Figure 1. Supratherapeutic acetaminophen dosing instances and acetaminophen exposure time. A, Examples of supratherapeutic acetaminophen dosing instances and the length of supratherapeutic dosing time (each time-stamp indicates that the patient took 1 g of acetaminophen). B, Examples of acetaminophen exposure time for Cox regression model (each time-stamp indicates that the patient took 1 g of acetaminophen).
Figure 2. Distribution diagrams of supratherapeutic dosing amounts and periods for supratherapeutically dosed patients during their hospital stay. A, Frequency distribution of the maximum supratherapeutic dosing amounts. B, Cumulative frequency of supratherapeutic dosing by total number of days.
Figure 3. Changes in alkaline phosphatase (ALP) test results for patients who received supratherapeutic acetaminophen dosing and who did not. (For patients who received supratherapeutic dosing patient, “before” means the latest laboratory test result before the first supratherapeutic dosing and “after” means the first result within 14 days after the last supratherapeutic dosing. For patients who did not receive supratherapeutic dosing, “before” means the first laboratory test result and “after” means the last result of their hospitalization.) To convert ALP to microkatals per liter, multiply by 0.0167.
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Zhou L, Maviglia SM, Mahoney LM, et al. Supratherapeutic Dosing of Acetaminophen Among Hospitalized Patients. Arch Intern Med. 2012;172(22):1721–1728. doi:10.1001/2013.jamainternmed.438
Author Affiliations: Information Systems, Partners HealthCare System Inc, Wellesley, Massachusetts (Drs Zhou, Maviglia, Mahoney, Bates, and Rocha, Mssrs Chang, Plasek, and Lou, and Ms Boulware); and Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Drs Zhou, Maviglia, Orav, Bates, and Rocha).
Background We investigated acetaminophen use and identify factors contributing to supratherapeutic dosing of acetaminophen in hospitalized patients.
Methods We retrospectively reviewed the electronic health records of adult patients who were admitted to 2 academic tertiary care hospitals (hospital A amd hospital B) from June 1, 2010, to August 31, 2010, and who received acetaminophen during their hospitalization. Patients' acetaminophen administration records (including drug name, dose, administration time, hospital units, etc), demographic data, diagnoses, and results from liver function tests were obtained. The main outcome measures included acetaminophen exposure rate and supratherapeutic dosing rate among hospitalized patients, hazard ratios (HRs) and 95% confidence intervals (CIs) for risk factors for supratherapeutic dosing, and changes in liver function test before and after supratherapeutic dosing.
Results A total of 14 411 patients (60.7%) were exposed to acetaminophen, of whom 955 (6.6%) exceeded the 4 g per day maximum recommended dose. In addition, 22.3% of patients who were 65 years or older and 17.6% of patients with chronic liver diseases exceeded the recommended limit of 3 g per day. Patients receiving excessive doses of acetaminophen tended to have significant alkaline phosphatase elevations, although causal relationship cannot be concluded. A significantly higher risk of supratherapeutic dosing was observed in hospital A (HR, 1.6 [95% CI, 1.4-1.8]), white patients (HR, 1.5 [95% CI, 1.3-1.7]), patients diagnosed as having osteoarthritis (HR, 1.4 [95% CI, 1.3-1.6]), and those who received scheduled administrations (HR, 16.6 [95% CI, 13.5-20.6]), multiple product formulations (HR, 2.4 [95% CI 2.0-2.9]), or the 500-mg strength formulation (HR, 1.9 [95% CI, 1.5-2.3]). A lower risk was found for pro re nata (as needed) administrations (HR, 0.7 [95% CI, 0.6-0.9]) and in nonsurgical and non–intensive care units (HR, 0.6 [95% CI, 0.5-0.7]).
Conclusions Supratherapeutic dosing of acetaminophen was significantly associated with multiple factors. Interventions to reduce the incidence of some risk factors may prevent supratherapeutic acetaminophen dosing in hospitalized patients.
