EJINME-02753; No of Pages 9

European Journal of Internal Medicine xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original Article

Altered mental status in older adults with histamine2-receptor antagonists: A

population-based study
Davy Tawadrous a,b, Stephanie Dixon a,b,c,d, Salimah Z. Shariff a,d, Jamie Fleet b, Sonja Gandhi a,b,c, Arsh K. Jain a,b,c,
Matthew A. Weir a,b,c, Tara Gomes d,e,f, Amit X. Garg a,b,c,d,⁎
a
Schulich School of Medicine, Western University, London, Canada
b
Division of Nephrology, Western University, London, Ontario, Canada
c
Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
d
Institute for Clinical Evaluative Sciences, Ontario, Canada
e
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
f
Keenan Research Centre, Li Ka Shing Knowledge Institute, Toronto, Ontario, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Background: Standard doses of histamine2-receptor antagonists (H2RAs) may induce altered mental status in
Received 4 November 2013 older adults, especially in those with chronic kidney disease (CKD).
Received in revised form 17 May 2014 Methods: Population-based cohort study of older adults who started a new H2RA between 2002 and 2011 was
Accepted 24 June 2014 conducted. Ninety percent received the current standard H2RA dose in routine care. There was no significant dif-
Available online xxxx
ference in 27 baseline patient characteristics. The primary outcome was hospitalization with an urgent head
computed tomography (CT) scan (proxy for altered mental status), and the secondary outcome was all-cause
Keywords:
Histamine H2 antagonists
mortality also within 30 days of a new H2RA prescription.
Altered mental status Results: Standard vs. low H2RA dose was associated with a higher risk of hospitalization with an urgent head CT
Aged scan (0.98% vs. 0.74%, absolute risk difference 0.24% [95% CI 0.11% to 0.36%], relative risk 1.33 [95% CI 1.12 to
Chronic renal insufficiency 1.58]). This risk was not modified by the presence of CKD (interaction P value = 0.71). Standard vs. low H2RA
Cohort studies dose was associated with a higher risk of mortality (1.07% vs.0.74%; absolute risk difference 0.34% [95% CI
Risk 0.20% to 0.46%], relative risk 1.46 [95% CI 1.23 to 1.73]).
Interpretation: Compared to a lower dose, initiation of the current standard dose of H2RA in older adults is asso-
ciated with a small absolute increase in the 30-day risk of altered mental status (using neuroimaging as a proxy),
even in the absence of CKD. This risk may be avoided by initiating older adults on low doses of H2RAs for
gastroesophogeal reflux disease, and increasing dosing as necessary for symptom control.
© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction However, older adults have age-related changes in pharmacokinet-

Each year millions of patients in Canada are prescribed histamine2-
receptor antagonists (H2RAs) for the treatment of gastroesophageal
reflux disease [1]. Histamine2-receptor antagonists are also widely
available without a prescription in many countries including Canada,
implying that their use is even more widespread than prescription
data suggests. A standard daily dose of a H2RA (ranitidine [Zantac]
300 mg/day or famotidine [Pepcid] 40 mg/day; usually divided into
twice a day) is recommended in popular drug prescribing references
for gastroesophageal reflux symptom control in patients of all ages
when kidney function is preserved (Table 1) [2–5].
⁎ Corresponding author at: London Kidney Clinical Research Unit, Room ELL-101,
London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, N6A
4G5, Canada. Tel.: +44 519 685 8502; fax: +44 519 685 8072.
E-mail address: amit.garg@lhsc.on.ca (A.X. Garg).
ics and pharmacodynamics such as reduced first-pass liver metabolism,
as well as increased fat content and decreased body water that reduces a
drug's volume of distribution (important with hydrophilic drugs such as
H2RAs) [6,7]. Such changes can increase the risk of drug toxicities with
standard dosing [6,7]. Furthermore, H2RAs undergo renal excretion, and
older adults often experience an age-related decrease in glomerular
filtration rate, even in the absence of kidney disease [8]. The loss of kid-
ney function has been attributed primarily to a loss of glomeruli, tubular
atrophy, interstitial fibrosis and arteriosclerosis [8]. As such, the current
standard dose of H2RA in older adults may lead to adverse drug events
such as mental status changes (e.g., confusion, hallucination) or ar-
rhythmias (e.g., tachycardia, atrioventricular block) [4,5]. Older adults
with bona fide chronic kidney disease may be the most vulnerable to
H2RA toxicity from reduced renal elimination [9].
To date, hundreds of case reports from the United States Food and
Drug Administration in addition to several literature reviews and pro-
spective studies have noted the potential for H2RAs to induce an altered

