Supratherapeutic Dosing of
Acetaminophen Among
Hospitalized Patients
Li Zhou, MD, PhD
ISQUA Webinar
10 September 2013
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
2
Outline
Supratherapeutic Dosing of Acetaminophen
Among Hospitalized Patients
Use of Health Information Technology to
Prevent Excessive dosing
3
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.
4
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.
5
6
7
Most research has focused on acetaminophen
overuse as a consumer issue.
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
"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….
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.
9
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, 2010
who 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.
10
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.
11
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.
12
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).
13
Almost half of the instances of supratheratpeutic dosing was over 5 g/d.
48.9
50
42.7
40
%
30
20
10
5.2
1.4
1.3
0.4
0.1
5.5-5.9
grams
6.0-6.4
6.5-6.9
≥7
0
4.0-4.4
4.5-4.9
5.0-5.4
Frequency distribution of the maximum supratherapeutic dosing amounts 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.
100%
955
90%
80%
Cumulative %
70%
595
60%
50%
40%
358
30%
226
20%
149
106
10%
86
70
49
38
31
25
10
11
12
18
14 14
0%
1
2
3
4
5
6
7
8
9
Days
13
14
15+
Cumulative frequency of supratherapeutic dosing by total number of days for
supratherapeutically dosed patients during their hospital stay
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
0
975
1950
6/3 20:52
2925
4225
6/4 4:29
6/4 0:27
5525
6/4 12:53
6/4 8:10
6175
6825
7475
6/4 18:50
6/4 16:36
6/4 20:22
Acetaminophen exposure rates and supratherapeutic dosing rates by patient and dosing characteristics
Supratherapeutic Dosing of Acetaminophen (>4g)
Characteristic
Age, mean (range), y
Age, y
12-17
18-39
40-64
≥ 65
Sex
Female
Male
Race or ethnic group
White
Non-white
Asian
Black
Hispanic
Others
Hospitals
Hospital A
Hospital B
Hospital units₣
Surgery
Intensive-care unit (ICU)
Medicine
Others (e.g., obstetrics, gynecology, psychiatry)
Diagnoses
Chronic liver diseases
Osteoarthritis
Acetaminophen
Users, No. (%)
(N = 14411)
55.4 (12-110)
Yes, No. (%)
(n = 955)
No, No. (%)
(n = 13456)
Unadjusted OR
(95%CI)
56.6 (14-104)
55.4 (12-110)
148 (1.0)
3421 (23.7)
5789 (40.2)
5053 (35.1)
4 (0.4)
161(16.9)
458 (48.0)
332 (34.8)
144 (1.1)
3260 (24.2)
5331 (39.6)
4721 (35.1)
8356 (58.0)
6055 (42.0)
525 (55.0)
430 (45.0)
7831 (58.2)
5625 (41.8)
1.0
1.1 (1.0-1.3)
11304 (78.4)
837 (87.6)
10467 (77.8)
2.0 (1.7 -2.5)
1.0
460 (3.2)
1169 (8.1)
1117 (7.8)
361 (2.5)
12 (1.3)
52 (5.5)
39 (4.1)
15 (1.6)
448 (3.3)
1117 (8.3)
1078 (8.0)
346 (2.6)
6594 (45.8)
7817 (54.2)
630 (66.0)
325 (34.0)
5964 (44.3)
7492 (55.7)
2.4 (2.1-2.8)
1.0
5856 (40.6)
2065 (14.3)
4447 (30.9)
4274 (29.7)
620 (64.9)
169 (17.7)
208 (21.8)
217 (22.7)
5236 (38.9)
1896 (14.1)
4239 (31.5)
4057 (30.2)
2.9 (2.5-3.3)
1.3 (1.1-1.6)
0.6 (0.5-0.7)
0.7 (0.6-0.8)
991 (6.9)
1220 (8.5)
36 (3.8)
239 (25.0)
955 (7.1)
981 (7.3)
0.5 (0.4-0.7)
4.2 (3.6-5.0)
1.4 (1.2-1.6)§
Acetaminophen exposure rates and supratherapeutic dosing rates by patient and dosing characteristics
