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Cognitive and Other Adverse Effects of Diphenhydramine Use in Hospitalized Older Patients
Joseph V. Agostini, MD;
Linda S. Leo-Summers, MPH;
Sharon K. Inouye, MD, MPH
Arch Intern Med. 2001;161:2091-2097.
ABSTRACT
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Background Diphenhydramine hydrochloride is a commonly prescribed medicine in hospitalized
patients, but its adverse effects on older patients remain unclear.
Methods We enrolled 426 hospitalized medical patients aged 70 years or older
in a prospective cohort study in a university hospital. Measurements included
baseline and daily assessments including Mini-Mental State Examination scores,
Confusion Assessment Method ratings, direct observations for medical devices
(urinary catheter or physical restraints), and blinded medical record extractions
for diphenhydramine use.
Results Of the 426 patients, 114 (27%) received diphenhydramine during hospitalization
and shared similar baseline characteristics including age, sex, delirium risk,
and Mini-Mental State Examination scores compared with nonexposed patients.
The diphenhydramine-exposed group was at an increased risk for any delirium
symptoms (relative risk [RR], 1.7; 95% confidence interval [CI], 1.3-2.3)
and for individual delirium symptoms, including inattention (RR, 3.0; 95%
CI, 1.5-5.9), disorganized speech (RR, 5.5; 95% CI, 1.0-29.8), and altered
consciousness (RR, 3.1; 95% CI, 1.6-6.1). Exposed patients also had increased
risk for urinary catheter placement (RR, 2.5; 95% CI, 1.0-6.0) and longer
median length of stay (7 vs 6 days; P = .009). A
dose-response relationship was demonstrated for most adverse outcomes. Overall,
24% of diphenhydramine doses were administered inappropriately.
Conclusions Diphenhydramine administration in older hospitalized patients is associated
with an increased risk of cognitive decline and other adverse effects with
a dose-response relationship. Careful review of its use is necessary in this
vulnerable population.
INTRODUCTION
ADVERSE DRUG reactions are a common iatrogenic complication in older
hospitalized patients.1 Polypharmacy exacerbates
the problem,2 as do inappropriate prescribing
patterns,3 enhanced sensitivity to adverse
effects due to age-related changes in pharmacodynamics and pharmacokinetics,4-5 and interactions among multiple, often
new, medications. An important drug-related iatrogenic outcome in the elderly
is cognitive impairment.6-7 Drug-related
cognitive impairment and delirium are particularly important in the inpatient
setting, which represents an already vulnerable time because of the superimposition
of acute illness and multiple drug use onto existent cognitive and medical
comorbidities. In fact, the addition of a multiple-medication regimen during
a hospital stay is an independent risk factor for delirium in older hospitalized
patients.8
The use of medications with anticholinergic effects in particular leads
to important problems in older patients.9 Overall,
these medications are associated with delirium more commonly than any other
drug class.10 Other potential adverse effects
include orthostasis, central nervous system depression, paradoxical excitement,
visual disturbances, tachycardia, dry mouth, urinary retention, and constipation.11-12 Even mild disturbances in these cholinergic
pathways can initiate a range of adverse effects that decrease an older patient's
independence in functioning and ability to withstand the stressors of inpatient
hospitalization.
Diphenhydramine hydrochloride, an antihistamine sedative drug with strong
anticholinergic properties, is commonly prescribed in the elderly population.
In an outpatient study of 850 elderly patients in intermediate-care facilities
in Massachusetts, for example, more than one quarter were receiving some form
of sedative and/or hypnotic medication, with diphenhydramine alone accounting
for 26% of this total (14%-41% over all study sites).13
In the inpatient setting, fewer data are available on frequency of use. At
our institution (an urban teaching hospital) approximately 15% of patients
70 years or older hospitalized on all services during a 10-month period in
1999 received at least 1 dose of diphenhydramine during their hospital stay.
Indications for diphenhydramine use include sedation, treatment of allergic
reactions and vertigo, and prophylaxis for patients with prior transfusion
reactions. Its potential adverse effects include those of the anticholinergic
medications as noted above. We chose this drug to study because of its widespread
use and its potential for substantial morbidity.
The current data about the effect of anticholinergic medications on
cognitive function in the elderly are conflicting. Three prospective studies14-16 have shown no association
between the use of anticholinergic drugs and delirium, while a prospective
study of elderly patients treated for femoral neck fractures showed that anticholinergic
drugs were a contributing factor for acute states of confusion.17
Small studies of older patients given diphenhydramine specifically have reported
results ranging from a lack of sedative and cognitive effects (using visual
analog scales, reaction times, verbal recall, and digit-symbol substitution)18 to some degree of cognitive impairment (using verbal
memory, visuospatial cognition, and Trails B testing)19
to delirium in patients with mild dementia.20
Thus, further study is needed to clarify the effects of diphenhydramine use
on cognitive outcomes as well as other adverse effects during hospitalization.