Acetaminophen is one of the most commonly used drugs for pain relief and fever reduction.1-3 At the same time, acetaminophen toxicity is the leading cause of acute liver failure (ALF).4-7 A study of 22 specialty medical centers in the United States reported that the annual percentage of acetaminophen-related ALF rose from 28% in 1998 to 51% in 2003.4 Patients who took more than the recommended maximum dose (eg, 4 g/d for persons >12 years) of acetaminophen-containing products or who consumed alcohol while taking acetaminophen were at risk for hepatotoxicity, ranging from abnormalities in liver function blood tests,8 to ALF, and even death.9,10 Other complications include coagulopathy10 and deafness.11 The US Food and Drug Administration (FDA) has taken several steps to cut risks from acetaminophen, including asking manufactures of prescription acetaminophen combination products to limit the amount of acetaminophen to 325 mg per dosage unit and requiring a boxed warning on all products that highlights the potential risk for severe liver injury.2,12
Historically, acetaminophen has been marketed as “the safer”13 pain reliever because it lacks the adverse effect profile of other well-known analgesic classes, for example, nonsteroidal anti-inflammatory–induced gastritis or opioid-induced respiratory depression. Acetaminophen comes in a variety of dosage forms (eg, tablet and liquid). It is marketed under a wide array of brand names and generic labels and is common in both over-the-counter drugs (eg, Tylenol) and prescription drugs (eg, Percocet). Acetaminophen is available as a single ingredient, or in combination with other ingredients for the purpose of multisymptom relief (eg, fever, cough, and insomnia). It is difficult for consumers and sometimes even health care professionals to recognize that acetaminophen is a component of so many products.
Previous studies of excessive acetaminophen use often focused on the outpatient setting, where it was hypothesized that patients may have poor knowledge about the safe maximum daily dose and may choose more than 1 drug containing acetaminophen concurrently to treat different clinical conditions or symptoms.14 Heaton et al15 observed that over 3% of Ohio Medicaid patients had potentially ingested at least 4 g/d, or at least 3 g/d with a previous underlying liver dysfunction. Albertson et al16 examined the pharmacy claims data of California's Medicaid fee-for-service population and found that 5.9% of patients were potentially exposed to at least 1 day of 4 g/d or more of acetaminophen.
In the inpatient setting, clinicians are more aware of acetaminophen's risks, and patients' actual acetaminophen consumption is monitored and recorded. Nevertheless, the complexities of tracking the daily cumulative dose of acetaminophen may result in ineffective monitoring and inadvertent supratherapeutic dosing. Thus far, little research has been done in investigating acetaminophen exposure in the inpatient setting.
In this study, we used patients' inpatient medication administration data recorded in an electronic medication administration record (eMAR) system17,18 to examine the acetaminophen exposure among hospitalized patients. The eMAR system is typically implemented in conjunction with other technologies (such as barcode technology) at the bedside to allow clinicians to verify a patient's identity and her or his medication administrations.
This study was conducted at 2 academic tertiary care hospitals located in Boston, Massachusetts, hospital A and hospital B. Patients 12 years or older admitted to these 2 hospitals from June 1, 2010, to August 31, 2010, who received acetaminophen during their hospital stay were included in this study. This study was approved by the human research committee of Partners HealthCare System.
Patients' medication administration records were obtained from the institutions' eMAR system.17,18 Each record included medication name, strength, dose amount, route, administration time, instructions, administering hospital unit (eg, intensive care unit [ICU]), and other information. Patients' demographic data (including age, sex, and race/ethnicity) were obtained from the institutions' common Clinical Data Repository (CDR). Patients' primary diagnoses were obtained from the institutions' common Research Patient Data Registry (RPDR)19 using claims data and patients' problem lists in their electronic health records. Diseases identification (eg, chronic liver diseases [CLDs]20) was based on a set of International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes. We also obtained patients' liver function test results measured during their hospital stay, including serum alanine transaminase (ALT), aspartate transaminase, alkaline phosphatase (ALP), direct bilirubin, and total bilirubin levels, and prothrombin time international normalized ratios.
A supratherapeutic dosing instance was defined as any cumulative administration of acetaminophen of more than 4 g/d. Secondary analyses of patients who were 65 years or older and patients with CLD were performed using a supratherapeutic dosing threshold of 3 g/d.15
Among inpatients exposed to acetaminophen, we calculated the percentage who had at least 1 episode of supratherapeutic acetaminophen dosing and the number of supratherapeutic dosing instances each patient had. Because an instance was defined for any 24-hour window, instances can overlap (Figure 1A). We determined the length of time (in days) during which a patient received excessive acetaminophen by totaling the duration of each supratherapeutic dosing period without double counting the periods of overlap. We compared the average number of administrations of acetaminophen per day and the average amount per dose for patients who had supratherapeutic dosing with those who did not.
