Supratherapeutic Dosing of Acetaminophen Among Hospitalized Patients

Li Zhou, MD, PhD

ISQUA Webinar

10 September 2013

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Supratherapeutic Dosing of Acetaminophen Among

Hospitalized Patients

Li Zhou, MD, PhD

Knowledge Management & Clinical Decision Support, Partners eCare, Division of General Medicine and Primary Care, Brigham and Women’s

Hospital, Harvard Medical School

Outline

Supratherapeutic Dosing of Acetaminophen Among Hospitalized Patients

Use of Health Information Technology to Prevent Excessive dosing

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Acetaminophen

Acetaminophen is one of the most commonly used drugs for pain relief and fever reduction.

Used by nearly one in four American adults every week.

Acetaminophen overdose is the leading cause of acute liver failure (ALF).

Adult patients who took > 4 g/d of acetaminophen were at risk for hepatotoxicity, ranging from abnormalities in liver function blood tests, to ALF, and even death.

51% of acute live toxicity was related to acetaminophen (Larson, Hepatology, 2005).

Of the overdose cases, 48% were unintentional.

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Is Acetaminophen in Everything?

> 600 over-the-counter and prescription products

A variety of dosage forms, brand names and generic labels, and single and combination ingredients.

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"People don't really read labels," Strom says. Changing the daily dose recommendation "was a good move, but it was not enough." He says manufacturers need to make it harder to overdo it with over-the-counter drugs….

What’s the main lesson from the panel review of acetaminophen?Because acetaminophen is in so many products, consumers need to be vigilant about reading labels, and they need to keep track of how much of the drug they are ingesting daily

Most research has focused on acetaminophen overuse as a consumer issue.

Acetaminophen Use in Hospitals

Previous studies of acetaminophen overdoses were based on prescriptions or pharmacy claims data in outpatient populations, so the actual amount consumed was not measured.

Our study used patients’ inpatient medication administration data recorded in an electronic medication administration record (eMAR) system to examine the acetaminophen exposure among hospitalized patients.

Zhou L, et al. Supratherapeutic Dosing of Acetaminophen among Hospitalized Patients. Archives of Internal Medicine, 2012.

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Setting and Patients

Retrospectively reviewed the electronic health records of adult patients (≥ 12 years old)

who were admitted to two academic tertiary care hospitals located in Boston, U.S., Brigham and Women’s Hospital and Massachusetts General Hospital, from June 1, 2010 to August 31, 2010who received acetaminophen during their hospitalization.

Patients’ acetaminophen administration records were obtained from eMAR system.

Med name, strength, dose, route, administration time, hospital unit, etc

Patients’ demographic data (including age, sex and race)

Liver function test results (including ALT, AST, ALP, DBIL, TBIL, and PT-INR)

Patients’ primary diagnoses were identified using claims data and patients’ problem lists in their EHRs.

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Supratherapeutic Dosing

A supratherapeutic dosing instance was defined as any cumulative administration of acetaminophen over 4 grams in 24 hours.

Secondary analyses of elderly patients (65 years or older) or patients with chronic liver disease were performed using an threshold of 3 grams in 24 hours.

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Main Outcome Measures

Acetaminophen exposure rate, supratherapeutic dosing rate.

Compared patients who had at least one supratherapeutic dosing to those who had none with respect to demographic characteristics, diagnoses, hospital units, and the kinds of acetaminophen-containing products administered (ingredients, numbers of products, strengths and instructions).

Potential risk factors identified by univariate analysis were entered into a multivariate Cox model. Hazard Ratio (HR) and 95% confidence interval [CI] for risk factors for supratherapeutic dosing were calculated.

Examined the effect of acetaminophen use on patients’ liver function tests. Calculated and compared changes in liver function test before and after supratherapeutic dosing.

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Results

A total of 14,411 (60.7%) patients received acetaminophen, of whom 955 (6.6%) experienced a supratherapeutic dosing of acetaminophen, which was 4.0% of all hospitalized adults.

22.3% of elderly and 17.6% of CLD patients exceeded the recommended limit of 3 grams/day.

Each patient who received supratherapeutic dosing of acetaminophen had an average of 4.9 incidences (range, 1-48), comprising an average total of 2.9 days (range, 1-29.5 days).

4.0-4.4 4.5-4.9 5.0-5.4 5.5-5.9 6.0-6.4 6.5-6.9 ≥70

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20

30

40

50

5.2

48.9

42.7

1.4 1.3 0.4 0.1

%

grams

Frequency distribution of the maximum supratherapeutic dosing amounts for supratherapeutically dosed patients during their hospital stay

Almost half of the instances of supratheratpeutic dosing was over 5 g/d.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15+0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%955

595

358

226

149106

8670 49 38 31 25 18 14 14

Days

Cu

mu

lati

ve

%

Cumulative frequency of supratherapeutic dosing by total number of days for supratherapeutically dosed patients during their hospital stay

Among patients who had supratherapeutic dosing, about 40% received for 3 days or more, 4% for 10 days or more.