The specific aims of our present study are to examine the rate of diphenhydramine
use in a large prospective cohort of elderly hospitalized patients; to evaluate
potential adverse outcomes (eg, cognitive, behavioral, and other anticholinergic
effects) associated with diphenhydramine use; and to describe current diphenhydramine
use in the study cohort. Our underlying hypothesis is that diphenhydramine
use results in an increased risk of adverse outcomes and that this risk will
increase with the dose of diphenhydramine received.
PATIENTS AND METHODS
STUDY POPULATION
We studied a prospective cohort consisting of consecutive admissions
of older patients on a medicine service at Yale–New Haven Hospital (New
Haven, Conn), a 900-bed urban teaching hospital serving the local community
as well as a large referral base. All patients were admitted to the general
medical service in a non–intensive care setting between March 1995 and
February 1998. Patients were required to be 70 years or older with no baseline
delirium. Exclusion criteria included profound dementia precluding verbal
communication, hospital discharge or death within 48 hours of admission, and
non-English speakers.
ASSESSMENTS
Trained clinician-researchers, blinded to study hypotheses and to patients'
diphenhydramine use, carried out all assessments. Informed consent for participation
was obtained from the patient or from a proxy (usually the closest relative)
by procedures that were approved by the institutional review board of the
Yale University School of Medicine, New Haven. All patients were screened
within 48 hours of admission and data were collected on standardized forms.
Research staff collected demographic and living situation information from
the baseline interview followed by a cognitive evaluation consisting of a
Folstein Mini-Mental State Examination (MMSE)21
and a Confusion Assessment Method (CAM) rating for delirium.22
Baseline delirium risk was defined according to a predictive model described
previously.23 Researchers also reviewed charts
to gather data on admission diagnoses and laboratory results, medical history,
Charlson comorbidity scores,24 and APACHE II
APACHE II (Acute Physiology and Chronic Health Evaluation II) scores.25 Thereafter, research staff carried out daily interviews
to obtain MMSE and CAM ratings. They also observed the patient daily for addition
of medical devices, such as a urinary catheter or physical restraints.
A separate researcher, blinded to the cognitive scores of each patient,
extracted detailed information on diphenhydramine administration from the
medical record, including dose, time, and frequency of administration, and
documented indications and contraindications to determine those patients who
had diphenhydramine exposure during hospitalization. Based on well-defined
criteria,11 a contraindication was defined
as 1 of the following processes documented in the medical record: angle-closure
glaucoma, stenosing peptic ulcer, obstructive urinary symptoms, or allergy
to diphenhydramine. Doses of diphenhydramine administered within 1 hour of
each other were treated as 1 cumulative dose, with time of administration
recorded as time of the first dose. Any patient receiving at least 1 dose
of diphenhydramine was considered part of the diphenhydramine-exposed group.
COGNITIVE OUTCOMES
Evaluation of cognitive decline was determined using commonly accepted
delirium symptoms in addition to standardized, validated instruments including
the CAM rating for delirium and the MMSE score. Delirium symptoms were defined
as the presence of any 1 of the 9 commonly accepted features of delirium:
acute onset and fluctuating course, inattention, disorganized speech, altered
level of consciousness, disorientation, memory impairment, perceptual disturbance,
abnormal psychomotor activity, and an altered sleep-wake cycle. The CAM criteria
for delirium require the presence of acute onset and fluctuating course, inattention,
and either altered level of consciousness or disorganized thinking. The CAM
criteria provide a standardized delirium rating with a sensitivity of 94%
to 100%, a specificity of 90% to 95%, and high interobserver reliability.22 Acute onset is not separately recorded because the
development of these clinical features represents a change from the baseline
admission status; that is, by definition any change during the daily assessments
is considered an acute or new onset. For diphenhydramine-exposed patients,
cognitive decline was required to occur within 48 hours of administration
of any diphenhydramine dose. To meet CAM criteria, all criteria needed to
be present at the same assessment. Delirium symptoms could arise at any time
within 48 hours of the administration of any diphenhydramine dose. For all
patients, the "at-risk" or exposure period was truncated at hospital day 12
to create comparable at-risk periods for the diphenhydramine-exposed and nonexposed
groups, as well as to minimize the effects of long hospitalizations. This
exposure period accounted for 84% of all patient-days. In addition, 94% of
cases of delirium had occurred by hospital day 12.