To identify potential risk factors for supratherapeutic dosing, we compared patients who had at least 1 instance of supratherapeutic dosing with patients who remained under the recommended limit with respect to demographic characteristics, diagnoses, hospitals, hospital units, and the types of acetaminophen products administered (ingredients, numbers of products, strengths, and instructions). We assessed statistical significance using the χ2 test for categorical variables and t test for continuous variables, and P < .05 was considered statistically significant. Potential risk factors for supratherapeutic dosing identified by the univariate analysis were entered into a multivariate Cox model. In the Cox model, the start of the acetaminophen exposure time of each patient was defined as either the time of the first administration of acetaminophen or the start of a new dosing sequence after a supratherapeutic dosing event. If a supratherapeutic dosing event occurred, the stop time was when the supratherapeutic dose was administered. For the patient's last acetaminophen exposure time period or for cases in which the patient did not experience any supratherapeutic dosing during hospitalization, the stop time was censored at the patient's last administration of any drug (Figure 1B). We divided each acetaminophen exposure into 24-hour periods, calculating and updating the time-varying covariates in each period. Different acetaminophen products were not included in the Cox model because they highly correlated with variables for different dose strength formulations. Hazard ratios (HRs) and their 95% confidence interval (CIs) were calculated from the Cox model. We also examined whether patients' liver function test results were affected by supratherapeutic dosing of acetaminophen during their hospital stay. Because studies showed that the normalization of liver function tests often take 1 to 3 weeks,21 we calculated the difference between the latest laboratory test result before the first supratherapeutic dosing and the first result within 14 days (if any) after the last supratherapeutic dosing. For patients who had no instances of supratherapeutic dosing, we calculated the difference between the first and the last laboratory test results of their hospitalization. Then, we compared the differences between the 2 groups using a linear regression model adjusted for available characteristics and diagnoses (eg, the presence or absence of CLD) of the patients.
Patient data were managed in a Microsoft SQL Sever (version 8.0) database, and data analysis was performed with SAS statistical software (version 9.2; SAS Institute Inc).
From June through August 2010, 23 750 patients at the 2 hospitals had eMAR records and were at least 12 years old. Of these, 14 411 patients (60.7%) received acetaminophen and comprised the study population. The average age of the patients was 55.4 years (range, 12-110 years), and 35.1% of the patients were 65 years or older. White patients comprised 78.4% of the study sample, 58.0% were female, and 6.9% had CLD.
Of the 14 411 study patients, 955 (6.6%) exceeded the 4 g/d limit (9.6% at hospital A and 4.2% at hospital B). Overall, 955 of 23 750 (4.0%) of all hospitalized adults were exposed to supratherapeutic dosing of acetaminophen. In addition, 22.3% of patients 65 years or older and 17.6% of patients with CLD exceeded the recommended limit of 3 g/d.
Averaged over their entire hospital stays, patients who received a supratherapeutic dosing had more administrations per day (3.5 vs 1.5; P < .001) and a higher dose per administration (791 mg vs 651 mg; P < .001). Almost half of the instances of supratherapeutic dosing were more than 5 g/d (Figure 2A). Each patient who received supratherapeutic dosing had a mean (SD) of 4.9 (5.3) incidences (range, 1-48 incidences), comprising a mean of 2.9 (3.0) days (range, 1-30 days). Figure 2B demonstrates the distribution of the total number of supratherapeutic dosing days for the supratherapeutically dosed patient population. About 40% of the patients received supratherapeutic dosing for 3 days or more and 4.0% for 10 days or more.
Univariate results are summarized in Table 1. Patients who received supratherapeutic dosing tended to be older (56.6 vs 55.4 years; P = .04). White and 40- to 64-year-old patients were more likely to receive supratherapeutic dosing (odds ratio [OR], 2.0 [95% CI, 1.7-2.5] and OR, 1.4 [95% CI, 1.2-1.6], respectively), as were patients at hospital A (OR, 2.4 [95% CI, 2.1-2.8]). Surgical units and ICUs were associated with higher risk of supratherapeutic dosing (OR, 2.9 [95% CI, 2.5-3.3] and OR, 1.3 [95% CI, 1.1-1.6], respectively). In contrast, medicine and other units were associated with a lower risk (OR, 0.6 [95% CI, 0.5-0.7] and OR, 0.7 [95% CI, 0.6-0.8], respectively). While preexisting CLD was associated with decreased likelihood of supratherapeutic dosing (OR, 0.5 [95% CI, 0.4-0.7]), osteoarthritis was associated with increased risk (OR, 4.2 [95% CI, 3.6-5.0]). No difference in supratherapeutic dosing rate was noted between patients who received multi-ingredient products and those who did not, but single-ingredient products was demonstrated to have a higher risk (OR, 3.4 [95% CI, 2.5-4.6]). Patients who received more than 1 type of acetaminophen-containing product had higher rates of supratherapeutic dosing (OR, 1.8 [95% CI, 1.5-2.1]). Of 164 patients who received 3 or more different acetaminophen-containing products, the rate of supratherapeutic dosing was 20.7%. Products containing 500 mg of acetaminophen per dosage unit were associated with supratherapeutic dosing (OR, 10.7 [95% CI, 9.3-12.2]), as were recurring scheduled administrations (ie, standing doses) (OR, 29.3 [95% CI, 24.5-35.1]), but not pro re nata (PRN) (as needed) (OR, 0.1 [95% CI, 0.1-0.2]) and 1-time administrations.
