longer period of time compared with the i.v. protocol. Smilkstein and colleagues10 studied the efcacy of a high-dose (140mg/kg i.v. loading dose, followed by 12 70-mg/kg i.v. doses every 4 hours), 48-hour acetylcysteine protocol. This protocol was as effective as the 721822

hour oral and 20-hour i.v. protocols when started within 10 hours of acetaminophen overdose. The 48-hour i.v. protocol was more effective than the 20-hour i.v. protocol when treatment was delayed. Woo et al.11 conducted a retrospective study of 75 patients with acetaminophen poisoning to determine the safety and efcacy of oral acetylcysteine until serum acetaminophen levels were not detectable. All patients had toxic serum acetaminophen levels and were treated within 24 hours of overdose. Oral acetylcysteine was administered using a loading dose of 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours until serum acetaminophen was not detectable. One third of the patients were treated for less than 24 hours, one third for 2436 hours, and one third for 3764 hours. Six patients developed hepatotoxicity (i.e., aminotransferase concentration of >1000 IU/L), 2 in the 2436-hour group and 4 in the 3764-hour group. Three of these patients were treated at least 13 hours after ingesting acetaminophen. The occurrence of hepatotoxicity in this study was similar to the rates reported in the previously mentioned studies.7,8,10 Oral versus i.v. acetylcysteine Oral and i.v. acetylcysteine appear to be equally effective when given within 810 hours of acetaminophen overdose and when the oral route is tolerated. Perry and Shannon12 compared a 52-hour i.v. acetylcysteine protocol (140-mg/kg loading dose, followed by 70 mg/kg every 4 hours for 12 maintenance doses) with historical control pediatric patients treated using Smilkstein et al.8 72-hour oral acetylcysteine protocol. They found the 52-hour i.v. protocol to be as effective as the 72-hour oral protocol. The mean time to treatment was signicantly longer in the i.v. treatment group (14.4 versus 10.4 hours for the oral treatment group) (p = 0.001). Hepatotoxicity did not

occur in patients treated within 10 hours of ingestion. The rate of hepatotoxicity was the same for both groups when treatment was delayed 1024 hours after acetaminophen overdose. In another study, Buckley et al.13 retrospectively analyzed a series of acetaminophen poisonings treated with an i.v. acetylcysteine protocol (300 mg/kg was administered over 20 hours). These retrospective data were derived from the investigators poison center database. Patients were assessed for adverse effects, including hepatotoxicity. The authors then incorporated their results in a metaanalysis of previously reported studies of both i.v. and oral acetylcysteine. During the retrospective portion of the study, 3% of patients were noted to have developed hepatotoxicity. Compared with patients without hepatotoxicity, these patients ingested larger quantities of acetaminophen, sought treatment later, had higher serum acetaminophen levels, and received acetylcysteine later. The meta-analysis indicated that patients with probable or high-risk serum acetaminophen concentrations (dened using the Rumack et al.14 nomogram for treating acetaminophen poisoning) had similar outcomes regardless of whether they were treated with oral or i.v. acetylcysteine.13 Rates of hepatotoxicity were similar in patients who were treated within 10 and 1024 hours postingestion (regardless of route of administration). The authors concluded that any differences in studies comparing outcomes with i.v. and oral acetylcysteine were artifactual and likely the result of inappropriate subgroup analysis. They recommended treating patients with acetaminophen poisoning with i.v. acetylcysteine because it requires shorter hospitalization times. Compounded i.v. acetylcysteine versus Acetadote According to the American As-

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sociation of Poison Control Centers, 1886 patients were treated with i.v. acetylcysteine in 2003.15 The next year, a commercially prepared i.v. formulation of acetylcysteine (Acetadote) received FDA-approved labeling. Clinicians treating acetaminophen poisoning suddenly had a choice: use Acetadote or continue compounding the i.v. acetylcysteine preparation from the oral solution. However, the cost of Acetadote far exceeded that of compounded i.v. acetylcysteine. According to Lavonas et al.,16 the treatment of a 70-kg patient for 20 hours cost the pharmacy $416 for Acetadote, $57 for Mucomyst (Bristol-Myers Squibb), and $32 for generic acetylcysteine. These authors concluded that the compounded product and Acetadote were appropriate for treating acetaminophen overdose, considering that Acetadote has thus far not been shown to be safer than the compounded product. Preparation of i.v. acetylcysteine from the oral product is considered compounding and, according to Crouch and Rusho,17 is governed by state law. Clinicians treating patients with compounded acetylcysteine should consult their state pharmacy board to determine the legality of this process in their state now that an i.v. preparation is commercially available. Pediatric concerns Hyponatremia and seizures may occur in pediatric patients if they are treated according to standard acetylcysteine i.v. dosing guidelines for adults.18 This is primarily due to the excess free water they will receive with the medication. The authors of one case report described a 3year-old girl whose serum sodium concentration dropped from 141 to 118 mmol/L after 9 hours of i.v. acetylcysteine therapy. Had the 20-hour protocol been completed, she would have received 1540 mL of i.v. uid. As a result, the authors developed a treatment protocol for