DEFINITION OF VARIABLES
During patient interviews, trained clinician-researchers used the following
definitions in recording patient data. Inattention is defined as difficulty
maintaining focus or being easily distracted during the interview. Disorganized
speech is speech that is irrelevant, unclear, illogical, or unpredictable
in subject matter. Altered consciousness is any state other than alert (normal),
ranging from hypervigilant to lethargic, stuporous, or unarousable. Memory
impairment is difficulty recalling basic instructions, prior interactions,
or hospital events. Disorientation is misidentification of time of day, patient
location (eg, responding with a nonhospital location), or personal hospital
bed. Abnormal psychomotor activity includes psychomotor agitation (an increased
level of motor activity) and retardation (decreased motor activity). Altered
sleep-wake cycle refers to patients reporting increased frequency of nighttime
awakening and daytime naps compared with baseline (admission) sleep history.
Behavioral disturbance includes combative behavior, repeated unsafe behaviors
(eg, climbing over bed rails), pulling at dressings or tubes, yelling, or
swearing. The use of physical restraint indicates immobilization of the hands,
feet, or chest with a restraining device during the patient interview. New
urinary catheterization includes the use of indwelling (Foley) catheters either
within 48 hours of diphenhydramine exposure or any time during hospitalization
for patients not exposed to diphenhydramine.
ANALYSIS
Following standardized coding and entry of data, statistical analysis
was completed using PC-based SAS software (SAS version 6.12; SAS Institute
Inc, Cary, NC). Baseline characteristics and outcomes were compared with  2 tests for binary measures and t tests for
continuous measures. Relative risks (RRs) were calculated with 95% confidence
intervals (CIs). The Mantel-Haenszel 2 statistic was used
to test for trends among categorical outcomes and 1-way analysis of variance
was used for continuous outcomes across diphenhydramine-exposed and nonexposed
groups. A logistic regression model was carried out with the outcome of delirium
symptoms in the diphenhydramine-exposed group, controlling for baseline delirium
risk, sex, and age. The odds ratios were calculated using 95% CIs.
RESULTS
A total of 426 patients were enrolled in the study (Table 1) with 114 patients (27%) comprising the diphenhydramine-exposed
group. The 2 cohorts shared similar sociodemographic characteristics, baseline
delirium risk, and MMSE scores. There were no significant differences in baseline
illness severity or comorbidity or report of sleep difficulty. The number
of patients in either group who were exposed to other potentially psychoactive
medications was likewise similar. Exposure to a psychotherapeutic medication
during hospitalization (eg, an antidepressant or antipsychotic drug such as
haloperidol) occurred in 16% of the diphenhydramine-exposed patients and 13%
of nonexposed patients (P = .48), whereas exposure
to an anxiolytic, sedative, or hypnotic drug other than diphenhydramine occurred
in 39% of the exposed and 31% of the nonexposed patients (P = .08).
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Table 1. Patient Characteristics at Baseline*
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The presence of delirium symptoms was much more likely to occur in the
diphenhydramine-exposed group than the nonexposed group (Table 2). There was a 70% increased risk of cognitive decline in
the diphenhydramine-exposed group (42% of those exposed vs 24% of those not
exposed [RR, 1.7; 95% CI, 1.3-2.3; P<.05]). In
addition, the diphenhydramine-exposed group was at significantly increased
risk for inattention (RR, 3.0), disorganized speech (RR, 5.5), altered level
of consciousness (RR, 3.1), abnormal psychomotor activity (RR, 2.3), altered
sleep-wake cycle (RR, 2.0), and behavioral disturbance (RR, 5.6). New urinary
catheter use occurred in 8% of the diphenhydramine-exposed group compared
with 3% in the nonexposed group (RR, 2.5; 95% CI, 1.0-6.0). Length of stay
was significantly longer on average in the diphenhydramine-exposed group (median
of 7 vs 6 days; P = .009).
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Table 2. Potential Adverse Outcomes Associated With Diphenhydramine
Use*
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In a multiple logistic regression model involving 423 observations (3
excluded for missing variables), the adjusted odds ratio for the risk of cognitive
decline in the diphenhydramine-exposed group was 2.3 (95% CI, 1.4-3.6). This
result controlled for age, sex, and baseline delirium risk, none of which
were independently statistically significant. These multivariable results
confirm the bivariate analyses reported above.
An examination of dose-response relationships (Table 3) showed a significant trend toward increased cognitive decline
with increasing diphenhydramine dosage for both delirium symptoms and the
CAM or MMSE outcomes. Four delirium symptoms (inattention, altered consciousness,
abnormal psychomotor activity, and altered sleep-wake cycle) showed significant
dose-response trends, as did length of stay outcomes.