Since the supratherapeutic dose rates differed by location, we compared the patient characteristics and acetaminophen administrations of hospital A and hospital B (Table 2). Hospital A had more female patients (62.9% vs 53.9%; P < .001), fewer patients with CLD (4.2% vs 9.2%; P < .001), fewer patients with osteoarthritis (7.2% vs 9.6%; P < .001), fewer patients in surgical units and ICUs (27.4% vs 51.8%, P < .001; and 8.7% vs 19.1%, P < .001, respectively), more patients in medicine and other units (35.6% vs 26.9%; P < .001; and 42.4% vs 18.6%; P < .001, respectively), more frequent use of single-ingredient (98.6% vs 77.5%; P < .001) and 500-mg products (19.1% vs 5.1%; P < .001), and a much higher percentage of standing dose administrations (25.3% vs 15.9%; P < .001). Hospital B administered more combination products (44.8% vs 4.7%; P < .001) and was more likely to administer multiple products to patients (23.2% vs 3.2%; P < .001).
Multivariate Cox modeling analysis (Table 3) revealed that the strongest risk factors associated with supratherapeutic dosing were recurring scheduled (standing-order) administrations (HR, 16.6 [95% CI, 13.5-20.6]), the number of different products a patient received (HR, 2.4 for each additional product [95% CI, 2.0-2.9]), and the use of products containing 500-mg acetaminophen (HR, 1.9 [95% CI, 1.5-2.3]). In addition, white patients (HR, 1.5 [95% CI, 1.3-1.7]), patients with osteoarthritis (HR, 1.4 [95% CI, 1.3-1.6]), and patients who were at hospital A (HR, 1.6 [95% CI, 1.4-1.8]) were more likely to receive excessive dosing. A lower risk was found among patients who were in medicine or other units (HR, 0.6 [95% CI, 0.5-0.7]) and those who had PRN administrations (HR, 0.7 [95% CI, 0.6-0.9]).
Table 4 summarizes the observed changes in liver function tests between patients who received supratherapeutic dosing and those who did not. While no causal relationship can be inferred, patients who received supratherapeutic dosing were more likely to have statistically significant elevations in ALP level (Figure 3), statistically insignificant elevations in ALT level, but neither clinically nor statistically significant changes in other liver injury markers.
Previous studies of supratherapeutic acetaminophen dosing in outpatient populations assumed that a prescription filled is a prescription consumed.15,16 Prescriptions that specify dosing ranges or PRN instructions limit one's ability to determine whether a supratherapeutic dosing occurred. Supratherapeutic dosing of acetaminophen could be precisely and reliably determined for this study owing to the use of inpatient eMAR data that accurately recorded patients' medication intake.
Our findings showed that despite policies and procedures to monitor and control patients' acetaminophen exposure, the incidence of supratherapeutic acetaminophen dosing in hospitalized patients remains high. Overall, 4.0% of all hospitalized adults experienced a supratherapeutic dosing of acetaminophen. These were not isolated events but often were successive and overlapping. A few studies assessing physician knowledge about acetaminophen dosing and recognition of acetaminophen-containing products had inconsistent results.22,23 While 96.4% of physicians knew their patients' total acetaminophen dose,23 only 76% of physicians were aware of the maximum recommended daily dose of acetaminophen, and many physicians had some difficulty identifying acetaminophen-containing products.22 Several other studies24-26 reported that many practicing nurses do not possess knowledge about pain relief medications that would enable them to monitor the medication administrations effectively. Hospital policy and increased clinician training are warranted to help clinicians identify acetaminophen-containing products and monitor closely the daily dose of acetaminophen.
In line with a previous randomized controlled trial that revealed that recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT level elevation,8 our results showed that patients who received supratherapeutic dosing were more likely to have elevated levels of ALP. Our study was not designed to pick up subtle differences in liver function tests, and the available information in our database prevented us from drawing any conclusion about the causal relationship between acetaminophen and ALP level elevation.