Acetaminophen Overdose (>4g)
Characteristic
Drug components₣
Single-ingredient, acetaminophen only
Multi-ingredient (combination) products containing
acetaminophen
Different combination products (strength, mg)
Acetaminophen
Users, No. (%)
(N = 14411)
Yes, No. (%)
(n = 970)
No, No. (%)
(n = 13441)
Unadjusted OR
(95%CI)
12558 (87.1)
3809 (26.4)
913 (95.6)
235 (24.6)
11645 (86.5)
3574 (26.6)
3.4 (2.5-4.6)
0.9 (0.8-1.1)
Butalbital + caffeine + acetaminophen (325)
Codeine + acetaminophen (24 or 300)
335 (2.3)
185 (1.3)
30 (3.1)
4 (0.4)
305 (2.3)
181 (1.4)
1.4 (1.0-2.0)
0.3 (0.1-0.8)
Hydrocodone + acetaminophen (500)
562 (3.9)
88 (9.2)
474 (3.5)
2.7 (2.2-3.5)
2781 (19.3)
135 (14.1)
2646 (19.7)
0.7 (0.6-0.8)
215 (1.5)
27 (2.8)
188 (1.4)
2.1 (1.4-3.1)
12380 (85.9)
749 (78.4)
11631 (86.4)
1.0
2031 (14.1)
206 (21.6)
1825 (13.6)
1.8 (1.5-2.1)
13406 (93.0)
682 (71.4)
12724 (94.6)
0.1 (0.1-0.2)
1660 (11.5)
752 (5.2)
484 (50.7)
82 (8.6)
1176 (8.7)
670 (5.0)
10.7 (9.3-12.3)
1.8 (1.4-2.3)
12815 (88.9)
548 (57.4)
12267 (91.2)
0.1 (0.1-0.2)
2905 (20.2)
900 (6.3)
806 (84.4)
60 (6.3)
2099 (15.6)
840 (6.2)
29.3 (24.4-35.1)
1.0 (0.8-1.3)
Oxycodone + acetaminophen (325)
Propoxyphene + acetaminophen (650)
Number of acetaminophen products administered
1
≥2
Acetaminophen strength, mg₣
≤ 325
500
650
Instructions£₣
PRN (as needed)
Standing dose
One-time dose
Multivariate Cox Modeling Analyses: Adjusted Hazard Ratios for
Supratherapeutic Dosing of Acetaminophen
Risk Factor
Age
Sex (Male vs. Female)
White (Race)
Hospital A vs. Hospital B
Hospital Units₣
Surgery
ICU
Medicine and others
Diagnoses
Chronic liver disease
Osteoarthritis
Number of Acetaminophen
Products Administered
Acetaminophen strength, mg₣
≤ 325
500
650
Instructions₣
PRN (as needed)
Standing Dose
One-Time Dose
HR (95% CI)*
0.9 (0.9-0.9)
1.1 (1.0-1.2)
1.5 (1.3-1.7)
1.6 (1.4-1.8)
p Value
<.001
.08
<.001
<.001
0.8 (0.7-1.1)
1.3 (1.0-1.6)
0.6 (0.5-0.7)
.37
.13
.002
0.8 (0.6-1.1)
1.4 (1.3-1.6)
2.4 (2.0-2.9)
0.29
<.001
<.001
1.0 (0.8-1.2)
1.9 (1.5-2.3)
1.5 (1.1-2.0)
.84
< .001
.08
0.7 (0.6-0.9)
16.6 (13.5-20.6)
0.8 (0.5-1.1)
.002
<.001
.38
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
130
Alkaline Phosphatase (ALP)
(p<.001)
120
U/L
110
Nonsupratherapeutic
dosing (n=5455)
100
90
80
Supratherapeutic
dosing
(n=211)
70
Before
After
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
21
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.
22
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.
23
HIT / CDS Interventions (2)
Computerized clinical decision support (CDS) functionality
embedded within electronic health records (EHRs) could
mitigate these risks.
Pharmacy (dispense)
CPOE (order)
eMAR (administration)
Bar coding
24
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.
25
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.
26
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.
27
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.
28
Acknowledgements
Research Team
Li Zhou
Saverio Maviglia
Lisa Mahoney
Frank Chang
Acknowledgements
Roberto Rocha, David Bates, Hong Lou,
Joy Boulware, John Orav, Joseph Plasek
This project was funded by the Partners-Siemens
Research Council.
29
Thank you!
Questions?
30