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Table 3. Potential Adverse Reactions by Diphenhydramine Dose Received*
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Results from subgroup analyses of the 114 patients who received diphenhydramine
during hospitalization revealed that a total of 237 doses were administered
(Table 4). Patients received a
mean of 2.1 doses, with 97% of dose administered orally. The maximum cumulative
daily dose for any given patient was 100 mg. Indications for diphenhydramine
use (Table 5) included sleep (68%),
prophylaxis prior to blood transfusion (21%), and therapy for allergic reactions
or pruritus (3%). Of the 50 diphenhydramine doses given for prophylaxis prior
to blood transfusion, none were for an appropriate indication, ie, prior transfusion
reaction. Other contraindications, specifically obstructive urinary symptoms,
were present during the administration of 6 doses (3% of total doses). Overall,
56 (24%) of 237 doses were given inappropriately (50 doses for transfusion
prophylaxis and 6 doses to patients with obstructive urinary symptoms).
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Table 4. Description of Diphenhydramine Use
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Table 5. Indications and Contraindications for Diphenhydramine Use
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COMMENT
This study shows that diphenhydramine use in hospitalized elderly patients
carries substantial risk. Diphenhydramine use was associated with significant
risk of cognitive decline, behavioral disturbance, and urinary catheter placement,
of which the latter 2 may be markers of the anticholinergic effects of delirium
resulting in agitation and urinary retention. In addition, a dose-response
relationship was demonstrated for many of these adverse outcomes, and length
of stay was significantly longer. Finally, diphenhydramine was inappropriately
administered to 24% of patients. This study represents, to our knowledge,
the largest and most detailed prospective cohort study in older patients that
examines cognitive and other adverse outcomes following diphenhydramine use.
The delirium symptoms reported in this study likely capture more subtle
and partial forms of delirium that do not meet full delirium criteria. The
CAM criteria were limited to a 1-time observation, whereas the recognition
of these delirium symptoms allowed the detection of more subtle changes in
cognitive functioning over any 48-hour period following diphenhydramine exposure.
The prognostic importance of these partial forms of delirium has been demonstrated
in previous studies.26-27
This study documents that therapy with this widely used sedative-type
medication (diphenhydramine) leads to substantial morbidity in older patients.
Given its contribution to cognitive and anticholinergic adverse outcomes,
the use of diphenhydramine as a routine sleep aid (the most common indication
seen in our cohort) should be discouraged. This study lends strong support
to a previously published expert consensus report on inappropriate medication
use in the elderly, which deemed that diphenhydramine was inappropriate for
use as a sedative in the elderly, independent of patient diagnosis.28 A thorough patient history, physical examination,
and review of proper sleep hygiene is the recommended clinical workup, and
therapy using nonpharmacologic intervention is the preferred management.29 Our results suggest that the clinician's review of
a patient's list of daily medications to remove the "routine" or "as needed
for sleep" prescriptions is critically important in reducing unwanted outcomes
such as cognitive decline.
Another finding with important implications for inpatient physicians
concerns the administration of diphenhydramine for routine transfusion prophylaxis.
In the absence of a documented transfusion reaction, this therapy carries
with it the risk of increased patient morbidity without documented benefit,
and its practice has been widely discouraged. The 50 diphenhydramine doses
administered with transfusion in this study were all administered inappropriately.
Although it is possible that patients notified house staff about previous
transfusion reactions, which led to diphenhydramine administration immediately
prior to transfusion, the medical records did not support such occurrences.
This study derived strength from the prospective cohort design that
provided precise data on exposures, eliminated recall bias, and provided carefully
documented outcomes from daily interviews. In addition, well-accepted, validated
cognitive instruments were used as part of comprehensive daily assessments
to determine the presence of cognitive impairment. Furthermore, we took careful
steps to ensure that the temporal precedence of diphenhydramine administration
and subsequent delirium was clearly documented.
Because the precise temporal correlation between diphenhydramine administration
and onset of delirium or other adverse outcomes has not been clearly studied,
we used a period of 48 hours for this study. A prior study documented a diphenhydramine
elimination half-life of more than 13 hours in elderly patients,30
supporting our use of 48 hours after administration as a reasonable time frame
in which to look for cognitive outcomes, particularly because the clinical
components of acute confusion may last for days or longer.
One limitation of this study was the difficulty in controlling for other
concurrently administered pharmacotherapies during hospitalization. However,
there were no other sedative and/or hypnotic medications similar to diphenhydramine
that were administered to such a large group, partly because of the hospital
formulary's restriction on the use of drugs of this class at the institutional
setting of this study. Further study of similar medications would prove valuable.
