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Clinical Toxicology Fellow, Maryland Poison Center, School of Pharmacy, University of Maryland, Baltimore, MD
Coordinator of Research and Education; Associate Professor of Pharmacy Practice and Science, Maryland Poison Center, School of Pharmacy, University of Maryland
Medical Director, Maryland Poison Center, School of Pharmacy, University of Maryland
Reprints: Dr. Hayes, Maryland Poison Center, 220 Arch St., Office Level 1, Baltimore, MD 21201, fax 410/706-7184, bryan_d_hayes{at}yahoo.com
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Abstract |
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OBJECTIVE: To analyze the frequency of medication errors related to the complex dosing regimen for intravenous acetylcysteine.
METHODS: A retrospective chart review of a regional poison center's records was performed for all patients treated with intravenous acetylcysteine from August 1, 2006, to August 31, 2007. Data collected included acetylcysteine dose, infusion rate, interruptions in therapy, unnecessary administration, and medical outcome. Records that revealed medication errors were further examined for the time and location of the errors.
RESULTS: There were 221 acetaminophen overdose cases treated with intravenous acetylcysteine that met inclusion criteria. Of these, 84 medication errors occurred in 74 (33%) patients. The frequency and types of errors were 1.4% incorrect dose, 5% incorrect infusion rate, 18.6% more than 1 hour of interruption in therapy, and 13.1% unnecessary administration. The frequency and types of medication errors in pediatric patients were similar to those in the total patient population. Errors occurred most frequently in the emergency department compared with intensive care units or general medical floors. In addition, errors occurred most frequently on third shift, compared with first or second shift. Evaluation of medical outcomes in cases involving acetaminophen only found that medication errors did not have an impact on coded outcomes.
CONCLUSIONS: Medication administration errors occur frequently with intravenous acetylcysteine. Awareness of this problem, coupled with increased vigilance in identifying factors associated with errors, should decrease medication errors with intravenous acetylcysteine therapy for acetaminophen poisoning.
Key Words: acetaminophen, acetylcysteine, medication error, overdose
www.theannals.com, DOI 10.1345/aph.1K685
Ideally, there should be no interruption in therapy between each of the 3 infusions. Practically, however, the loading dose and/or second dose are usually started in the emergency department (ED). In the meantime, patients may be transferred from the ED to an intensive care unit (ICU) or general medical floor where the antidotal therapy must be continued. Each dose is made up separately and sent from the pharmacy. The complicated regimen, length of therapy, and need for multiple health professionals to administer doses to a given patient at multiple treatment sites potentiate the possibility of medication errors. The purpose of this study was to analyze the rate of medication errors related to the complex dosing regimen for Acetadote.
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This study was reviewed by the University of Maryland–Baltimore Institutional Review Board and was determined to be exempt.
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Thirty-five patients were less than 18 years of age. In this subset, 14 errors were documented in 12 (34.3%) patients. The frequency and types of medication errors in the pediatric patients were 2.8% incorrect dose, 0% incorrect infusion rate, 20% more than 1 hour interruption in therapy, and 17.1% unnecessary administration.
Therapy with intravenous acetylcysteine was initiated within 10 hours of acetaminophen ingestion in 92 (41.6%) patients. Therapy was begun more than 10 hours after ingestion in 70 (31.7%) patients. Time of ingestion could not be definitively determined in the remaining 59 (26.7%) patients.
Twenty-two errors occurred during first shift (0700 to 1500), 19 during second shift (1500 to 2300), and 30 during third shift (2300 to 0700). The exact time of error could not be determined in 13 cases. With regard to error location, 45 occurred in the ED, 11 in the ICU, 13 on the general medical floors, and 4 during patient transfers between treatment locations. The error location could not be determined in 11 cases. Evaluation of medical outcomes in cases involving acetaminophen only (n = 77) found that medication errors did not have an impact on coded outcomes.
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The most common type of error in this study was an interruption in therapy of greater than 1 hour. Given acetylcysteine's elimination half-life of 5.7 hours, interruptions in therapy less than 1 hour should not result in a clinically significant reduction in plasma concentrations.6 Longer breaks in therapy may decrease efficacy, although this has not been studied. It should be noted that our study was not intended to look at the impact of medication errors on outcomes, but rather was designed to investigate errors associated with the drug administration process.