pediatric patients weighing less than 40 kg to avoid this potentially lifethreatening situation. This protocol incorporates a nal acetylcysteine concentration of 40 mg/mL, thereby minimizing the risk of hyponatremia and hypervolemia in young children.18 Use in pregnancy Acetylcysteine has been detected in cord blood.19 Riggs et al.20 conducted a prospective study evaluating oral acetylcysteine for the treatment of acetaminophen toxicity. Of the 60 pregnant patients studied who ingested acetaminophen, 24 had plasma concentrations exceeding therapeutic values (using Rumack et al.s14 nomogram). Ten patients received oral acetylcysteine within 10 hours of acetaminophen ingestion, 10 were treated 1016 hours after ingestion, and 4 were treated 1624 hours after ingestion.20 Multiple logistic regression analyses showed signicant correlation between the risk of fetal death and the delay in initiating acetylcysteine therapy. The benets of using acetylcysteine early in the management of acetaminophen poisoning in pregnancy outweigh the risks of no treatment. Adverse eects Anaphylactoid reactions after acetaminophen poisoning. Anaphylactoid reactions to i.v. acetylcysteine, which likely result from histamine release,21 have generally been reported in 36% of acetaminophenp o i soned patients, 22,23 although a recent study reported the rate to be as high as 48%.24 Symptoms may include pruritis, rash, angioedema, bronchospasm, tachycardia, hypotension, nausea, and vomiting. Anaphylactoid reactions generally occur within 30 minutes after infusion of the loading dose. Oral acetylcysteine administration has resulted in minimal anaphylactoid reactions.25-27 Sunman et al.28 found that the rate of anaphylactoid reactions to i.v.

acetylcysteine was higher in patients who received iatrogenic overdoses of acetylcysteine (73%) compared with patients who did not receive overdoses (up to 3%). They also found the rate of hypotension to be higher in acetylcysteine overdose patients (6 of 11) compared with those who did not receive an overdose (6 of 38). Pruritis, angioedema, and bronchospasm occurred more frequently in patients who did not receive an overdose. Dawson et al.29 reported on 29 cases of adverse reactions to i.v. acetylcysteine that were reported to the Adverse Drug Reactions Advisory Committee in Australia over an eight-year period. All adverse reactions were anaphylactoid in nature, and all patients had good outcomes. There are reports of fatalities from overdoses of i.v. acetylcysteine. In one study, a follow-up questionnaire was sent to physicians who had consulted (over a 2.5-year period) with the National Poisons Information Service regarding patients who overdosed on acetaminophen.22 The authors reported 19 cases of acetylcysteine overdose, 15 of which had sufcient clinical information to be evaluated. Two patients died after receiving between 2.5 and 10 times the recommended loading dose of i.v. acetylcysteine. It was not clear whether acetylcysteine contributed to these deaths. In addition, there is a case report of a four-year-old child who received twice the recommended dose of i.v. acetylcysteine despite a nontoxic acetaminophen level.30 This child had an anaphylactic reaction without bronchospasm and could not be resuscitated. Autopsy results revealed circulatory congestion and small bilateral subdural hematomas. Kao et al.31 conducted a survey over a six-year period to determine the rate of adverse events with i.v. acetylcysteine compounded from the oral preparation. Medical records of all patients who received compounded i.v. acetylcysteine were retrospec1823