In addition, our study site in a large teaching hospital with house staff
may not reflect the prescribing patterns of community hospital physicians,
although we believe that the practice of in-hospital diphenhydramine administration
is likely similar throughout the country. To address the potential for indication
bias, we examined several comorbidity measures that were demonstrated to be
well-balanced between our study groups. While acknowledging the potential
for other sources of indication bias (eg, patients requiring transfusion may
have been at higher risk for delirium), the careful examination of important
baseline differences in risk (including comorbidity, baseline insomnia, and
other patient characteristics) mitigated against such bias.
New bladder catheterization serves as an imperfect marker for acute
urinary retention; however, given the importance of anticholinergic effects
in older patients, we believed that this was a key area to examine. Even if
the sensitivity of placement of a bladder catheter is low for the presence
of urinary retention as an anticholinergic effect, catheterization in itself
is still a risk factor for acute confusional state in older patients.8 Moreover, our study did not attempt to record all
instances of straight catheterization (nonindwelling catheterization) for
urinary retention, which may have minimized the exposed cohort's already significantly
increased use of catheters. Further underestimation of the difference in risk
of catheterization between the 2 study groups is possible because the risk
period for nonexposed patients was the entire length of stay in contrast to
the 48-hour period for the diphenhydramine-exposed patients. Ideally, to document
the adverse effects of diphenhydramine use, whether they be anticholinergic
symptoms or confusion, a rechallenge would have been warranted, but ethical
considerations precluded this.
Ultimately, appropriate use of diphenhydramine in the elderly remains
an important clinical issue, not only because it is widely prescribed in older
hospitalized patients, but also because it is present in a vast array of over-the-counter
preparations and is used frequently in skilled nursing facilities. Thus, the
magnitude of diphenhydramine use demands that clinicians carefully consider
the potential for adverse outcomes in a population that is already at high
risk based on age, baseline cognitive impairment, and other medical comorbidities.
CONCLUSIONS
In summary, this study suggests that diphenhydramine use in the hospitalized
older patient contributes most notably to cognitive decline, behavioral disturbance,
and initiation of bladder catheterization. Based on these data, we recommend
that diphenhydramine be used with caution in elderly patients and not, for
instance, administered as a routine sleep aid. Also, the practice of administering
diphenhydramine prophylactically prior to blood transfusions in the absence
of previous transfusion reaction has no documented benefit and should be curtailed.
Increased attention to the potential for serious adverse effects in the elderly
should lead to modification of common prescribing patterns and heightened
awareness concerning the limited use of diphenhydramine in geriatric patients.
The applicability of this study to outpatients and inpatients in skilled
nursing facilities requires further examination given the widespread use of
diphenhydramine outside the hospital setting. Moreover, future studies are
needed to address the cost savings of minimizing diphenhydramine use and its
associated adverse outcomes as well as the benefits of minimizing hospital
resources if complications resulting from iatrogenic medication use are reduced.
AUTHOR INFORMATION
Accepted for publication February 22, 2001.
This study was funded in part by grant RO1AG12551 from the National
Institute on Aging, Bethesda, Md, and received in-kind support by grant P60AG10469
from the Claude D. Pepper Older Americans Independence Center, Baltimore,
Md. Dr Inouye is a recipient of a Midcareer Award from the National Institute
on Aging (grant K24AG00949) and a Donaghue Investigator Award from the Patrick
and Catherine Weldon Donaghue Medical Research Foundation, West Hartford,
Conn (grant DF98-105).
Presented in part at the American Geriatrics Society/American Federation
for Aging Research Annual Scientific Meeting, Nashville, Tenn, May 18, 2000.
The authors would like to thank the Project Recovery staff, the Elder
Life Program staff, and the patients and families at Yale–New Haven
Hospital who participated in the study. We are indebted to Leo M. Cooney,
Jr, MD, and Richard C. Lisitano, MS, RPh, for their contributions to this
work and to Robbin Bonanno for her assistance.
Corresponding author and reprints: Sharon K. Inouye, MD, MPH, Yale
University School of Medicine; Yale–New Haven Hospital, 20 York St,
Tompkins 15, New Haven, CT 06504.
From the Departments of Internal Medicine, (Drs Agostini and Inouye)
and Epidemiology and Public Health (Ms Leo-Summers), and the Robert Wood Johnson
Clinical Scholars Program (Dr Agostini), Yale University School of Medicine,
New Haven, Conn.
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Acute Delirium Associated with Combined Diphenhydramine and Linezolid Use
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Editorial: Hot Topics in Geriatrics
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Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2003;58:M30-36.
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