http://dx.doi.org/10.1016/j.ejim.2014.06.021
0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
2 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx
Table 1
Histamine2-receptor antagonist dosing in popular drug prescribing references.
Low dosea Standard dosea UpToDate recommendation
Famotidine 20 mg/day 40 mg/day • 20 to 80 mg/day
• Manufacturer recommends reduction by
50% in renal impairment
Ranitidine 150 mg/day 300 mg/day • 300 to 600 mg/day
• Oral dose should be 150 mg/day for renally
impaired patients
a
Low and standard dose as defined in this study.
mental status — which often precipitates hospitalization and death
among the elderly [9–18]. For example, Slugg et al. conducted a small
prospective convenience study of 41 inpatients to correlate ranitidine
pharmacokinetics with the incidence of altered mental status and
found 13 cases of ranitidine associated delirium (32%) primarily in the
context of older age and kidney disease [13]. However, studies have
generally been limited by the lack of data on outpatient H2RA use, rela-
tively limited sample sizes, and a general lack of evidence to support the
use of lower doses to reduce the incidence of altered mental status.
To inform this issue, we conducted a population-based cohort study
to compare the 30-day risk of altered mental status and mortality in
older adults initiated on an oral H2RA either at a standard dose or at a
low dose in routine outpatient settings. We also investigated whether
this association was modified by the presence of chronic kidney disease.
2. Methods
2.1. Setting and study design
Residents of the province of Ontario, Canada have universal access to
hospital care and physician services. Those 65 years of age or older also
have universal prescription drug coverage (approximately two million
individuals in 2012) [19]. All health care encounters are recorded in da-
tabases held securely in a linked, de-identified form at the Institute for
Clinical Evaluative Sciences (ICES) in Ontario, Canada. We conducted a
population-based retrospective cohort study using these data sources.
This study was conducted according to a pre-specified protocol that
was approved by the research ethics board at Sunnybrook Health Sci-
ences Centre (Toronto, Canada). The reporting of this study followed
guidelines for observational studies (detailed in Appendix A) [20].
2.2. Data sources
We ascertained baseline characteristics, H2RA use and dose, and
outcome data using eight linked healthcare databases. Demographic
and vital status information on all Ontario residents who have ever
been issued a health card is recorded in the Ontario Registered Persons
Database. Detailed diagnostic and procedural information on all hospital
admissions and emergency room visits is recorded in the Canadian
Institute for Health Information Discharge Abstract Database and the
National Ambulatory Care Reporting System, respectively. Health claims
for inpatient and outpatient physician services are recorded in the
Ontario Health Insurance Plan database. Diagnostic information on all
individuals ever admitted to a mental health unit is available in the
Ontario Mental Health Reporting System. Outpatient prescription drug
information including the dispensing date, quantity of pills, dose, and
number of days supplied is accurately recorded in the Ontario Drug
Benefit Program database, with an error rate less than 1% [21]. In a sub-
population of patients, we used two linked laboratory data sets to obtain
baseline serum creatinine values from the year prior to the new H2RA
prescription (median 94 days). All data sources have been used previ-
ously to study drug safety [22–25]. With the exception of prescriber in-
formation, the databases were complete for all variables used in this
study.
Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
Compendium of pharmaceuticals and specialties
• 20 mg to 40 mg/day
• Dosing should be reduced by half in patients with
renal insufficiency
• 150 mg taken twice daily or 300 mg once daily
(in some cases up to 600 mg/day)
• Recommended daily dose for patients with creatinine
clearance b50 mL/min is 150 mg
2.3. Patients
We established a cohort of all older adults in Ontario with evidence
of a new outpatient prescription for oral ranitidine or famotidine
between April 1, 2002 and December 31st 2011. Cimetidine prescrip-
tions were not included in our study as they made up less than 1.5% of
all H2RA prescriptions in our jurisdiction during the accrual period. All
eligible prescriptions were either standard dose or low dose (Table 1).
Patients with multiple eligible prescriptions could only enter the cohort
once, and the date of the first H2RA prescription served as the patient's
index date (cohort entry date; start of follow-up). We assessed baseline
demographic characteristics, comorbid conditions (5 years prior to
index date) and concurrent drug therapy (120 days prior to index
date). We excluded the following H2RA users from the analysis: those
in their first year of eligibility for prescription drug coverage (i.e., age
65 years; 5.8% of cohort) to avoid incomplete medication records;
those discharged from hospital in the 2 days prior to the index date
(5.7% of cohort) to ensure prescriptions were initiated in the outpatient
setting; those with end-stage renal disease as dialysis may influence
H2RA pharmacokinetics (1.0% of cohort); those with H2RA prescrip-
tions in the 180 days prior to index date (to restrict the analysis to
new H2RA initiations; 22.7% of cohort); and those living in long-term
care facilities as such residents tend to have multiple comorbidities
and may be more prone to altered mental status (6.7% of cohort) [26].
We identified individuals with chronic kidney disease using an algo-
rithm of diagnosis codes validated in our region for older adults [27].
The algorithm identified patients with a median estimated glomerular
filtration rate (eGFR) of 38 mL/min per 1.73 m2 (interquartile range
27 to 52), whereas its absence identified patients with a median eGFR
of 69 mL/min per 1.73 m2 (interquartile range 56 to 82).
2.4. H2RA dosing
As reported in drug prescribing references, the standard dose of H2RA
was defined as 300 mg/day of ranitidine, or 40 mg/day of famotidine
(Table 1) [2–5]. A low H2RA dose was defined as 150 mg/day of raniti-
dine, or 20 mg/day of famotidine.
2.5. Outcomes
As most reported H2RA-related altered mental status occurs within
the first few weeks of drug initiation, we followed all individuals for
30 days after the index date for two pre-specified outcomes [10–13].
Our primary outcome was hospitalization with evidence of an urgent
head computed tomography (CT) scan — a proxy measure for delirium.
We used an urgent head CT scan as a proxy for the presence of acute
altered mental status for several reasons: (i) in the setting of altered men-
tal status and the absence of an obvious drug toxidrome, metabolic distur-
bance or source of infection, neuroimaging is considered necessary to rule
out intracranial etiologies by many popular clinical references; [28,29]
(ii) based on prospective studies of common clinical practice, neuroimag-
ing is commonly utilized in the routine evaluation of acutely confused
older adults, even among those without focal neurologic findings or
 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx 3