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tively reviewed. Adverse events were possibly or probably related to i.v. acetylcysteine for 7 (3.7%) of the 187 patients whose records were reviewed (95% condence interval [CI], 1.0 6.5%). Six of these reactions were cutaneous, and 1 was life threatening (cardiorespiratory arrest). I.V. acetylcysteine was continued in the patient with the life-threatening reaction because the treating physician felt that the cardiovascular problems exhibited were unrelated to the therapy. However, no other explanation for this patients adverse reactions was found. Adverse reactions from acetylcysteine may result from the rate at which the infusion is administered (i.e., the faster the infusion rate, the greater the rate of adverse effects).10,12,13,24,32 Kerr et al.23 recently studied the effect of the loading-dose infusion rate on the frequency of adverse effects in patients with acetaminophen poisoning. In this twoyear, multicenter, randomized trial, the i.v. acetylcysteine loading dose was infused over 15 or 60 minutes. There was no signicant difference in the rates of anaphylactoid reactions (18% versus 14%, respectively) and overall adverse events (45% versus 38%, respectively) between the two groups. Horowitz et al.33 commented on this study, indicating that although there was no statistically signicant difference in the rates of anaphylactoid reactions between the two groups, the reported rates of 18% and 14% were still higher than what is usually reported. They noticed an increase in anaphylactoid reactions in their practice since using Acetadote and attributed the increase to the preparation of acetylcysteine in 200 mL of 5% dextrose injection regardless of the patients weight. In doing this, a 70-kg patient would receive a nal concentration of acetylcysteine of 5.25%, while a 100-kg patient would receive 7.5%. In Kao et al.31 study, a nal concentration of 3% resulted when i.v. acetylcysteine
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was compounded from the oral preparation, and anaphylactoid reactions occurred in only 3.7% of patients. It is not evident from Kerr et al.23 data whether there was a difference in the rate of anaphylactoid reactions in patients who received more concentrated acetylcysteine solutions. Another group contended that Kerr et al.s study was biased, did not use a blocked randomization process, and was underpowered and therefore unable to show a difference in the rates of adverse events in the two groups, even if a difference did exist.34 Gawarammana et al.35 commented that Kerr et al.23 study did not mention the number of atopic or asthmatic patients. This is important, since these patients are at higher risk for developing reactions to acetylcysteine. There was no mention of patients acetaminophen levels in Kerr et al.23 study and whether adverse events occurred more frequently with lower levels. Anaphylactoid reactions to nontoxic levels of acetaminophen. Several investigators found an increased rate of anaphylactoid reactions in patients treated with i.v. acetylcysteine whose pretreatment serum acetaminophen levels were below the nomogram treatment line (dened by an acetaminophen level of <150 mg/L at 4 hours and <37.5 mg/L at 12 hours.) 24,29,36,37 Lynch and Robertson24 conducted a prospective casecontrol study to determine if there are predictive factors for acetylcysteine-induced anaphylactoid reactions. Of the 31 patients who developed anaphylactoid reactions, 13 (42%) had acetaminophen concentrations below the treatment line on Rumack et al.14 nomogram. Lynch and Robertson suggested that patients who had nontoxic acetaminophen levels, had nondetectable acetaminophen levels, or were treated more than 8 hours after ingestion had an increased likelihood of developing an anaphylactoid reaction to acetylcysteine.

Bailey and McGuigan37 evaluated the efcacy of an institution-specic treatment guideline in patients who had developed anaphylactoid reactions to i.v. acetylcysteine. Of the 22 patients with urticaria, 5 had nontoxic levels of acetaminophen. Two of the 8 patients with facial edema and 3 of the 19 patients with respiratory symptoms had nontoxic levels of acetaminophen. Dawson et al.29 reported that most of their patients (26 of 29) had blood acetaminophen levels below the nomogram treatment line. Nonetheless, these patients received i.v. acetylcysteine and subsequently developed adverse reactions. The authors did not give information on the specic adverse effects exhibited. There was a signicant correlation (p = 0.00006) between low serum acetaminophen levels and the development of adverse effects to acetylcysteine in Schmidt and Dalhoff s36 retrospective review. This prompted the authors to speculate that toxic serum acetaminophen levels may be autoprotective against acetylcysteineinduced toxicity. Other researchers have found that lymphocytes, neutrophils, and thrombocytes are functionally inhibited by toxic acetaminophen levels but not by therapeutic levels. 38-40 This is thought to be due to acetaminophen-induced inhibition of cyclooxygenase and the subsequent inhibition of prostaglandin and thromboxane synthesis. Schmidt and Dalhoff36 postulated that acetaminophen inhibits the function of basophils and mast cells, resulting in decreased anaphylactoid reactions to acetylcysteine in patients with toxic acetaminophen serum levels. Bronchospasm. Acetylcysteineinduced bronchospasm in asthmatic patients may be due to local histamine release or inhibition of allergen tachyphylaxis. 41 Allergen tachyphylaxis is dened as a decrease in asthma severity after patients are sequentially challenged by allergen