The Rumack–Matthew nomogram is used to determine, based on plasma acetaminophen concentrations, whether or not acetylcysteine is indicated. The nomogram cannot be used for acetaminophen concentrations drawn before 4 hours postingestion.7,8 For patients presenting shortly after an acetaminophen overdose, with a clear time of ingestion, antidotal therapy can be withheld until the 4-hour concentration is obtained. Turnaround time for acetaminophen concentrations in most hospitals is rapid. Acetylcysteine has proven benefit if started within 10 hours of ingestion, which allows time for proper evaluation of a 4-hour acetaminophen concentration before starting therapy. In our study, 21 (10%) patients had subtoxic acetaminophen concentrations at 4 hours (<150 µg/mL) yet were started on intravenous acetylcysteine therapy prior to a 4-hour level having been obtained. All of these patients received a drug without an indication for its use; 1 (4.8%) developed an adverse reaction (facial flushing). Most of these patients were started on therapy by a healthcare provider prior to the poison center being contacted.
In total, 29 (13.1%) patients received unnecessary antidotal therapy. The pharmacy cost of treating one 70-kg patient with Acetadote is $416.9 This translates into a potential cost savings of $12,064 in these 29 patients. According to the annual report of the American Association of Poison Control Centers, intravenous acetylcysteine was used for 9191 patients nationally in 2006.10 Based on the 13.1% rate of unnecessary administration found in our study, we estimate a potential cost savings of $500,000 nationally each year.
Prescott et al.11 first reported the administration of intravenous acetylcysteine 300 mg/kg over 20.25 hours (using a loading dose of 150 mg/kg infused over 15 min, followed by 50 mg/kg over 4 h, and then 100 mg/kg over 16 h) to prevent liver toxicity in patients with acetaminophen poisoning who received treatment within 10 hours of the overdose. Although Great Britain, Canada, and Australia still use a 15-minute loading dose infusion rate, the FDA changed the rate to 60 minutes in 2006. One study with 180 patients did not demonstrate a statistically significant difference in anaphylactoid reactions between the 15- and 60-minute loading dose infusions (18% vs 14%, respectively; p = 0.45).12 However, the trend toward higher incidence of anaphylactoid reactions in the 15-minute loading dose infusion group, together with adverse event reports submitted to the FDA, prompted the 2006 change to 60 minutes for all patients treated in the US. Therefore, patients may be at higher risk if administered the loading dose over 15 minutes compared with 60 minutes. Older references still cite the 15-minute loading dose infusion rate protocol, which can lead to confusion among healthcare providers. Our study period included only patients treated after the loading dose rate was decreased, yet 5 patients still were administered the loading dose over 15 minutes. None developed adverse reactions. Two of these patients were administered the loading dose prior to consultation with our poison center. In the other 3 cases, the hospitals contacted the poison center initially and were advised to withhold therapy pending the 4-hour acetaminophen concentration. On obtaining a toxic 4-hour acetaminophen concentration, the loading dose of intravenous acetylcysteine was given (over 15 min) without recontact with the poison center.
The oral dosing regimen for acetylcysteine is vastly different from the intravenous schedule, with a loading dose of 140 mg/kg and maintenance doses of 70 mg/kg administered every 4 hours. Two patients were administered intravenous acetylcysteine at the oral regimen doses, both prior to consultation with the poison center. Selvan et al.13 assessed the ability of physicians and nurses to calculate correct doses using manual calculation skills and a weight-based dosing chart when prescribing and preparing acetylcysteine infusions. With manual calculations, errors were made by physicians and nurses in 26% of cases, while no errors were made using the dosing chart.
In the subset of patients less than 18 years of age, a comparable rate of total medication errors occurred compared with the total patient population. Similar to the total population, interruptions in therapy greater than 1 hour were the most frequent error. Age did not appear to be a risk factor for medication errors associated with intravenous acetylcysteine therapy for acetaminophen poisoning in our cohort.