An Example

Patient X ingested 7475 mg acetaminophen in total within a 24h window.

Two different products

ACETAMINOPHEN 325MG TABLET

BUTALBITAL/APAP/CAFFEINE

Each tablet containing 325mg Acetaminophen

6/3 20:52

0 975

6/4 0:27

1950

6/4 4:29

2925

6/4 8:10

4225

6/4 12:536/4 16:36

6/4 18:506/4 20:22

55256175

6825 7475

Acetaminophen exposure rates and supratherapeutic dosing rates by patient and dosing characteristics

Supratherapeutic Dosing of Acetaminophen (>4g)

CharacteristicAcetaminophen Users, No. (%)

(N = 14411)

Yes, No. (%)(n = 955)

No, No. (%)(n = 13456)

Unadjusted OR (95%CI)

Age, mean (range), y 55.4 (12-110) 56.6 (14-104) 55.4 (12-110)Age, y 12-17 148 (1.0) 4 (0.4) 144 (1.1) 18-39 3421 (23.7) 161(16.9) 3260 (24.2) 40-64 5789 (40.2) 458 (48.0) 5331 (39.6) 1.4 (1.2-1.6)§

≥ 65 5053 (35.1) 332 (34.8) 4721 (35.1)Sex Female 8356 (58.0) 525 (55.0) 7831 (58.2) 1.0 Male 6055 (42.0) 430 (45.0) 5625 (41.8) 1.1 (1.0-1.3)Race or ethnic group White 11304 (78.4) 837 (87.6) 10467 (77.8) 2.0 (1.7 -2.5) Non-white 1.0 Asian 460 (3.2) 12 (1.3) 448 (3.3) Black 1169 (8.1) 52 (5.5) 1117 (8.3) Hispanic 1117 (7.8) 39 (4.1) 1078 (8.0) Others 361 (2.5) 15 (1.6) 346 (2.6)Hospitals Hospital A 6594 (45.8) 630 (66.0) 5964 (44.3) 2.4 (2.1-2.8) Hospital B 7817 (54.2) 325 (34.0) 7492 (55.7) 1.0Hospital units₣

Surgery 5856 (40.6) 620 (64.9) 5236 (38.9) 2.9 (2.5-3.3) Intensive-care unit (ICU) 2065 (14.3) 169 (17.7) 1896 (14.1) 1.3 (1.1-1.6) Medicine 4447 (30.9) 208 (21.8) 4239 (31.5) 0.6 (0.5-0.7) Others (e.g., obstetrics, gynecology, psychiatry) 4274 (29.7) 217 (22.7) 4057 (30.2) 0.7 (0.6-0.8)Diagnoses

Chronic liver diseases 991 (6.9) 36 (3.8) 955 (7.1) 0.5 (0.4-0.7) Osteoarthritis 1220 (8.5) 239 (25.0) 981 (7.3) 4.2 (3.6-5.0)

Acetaminophen Overdose (>4g)

CharacteristicAcetaminophen Users, No. (%)

(N = 14411)

Yes, No. (%)(n = 970)

No, No. (%)(n = 13441)

Unadjusted OR (95%CI)

Drug components₣

Single-ingredient, acetaminophen only 12558 (87.1) 913 (95.6) 11645 (86.5) 3.4 (2.5-4.6) Multi-ingredient (combination) products containing acetaminophen

3809 (26.4) 235 (24.6) 3574 (26.6) 0.9 (0.8-1.1)

Different combination products (strength, mg)

Butalbital + caffeine + acetaminophen (325) 335 (2.3) 30 (3.1) 305 (2.3) 1.4 (1.0-2.0) Codeine + acetaminophen (24 or 300) 185 (1.3) 4 (0.4) 181 (1.4) 0.3 (0.1-0.8)

Hydrocodone + acetaminophen (500) 562 (3.9) 88 (9.2) 474 (3.5) 2.7 (2.2-3.5)

Oxycodone + acetaminophen (325) 2781 (19.3) 135 (14.1) 2646 (19.7) 0.7 (0.6-0.8)

Propoxyphene + acetaminophen (650) 215 (1.5) 27 (2.8) 188 (1.4) 2.1 (1.4-3.1)Number of acetaminophen products administered

1 12380 (85.9) 749 (78.4) 11631 (86.4) 1.0

≥2 2031 (14.1) 206 (21.6) 1825 (13.6) 1.8 (1.5-2.1)Acetaminophen strength, mg₣

≤ 325 13406 (93.0) 682 (71.4) 12724 (94.6) 0.1 (0.1-0.2)

500 1660 (11.5) 484 (50.7) 1176 (8.7) 10.7 (9.3-12.3) 650 752 (5.2) 82 (8.6) 670 (5.0) 1.8 (1.4-2.3)

Instructions£₣

PRN (as needed) 12815 (88.9) 548 (57.4) 12267 (91.2) 0.1 (0.1-0.2)