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inhalation. Dorsch et al.41 studied the effect of inhaled acetylcysteine on allergen tachyphylaxis in six asthmatic patients. Allergen tachyphylaxis was inhibited by inhaled acetylcysteine in two patients, prompting the authors to caution against acetylcysteine use in asthmatic patients. Schmidt and Dalhoff36 performed a retrospective chart review of 529 patients with acetaminophen poisoning to determine the risk factors for developing adverse reactions to acetylcysteine. Of the 529 patients, 33 (6.2%) had a history of asthma. Multipleregression analyses showed that adverse reactions occurred 2.8 times more frequently in asthmatic patients than those without asthma (p = 0.004). Systemic adverse reactions occurred 4.3 times more frequently in asthmatic patients (95% CI, 2.88.7). In the study conducted by Mant et al.,22 5 of the 38 patients who had anaphylactoid reactions after receiving appropriate doses of i.v. acetylcysteine developed bronchospasm. In addition, 2 patients who received overdoses of acetylcysteine had bronchospasm, and 1 developed respiratory depression. Of the 30 patients who developed adverse reactions to i.v. acetylcysteine in Dawson et al.29 study, 8 had bronchospasm. It is unclear whether any patients from either study had a history of asthma. All patients had good outcomes. Ho and Beilin42 described two cases of acetaminophen poisoning in which one patient had a nontoxic level of acetaminophen and the other had a level that was not interpretable. Both patients had a history of asthma and developed wheezing and worsening of asthma after receiving loading doses of i.v. acetylcysteine over 15 minutes. Acetylcysteine was discontinued in both patients, who then received i.v. aminophylline without sequelae. Appelboam and colleagues43 described a 40-year-old woman with a history of severe asthma who had a fatal reaction to a therapeutic dose

of i.v. acetylcysteine given for acetaminophen poisoning. No serum acetaminophen value was reported, but the patient admitted to ingesting about 15 g of acetaminophen over 48 hours. The patient developed shortness of breath and bilateral wheezing ve minutes after acetylcysteine was initiated. Acetylcysteine was immediately discontinued, and the patients condition rapidly deteriorated despite appropriate therapy. She experienced respiratory arrest followed by cardiac arrest and was resuscitated but died one week later. The authors recommended exercising extreme caution when administering i.v. acetylcysteine to patients with severe asthma. Status epilepticus. Two case reports of status epilepticus associated with i.v. acetylcysteine have been published.44,45 A previously healthy 30-month-old girl developed status epilepticus after receiving more than a 10-fold cumulative overdose of i.v. acetylcysteine.44 She was administered 44 mL/kg of 5% dextrose injection during the acetylcysteine infusion. She developed intracranial hypertension and subsequently died. Her serum sodium concentration was within normal limits, and the hypotonic uid that she received was not thought to have contributed to her seizures. The authors postulated that the intracranial hypertension might have resulted from a direct toxic effect of acetylcysteine, freewater overload, hypoxia from the seizure activity, or any combination of these. In the second case, a 30-month-old girl who potentially ingested acetaminophen 220 mg/kg developed status epilepticus and cortical blindness after 16 hours of i.v. acetylcysteine therapy.45 Her vision was almost completely recovered after 18 months. Effects on International Normalized Ratio. Jepsen and Hansen46 reported a significant decrease in prothrombin time and clotting factors II, VII, and X in healthy volun-