traumatic head trauma; [30–32] and finally (iii) considering other poten-
tial causes for urgent neuroimaging in the setting of delirium, we expect
that the incidence of neuroimaging indicated by trauma or focal neurolog-
ic findings to occur at similar frequency in our two H2RA dosing groups,
and therefore would not impact estimates of difference in risk. Further-
more, unlike diagnostic codes for acute delirium, completion of a head
CT scan is well coded in our data sources (these codes have high sensitiv-
ity and specificity as they are associated with physician reimbursement)
[33]. To focus on neuroimaging conducted for acute reasons at the time
of hospital admission, we only considered head CT scans performed in
the emergency department preceding the hospital admission or within
the first 5 days of a hospital admission. Our secondary outcome was all-
cause mortality which is also well coded in our databases. We considered
this measure given its importance, as delirium is a potential contributor of
mortality through multiple pathways (e.g., infection predisposition,
decreased food and water intake, inability to take medications) [34].
2.6. Statistical analysis
by the presence of CKD. All odds ratios were interpreted as relative risks
(appropriate given the low incidences observed). We conducted all
statistical analyses using SAS, version 9.2.
2.7. Additional analyses
We conducted several additional analyses to examine the stability of
our outcomes: (i) to ensure prescriptions were not the result of recent
hospitalization, we conducted a sensitivity analysis by excluding all
individuals with evidence of hospitalization in the 5 days prior to drug
prescription (versus two days as done in the primary analysis); (ii) to
ensure neuroimaging was done urgently, we conducted a sensitivity
analysis by restricting to head CT scans performed in the emergency
department preceding hospital admission or within the first 2 days of
a hospital admission (versus five days as done in the primary analysis);
and finally, (iii) to explore age effects, we conducted a subgroup analysis
to determine if the association between H2RA dose and outcome dif-
fered in the two different age strata (i.e., b74 years or ≥74 years).