Standing dose 2905 (20.2) 806 (84.4) 2099 (15.6) 29.3 (24.4-35.1) One-time dose 900 (6.3) 60 (6.3) 840 (6.2) 1.0 (0.8-1.3)

Acetaminophen exposure rates and supratherapeutic dosing rates by patient and dosing characteristics

Multivariate Cox Modeling Analyses: Adjusted Hazard Ratios for Supratherapeutic Dosing of Acetaminophen

Risk Factor HR (95% CI)* p ValueAge 0.9 (0.9-0.9) <.001Sex (Male vs. Female) 1.1 (1.0-1.2) .08White (Race) 1.5 (1.3-1.7) <.001Hospital A vs. Hospital B 1.6 (1.4-1.8) <.001Hospital Units₣

Surgery 0.8 (0.7-1.1) .37 ICU 1.3 (1.0-1.6) .13 Medicine and others 0.6 (0.5-0.7) .002Diagnoses Chronic liver disease 0.8 (0.6-1.1) 0.29 Osteoarthritis 1.4 (1.3-1.6) <.001Number of Acetaminophen Products Administered

2.4 (2.0-2.9) <.001

Acetaminophen strength, mg₣

≤ 325 1.0 (0.8-1.2) .84 500 1.9 (1.5-2.3) < .001 650 1.5 (1.1-2.0) .08Instructions₣

PRN (as needed) 0.7 (0.6-0.9) .002 Standing Dose 16.6 (13.5-20.6) <.001 One-Time Dose 0.8 (0.5-1.1) .38

Before After 70

75

80

85

90

95

100

105

110

115

Supratherapeutic dosing (n=211)

Non-suprather-apeutic dosing

(n=5455)

Alkaline Phosphatase (ALP) (p<.001)

U/L

Patients who received supratherapeutic dosing were more likely to have statistically significant elevations in alkaline phosphatase (ALP), though no causal relationship can be inferred.

Statistically insignificant elevations in alanine transaminase (ALT).

No clinically or statistically significant changes in other liver injury markers

Changes in Alkaline Phosphatases (ALP) test results for patients who received supratherapeutic acetaminophen dosing and who did not

Outline

Supratherapeutic Dosing of Acetaminophen

Use of Health Information Technology to Prevent Acetaminophen Overdose

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Policies and training

Only 76% of physicians were aware of the maximum recommended daily dose of acetaminophen, and many physicians had some difficulty identifying acetaminophen-containing products.

Many practicing nurses do not possess knowledge about pain relief medications that would enable them to monitor the medication administrations effectively.

Policies and clinician training may help.

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HIT / CDS Interventions (1)

On an annualized basis, > 3800 patients at these 2 hospitals alone were put at unnecessary risk.

Hundreds of thousands of patients nationwide may be receiving toxic doses of acetaminophen while in the hospital.

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.

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HIT / CDS Interventions (2)

Computerized clinical decision support (CDS) functionality embedded within electronic health records (EHRs) could mitigate these risks.

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Bar codingCPOE (order)

Pharmacy (dispense)

eMAR (administration)

HIT / CDS Interventions (3)

To avoid alert fatigue, alerting nurse at administration time may be more effective than alerting physicians during order entry.

To fit clinician work flow, alerts may fire when the current administration is about to exceed the daily dose limit.

Such decision support within eMAR is immature.

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Using HIT to Improve Health Care- Emphasizing Speed to Value

Change the culture of medicine to one that embraces innovation and rapid change in the delivery of care.

Hospitals and clinicians should demand flexible modern technology to support change and innovation rather than be held hostage to EHRs.

Need investment in performance improvement and process engineering, business intelligence systems, and analytical capabilities to take full advantage of HIT.

Go beyond the implementation of HER and create system that improve healthcare quality, safety, and efficiency.

Ettinger WH. Invited commentary: Using Health Information Technology to Improve Health Care – Emphasizing Speed to Value. Archive of Internal Medicine. 2012.

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Conclusion

The incidence of supratherapeutic acetaminophen dosing is high.

These were not isolated events, but often were successive and overlapping, with almost half of the supratherapeutic dosing cases lasting for 3 days or more.

Our results showed that patients received supratherapeutic acetaminophen dosing were more likely to have elevated ALP. Although the causal relationship cannot be concluded by this study, the association is clinically concerning.

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Conclusion

Our results also revealed several risk factors, some are avoidable by policy, such as restricting formularies to a single product with no more than 325 mg acetaminophen per dose, and regulating scheduled administrations.

Computerized CDS for monitoring the accumulated doses and alerting at the bedside may be valuable in reducing the incidence of overdose administrations.

Health IT should be used to in a meaningful way to improve health care.

Acknowledgements

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Research TeamLi ZhouSaverio MavigliaLisa MahoneyFrank Chang

Acknowledgements

Roberto Rocha, David Bates, Hong Lou,

Joy Boulware, John Orav, Joseph Plasek

This project was funded by the Partners-Siemens Research Council.

Thank you!

Questions?

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