teers who received i.v. acetylcysteine. Wasserman and Garg47 noted prolonged prothrombin times, especially after receiving the loading dose, in 19 of 30 pediatric patients who received i.v. acetylcysteine for acetaminophen toxicity. These patients had no signs of hepatotoxicity. Kao and Furbee 48 reexamined the data from their previous study31 and found that 63 patients treated with i.v. acetylcysteine had measured International Normalized Ratios (INRs) during treatment. These patients had no evidence of hepatotoxicity. The INR values in these patients ranged from 0.93 to 2.84, with 28 patients (44%) having INR values of 1.2 or greater. The increase in INRs may have resulted from the destabilization of the disulde bonds in clotting factors by the thiol group in acetylcysteine.49 However, Whyte et al.50 found that acetaminophen overdose itself causes a functional (but not antigenic) factor VII deciency and is associated with a prolonged INR without hepatotoxicity. Selecting the appropriate route of administration Clinicians unfamiliar with acetylcysteine therapy may nd the treatment options confusing because of the various protocols for i.v. and oral formulations. Acetylcysteine administration within the United States generally occurs via the oral route unless underlying patient conditions (e.g., refractory vomiting) dictate i.v. administration. I.V. acetylcysteine administration has been routinely used in other countries. Controversy exists regarding which route of administration is safer and more efcacious. Until Acetadotes recent marketing approval, all intravenously administered acetylcysteine in the United States had to be compounded using the oral preparation. The most important factors to consider when selecting the route of acetylcysteine administration include individual susceptibility, the
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severity of acetaminophen toxicity (measured by plasma concentration in relation to the time of ingestion), and the time interval between acetaminophen ingestion and initiation of acetylcysteine therapy.9 Considerations with oral acetylcysteine. Acetylcysteine has a putrid odor, and its taste is very difcult to mask. Because oral acetylcysteine is unpalatable, patient adherence becomes an issue. Many patients develop nausea and vomiting after the administration of oral acetylcysteine. This delays acetylcysteine administration when time is of the essence. Absorption time is critical because of the narrow 810-hour window in which acetylcysteine is most effective in preventing acetaminopheninduced hepatotoxicity. Acetylcysteine absorption may be further delayed if the patient is receiving any concomitant drugs with anticholinergic properties. Investigators have studied whether oral acetylcysteine reduces activated charcoals ability to adsorb acetaminophen. The results of one in vitro study showed that acetylcysteine signicantly decreased the binding of activated charcoal to acetaminophen (p < 0.005).51 Orally administered acetylcysteine undergoes a rst-pass effect so that the entire dose passes through the liver, resulting in high concentrations and the potential for hepatotoxicity.2 This may be advantageous in poisoned patients who present within 810 hours postingestion. Acetylcysteine for oral administration is less expensive than both compounded i.v. acetylcysteine and Acetadote.16 However, this cost saving may be lost because patients may spend less time in the hospital receiving i.v. acetylcysteine compared with the oral preparation, even if an abbreviated oral acetylcysteine protocol is followed. However, it is easier to prepare the oral product than to extemporaneously prepare the i.v. product.
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Adverse effects to oral therapy have been mild. 2 5 - 2 7 Therefore, acetaminophen-poisoned patients requiring antidotal therapy who have a history of asthma or hypersensitivity reactions should receive oral acetylcysteine unless circumstances preclude this route of therapy. Considerations with i.v. acetylcysteine. Serious anaphylactoid reactions,22,29 asthma,42,43 and status epilepticus44,45 have only been reported in patients receiving i.v. acetylcysteine. According to Kerr et al.,23 these reactions are not related to the rate of acetylcysteine infusion. Whether there is an increased rate of adverse events in patients treated with i.v. acetylcysteine who do not have toxic acetaminophen serum levels requires further study. Although iatrogenic dosing errors can occur with both oral and i.v. acetylcysteine, the resultant adverse effects from errors in i.v. acetylcysteine dosing are likely to have graver consequences. Mant et al.22 found dosing errors of 10 times the recommended dose in 5 of 15 patients. Most errors occurred during administration of the initial dose of acetylcysteine (11 of 15 patients). Ferner et al.52 conducted a prospective study to determine the variability of stated concentrations of acetylcysteine from patients i.v. bags before and after administration. They found the concentration to be within 10% of the stated concentration in 68 (37%) of 184 bags, and within 20% of the stated concentration in 112 bags (61%). The concentration was more than 50% different from the stated concentration in 17 bags (9.2%). Inadequate mixing occurred in 9% of the bags sampled (95% CI, 414%). Acetaminophen-poisoned patients requiring antidotal treatment who cannot tolerate oral acetylcysteine should receive i.v. therapy without delay. Likewise, patients who ingest acetaminophen and receive treatment approximately 810 hours postingestion should receive oral