In our study, errors occurred most frequently in the ED. This is not an unexpected finding considering that therapy is usually initiated in the ED setting. The unpredictable, hectic nature of an ED could lead to delays in prescribing and lapses in therapy or, conversely, to prescribing therapy unnecessarily while awaiting an acetaminophen concentration. Another finding in our study was that errors occurred most frequently on the overnight shifts. These findings should be viewed with caution considering that a 21-hour course of intravenous acetylcysteine therapy spans almost 3 full shifts and usually more than one patient location.
Ferner et al.14 prospectively collected samples of acetylcysteine infusions in 66 anonymous patients (184 individual bags) requiring treatment for acetaminophen overdose in the UK. The investigators measured the concentration in each infusion bag and deduced from the weight of the patient the percentage of the anticipated dose that had actually been given. Systematic calculation errors occurred in about 5% of cases, major errors in drawing up in 3%, and inadequate mixing in 9%. In total, doses in 17 bags were more than 50% from the anticipated doses. Although limitations of this study exist, including lack of a control solution and the possibility of acetylcysteine adherence to the intravenous bag, the results show that the preparation process is subject to error. The authors suggested that, instead of administering 3 bags at 3 different concentrations, with 3 different volumes being required, it may be possible to administer the dose in 2 bags of a similar volume.
It is important for healthcare providers to consult with poison centers and/or medical toxicologists early in the course of acetaminophen overdose cases. They can provide accurate and up-to-date dosing information as well as evidence-based protocols to ensure proper administration of antidotal therapy. Pharmacists can verify patient weights to confirm that the prescribed acetylcysteine dose is correct and can help facilitate efficiency and accuracy in preparation, delivery, and monitoring of intravenous acetylcysteine therapy.
Intravenous drug administration error rates are as high as 34–49%.15,16 Wirtz et al.15 observed errors in 34 per 100 patients in 3 teaching hospitals in the UK and Germany. A separate study in 2 UK hospitals reported administration errors in 49 of 100 patients.16 The Institute of Medicine report on preventing medication errors outlines numerous interventions that may promote decreasing errors in hospital care.17 Recommendations of the Institute that may help prevent intravenous medication errors with acetylcysteine include implementing computerized provider order entry; standardizing prescription writing; limiting and formally structuring verbal communication of prescriptions; and implementing standard processes for drug doses, dose timing, and dose scales in a given patient care unit. Specific recommendations for pharmacy include having a pharmacist review all medication orders before first doses, including a pharmacist during rounds of patient care units, having a central pharmacist supply high-risk intravenous drugs and pharmacy-based admixture systems, and having a pharmacist available on call after hours of pharmacy operation. Standardized order forms have been developed to reduce errors in ordering, dispensing, and administering chemotherapy.18 This approach may also be beneficial for intravenous medication use in other hospital settings.
Inherent in reviewing poison center data is that some data may be underdocumented (eg, exact start and stop time of each intravenous acetylcysteine infusion) based on the timing of follow-up calls by poison specialists. Based on the chart review, it appeared the poison specialist follow-up calls were made at appropriate times. However, due to the retrospective, observational nature of this study, it is impossible to quantify whether there was not strict compliance with the follow-up protocol. The poison center does not have access to patients' medical records. Reporting bias may also factor into the results obtained in this study. Because reporting to poison centers is voluntary, the frequency of errors reported in this study could reflect a hospital's propensity to contact the poison center only when problem cases are apparent. Healthcare providers who treat many acetaminophen poisoning cases may not contact the poison center routinely since they are familiar with the treatment. Therefore, it cannot be determined whether routine cases are subject to the same frequency of medication errors.
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This article has been cited by other articles:
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  M. Zolnierz, P. Sesin, and R. Motha Comment: Frequency of Medication Errors with Intravenous Acetylcysteine for Acetaminophen Overdose Ann. Pharmacother., January 1, 2009; 43(1): 152 - 152. [Full Text] [PDF]
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M. E Mullins, W. H Dribben, S E. Halcomb, and C. A McCammon Comment: Frequency of Medication Errors with Intravenous Acetylcysteine for Acetaminophen Overdose Ann. Pharmacother., December 1, 2008; 42(12): 1914 - 1915. [Full Text] [PDF]
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