Our results revealed several risk factors for supratherapeutic acetaminophen dosing. It is notable that hospital A's patients experienced almost twice as many supratherapeutic dosing events as hospital B's patients despite that hospital having the protective characteristics of more female patients, fewer patients with osteoarthritis, fewer patients in surgical units or ICUs, and greater use of single-ingredient formulations. This suggests that recurring scheduled vs PRN administrations, the use of products that contain more than 325 mg of acetaminophen per dose unit, and the use of multiple products are stronger correlates of supratherapeutic acetaminophen dosing. Unlike patient characteristics, these factors are controllable by hospitals, and, although not guaranteed, our results suggest that decreasing the frequency of these risks via policy changes could lead to decreased incidence of supratherapeutic acetaminophen dosing.
The use of a recurring scheduled dose (as opposed to PRN or 1-time administrations) was identified to be a major risk factor for supratherapeutic acetaminophen dosing. In pain management, it is a common strategy to provide baseline pain coverage to avoid the peaks and troughs of pain. Administering medications PRN has been found to be less effective when treating acute or postoperative pain.27 Using this strategy in the context of acetaminophen, however, may increase the risk of exceeding the safe dosing threshold by as much as an order of magnitude. Indeed, a typical regimen for extra-strength acetaminophen—1 g scheduled every 6 hours—allows no room for error in timing of acetaminophen administration. Therefore, a reassessment of long-accepted acetaminophen dosing regimens may be warranted, especially the scheduled use of products containing 500 mg of acetaminophen.
Our results also showed that patients diagnosed as having osteoarthritis tended to receive supratherapeutic dosing. Acetaminophen is recommended as initial therapy for many forms of osteoarthritis according to the American College of Rheumatology.3 Special attention should be paid to this population.
It is a challenge for clinicians to keep track of the total acetaminophen intake for each patient from the multiple drugs and doses given over a 24-hour period. Computerized clinical decision support functionality embedded within clinical information systems could mitigate these risks. For example, liver toxicity warnings for acetaminophen products, recommended by the FDA, could be displayed at order entry and during administration. However, to avoid alert fatigue, more judicious display of alerts may be more effective. For example, alerting nurses at administration time may be more effective than alerting physicians during order entry. Even better would be more specific alerts that fire only when the current administration is about to exceed the daily dose limit. Such decision support within eMAR is immature because it would require complicated time-based inferencing. Even the advanced barcode-assisted eMAR technology implemented at both hospitals in this study does not currently have such functionality. However, such decision support could have a profound impact on safe medication administration.
Our study has some limitations. While the record of administrations in an electronic system is accurate overall, there may be timing discrepancies between when the nurse records an administration and when the patient actually ingests the medicine, especially for PRN medications; however, such differences are unlikely to qualitatively affect our findings. Furthermore, not all patients had liver function tested, and patients lacking these tests may differ from those who had liver function testing performed, such as in their comorbid conditions and reason for hospitalization. There were also potential confounding factors that were not measured, such as clinician characteristics (eg, roles, responsibilities, different prescribing habits of physicians, or administration practices of nurses), and hospital-level factors (eg, patient volume). Finally, we excluded patients who were younger than 12 years because a weight-based calculation for the maximum recommended dose of acetaminophen is more appropriate for the pediatric population.
Correspondence: Li Zhou, MD, PhD, Clinical Informatics Research & Development, Partners HealthCare System Inc, 93 Worcester St, Second Floor, Wellesley, MA 02481 (Lzhou2@partners.org).
Accepted for Publication: July 23, 2012.
Published Online: November 12, 2012. doi:10.1001/2013.jamainternmed.438
Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Zhou and Maviglia contributed equally to this work. Study concept and design: Zhou, Maviglia, Mahoney, Chang, Bates, and Rocha. Acquisition of data: Zhou, Chang, Boulware, and Lou. Analysis and interpretation of data: Zhou, Maviglia, Chang, Orav, Plasek, Boulware, and Bates. Drafting of the manuscript: Zhou, Maviglia, and Chang. Critical revision of the manuscript for important intellectual content: Zhou, Maviglia, Mahoney, Orav, Plasek, Boulware, Lou, Bates, and Rocha. Statistical analysis: Zhou, Maviglia, Chang, Orav, and Boulware. Obtained funding: Zhou. Administrative, technical, and material support: Zhou, Maviglia, Mahoney, Chang, Plasek, Boulware, Lou, Bates, and Rocha. Study supervision: Zhou, Maviglia, and Rocha.
Conflict of Interest Disclosures: None reported.
Funding/Support: This project was funded by the Partners-Siemens Research Council.
Role of the Sponsors: The Partners-Siemens Research Council played no role in design or conduct of the study; in collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
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