acetylcysteine. I.V. acetylcysteine should be considered for patients who will require activated charcoal therapy, since oral acetylcysteine has been shown in vitro to diminish activated charcoals efcacy to bind acetaminophen.51 Conclusion Oral acetylcysteine administered within 810 hours of acetaminophen overdose prevents liver toxicity in the majority of patients who tolerate it and have no contraindications to therapy. I.V. acetylcysteine should be administered when patients are treated more than 10 hours postingestion of acetaminophen overdose or have underlying conditions preventing oral treatment. Anaphylactoid reactions are rare and occur more frequently in patients treated with the i.v. preparation.
References
1. Prescott LF, Matthew H. Cysteamine for paracetamol overdosage. Lancet. 1974; 1:998. Letter. 2. Prescott LF, Park J, Ballantyne A et al. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet. 1977; 2:432-4. 3. Corcoran GB, Mitchell JR, Vaishnav YN et al. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-pbenzoquinoneimine. Mol Pharmacol. 1980; 18:536-42. 4. Buckpitt AR, Rollins DE, Mitchell JR. Varying effects of sulfhydryl nucleophiles on acetaminophen oxidation and sulfhydryl adduct formation. Biochem Pharmacol. 1979; 28:2941-6. 5. Lauterburg BH, Corcoran GB, Mitchell JR. Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo. J Clin Invest. 1983; 71:980-91. 6. Slattery JT, Wilson JM, Kalhorn TF et al. Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther. 1987; 41:413-8. 7. Prescott LF, Illingworth RN, Critchley JA et al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J. 1979; 2:1097100. 8. Smilkstein MJ, Knapp GL, Kulig KW et al. Efcacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988; 319:1557-62.

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9. Prescott L. Oral or intravenous Nacetylcysteine for acetaminophen poisoning? Ann Emerg Med. 2005; 45:409-13. 10. Smilkstein MJ, Bronstein AC, Linden C et al. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991; 20:105863. 11. Woo OF, Mueller PD, Olson KR et al. Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose. Ann Emerg Med. 2000; 35:363-8. 12. Perry HE, Shannon MW. Efcacy of oral versus intravenous N-acetylcysteine in acetaminophen overdose: results of an open-label, clinical trial. J Pediatr. 1998; 132:149-52. 13. Buckley NA, Whyte IM, OConnell DL et al. Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen poisoning? J Toxicol Clin Toxicol. 1999; 37:759-67. 14. Rumack BH, Peterson RC, Koch GG et al. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981; 141:380-5. 15. Watson WA, Litovitz TL, Klein-Schwartz W et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2004; 22:335-404. 16. Lavonas EJ, Beuhler MC, Ford MD et al. Intravenous administration of Nacetylcysteine: oral and parenteral formulations are both acceptable. Ann Emerg Med. 2005; 45:223-4. Letter. 17. Crouch BI, Rusho WJ. Intravenous administration of N-acetylcysteine. Ann Emerg Med. 2005; 46:207. Letter. 18. Sung L, Simons JA, Dayneka NL. Dilution of intravenous N-acetylcysteine as a cause of hyponatremia. Pediatrics. 1997; 100:389-91. 19. Horowitz RS, Dart RC, Jarvie DR et al. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Toxicol Clin Toxicol. 1997; 35:447-51. 20. Riggs BS, Bronstein AC, Kulig K et al. Acute acetaminophen overdose during pregnancy. Obstet Gynecol. 1989; 74:24753. 21. Bateman DN, Woodhouse KW, Rawlins MD. Adverse reactions to N-acetylcysteine. Hum Toxicol. 1984; 3:393-8. 22. Mant TG, Tempowski JH, Volans GN et al. Adverse reactions to acetylcysteine and effects of overdose. Br Med J. 1984; 289:217-9. 23. Kerr F, Dawson A, Whyte IM et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of Nacetylcysteine. Ann Emerg Med. 2005; 45:402-8.

24. Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study. Accid Emerg Nurs. 2004; 12:10-5. 25. Charley G, Dean BS, Krenzelok EP. Oral N-acetylcysteine induced urticaria: a case report. Vet Hum Toxicol. 1987; 29:477. Abstract. 26. Rosencrance JG, Scharman EJ. Anaphylactoid reaction to oral N-acetylcysteine: a case report. Vet Hum Toxicol. 1993; 35:4. Abstract. 27. Mroz LS, Benitez JG, Krenzelok EP. Angioedema with oral N-acetylcysteine. Ann Emerg Med. 1997; 30:240-1. Letter. 28. Sunman W, Hughes AD, Sever PS. Anaphylactoid response to intravenous acetylcysteine. Lancet. 1992; 339:1231-2. Letter. 29. Dawson AH, Henry DA, McEwen J. Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning. Med J Aust. 1989; 150:329-31. 30. Death after N-acetylcysteine. Lancet. 1984; 323:1421. 31. Kao LW, Kirk MA, Furbee RB et al. What is the rate of adverse events after oral Nacetylcysteine administered by the intravenous route to patients with suspected acetaminophen poisoning? Ann Emerg Med. 2003; 42:741-50. 32. Chan TY, Critchley JA. Adverse reactions to intravenous N-acetylcysteine in Chinese patients with paracetamol (acetaminophen) poisoning. Hum Exp Toxicol. 1994; 13:542-4. 33. Horowitz BZ, Hendrickson RG, PizarroOsilla C. Not so fast! Ann Emerg Med. 2006; 47:122-3. Letter. 34. Manini AF, Snider C. Intravenous loading infusion rates of N-acetylcysteine. Ann Emerg Med. 2006; 47:123-4. Letter. 35. Gawarammana IB, Greene SL, Dargan PI et al. Australian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med. 2006; 47:124. Letter. 36. Schmidt LE, Dalhoff K. Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol. 2001; 51:87-91. 37. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med. 1998; 31:710-5. 38. Panush RS. Effects of certain antirheumatic drugs on normal human peripheral blood lymphocytes. Inhibition of mitogen- and antigen-stimulated incorporation of tritiated thymidine. Arthritis Rheum. 1976; 19:907-17. 39. Shalabi EA. Acetaminophen inhibits the human polymorphonuclear leukocyte

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

function in vitro. Immunopharmacology. 1992; 24:37-46. Lages B, Weiss HJ. Inhibition of human platelet function in vitro and ex vivo by acetaminophen. Throm Res. 1989; 53:60313. Dorsch W, Auch E, Powerlowicz P. Adverse effects of acetylcysteine on human and guinea pig bronchial asthma in vivo and on human broblasts and leukocytes in vitro. Int Arch Allergy Appl Immunol. 1987; 82:33-9. Ho SW, Beilin LJ. Asthma associated with N-acetylcysteine infusion and paracetamol poisoning: report of two cases. Br Med J. 1983; 287:876-7. Appelboam AV, Dargan PI, Knighton J. Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma. Emerg Med J. 2002; 19:594-5. Bailey B, Blais R, Letarte A. Status epilepticus after a massive intravenous Nacetylcysteine overdose leading to intracranial hypertension and death. Ann Emerg Med. 2004; 44:401-6. Hershkovitz E, Shorer Z, Levitas A et al. Status epilepticus following intravenous N-acetylcysteine therapy. Isr J Med Sci. 1996; 32:1102-4. Jepsen S, Hansen AB. The influence of N-acetylcysteine on the measurement of prothrombin time and activated partial thromboplastin time in healthy subjects. Scand J Clin Lab Invest. 1994; 54:543-7. Wasserman GS, Garg U. Intravenous administration of N-acetylcysteine: interference with coagulopathy testing. Ann Emerg Med. 2004; 44:546-7. Letter. Kao LW, Furbee RB. What is the rate of adverse events with intravenous versus oral N-acetylcysteine in pediatric patients? Ann Emerg Med. 2004; 44:547-8. Letter. Koterba AP, Smolen S, Joseph A et al. Coagulation protein function. II. Inuence of thiols upon acetaldehyde effects. Alcohol. 1995; 12:49-57. Whyte IM, Seldon M, Buckley NA et al. Effect of paracetamol poisoning on international normalised ratio. Lancet. 2003; 361:429. Letter. Tenenbein PK, Sitar DS, Tenenbein M. Interaction between N-acetylcysteine and activated charcoal: implications for the treatment of acetaminophen poisoning. Pharmacotherapy. 2001; 21: 1331-6. Ferner RE, Langford NJ, Anton C et al. Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example. Br J Clin Pharmacol. 2001; 52:573-7.

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