We compared 29 baseline characteristics between those prescribed 3. Results

standard vs. low daily doses of H2RAs by using standardized differences.
This metric describes differences between group means relative to the
pooled standard deviation and indicates a meaningful difference if
greater than 10% [35]. We expressed the risk for an outcome in relative
and absolute terms. Absolute risk was further quantified as the “number
needed to harm” (1/absolute risk difference, a lower number indicating
greater harm). The number needed to harm was calculated for ease of
interpretation and not to imply causality. We used multivariable logistic
regression analyses (PROC LOGISTIC; SAS Institute, Cary, North Carolina)
to estimate adjusted odds ratios and 95% confidence intervals. We adjust-
ed for 16 potential confounders related to our outcomes a priori: H2RA
type, age, sex, year of cohort entry, Charlson score (a co-morbidity
index), presence of dementia, chronic kidney disease, as well as
concurrent use of anticonvulsants, antidepressants, antipsychotics, bar-
biturates, benzodiazepines, dopamine agonists, muscle relaxants, opi-
oids, and over-active bladder medications. We identified individuals
with dementia using an algorithm of diagnosis codes (Appendix B). In
addition, we tested for interaction to determine whether the odds
ratio between drug dose (standard vs. low) and outcome was modified
The study included 212,250 eligible older adults in routine outpatient
care who were dispensed a new oral H2RA (Fig. 1). A total of 193,135 pa-
tients (91%) were initiated on a standard H2RA dose, and 19,115 patients
(9%) initiated on a low dose. Dosing remained largely unchanged for sub-
sequent prescriptions (Appendix C). Most prescriptions were written by
a primary care physician. There was no significant difference in 27 of
the 29 baseline characteristics measured in each of the standard and
low H2RA dose groups (Table 2). Patients in the standard vs. low dose
group were slightly younger (average 74.8 vs. 75.6 years) and were
more likely to receive ranitidine than famotidine (standard dose: 92.9%
vs. 7.1%; low dose: 88.0% vs. 12.0%).
3.1. 30-Day risk of hospitalization with urgent head computed tomography
(CT) scan
Standard vs. low H2RA dose was associated with a higher risk
of hospitalization with head CT scan (Table 3; 1895/193,135 [0.98%]
vs. 141/19,115 [0.74%], absolute risk difference 0.24% [95% CI 0.11%

Patients with evidence of an eligible outpatient oral prescription

for either a standard or low dose of ranitidine or famotidine
between April 1st 2002 and December 31st 2011.
N = 365,304

Patients excluded from study:

Age 65 on the prescription date: N =21,086
Hospital discharge in 2 days prior to the prescription date: N = 20,683
End-stage renal disease before prescription date: N = 3,775
Any H2RA prescription in the 6 months prior to prescription date: N = 83,065
Long-term care home residents: N = 24,419
More than one type of H2RA on prescription date: N = 26

Patients included in final cohort

N = 212,250
N = 193,135 Standard dose
N = 19,115 Low dose

Fig. 1. Patient selection.

Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
4 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

Table 2
Baseline characteristics by histamine2-receptor antagonist (H2RA) dose.

Standard dose Low dose Standardized difference

N = 193,135 N = 19,115

H2RA type, n (%)

Ranitidine 179,437 (92.9) 16,820 (88.0) 17%
Famotidine 13,698 (7.1) 2295 (12.0)
Demographics
Age, years, mean (SD) 74.8 (6.8) 75.6 (7.2) 13%
Women, n (%) 115,362 (59.7) 11,599 (60.7) 2%
Year of cohort entry, n (%)
2002–2003 63,925 (33.1) 5808 (30.4) 6%
2004–2005 43,738 (22.6) 3780 (19.8) 7%
2006–2007 30,226 (15.6) 2972 (15.6) 0%
2008–2009 26,018 (13.5) 2981 (15.6) 6%
2010–2011 29,228 (15.1) 3574 (18.7) 10%
Income quintile, n (%)
First (lowest) 42,203 (21.9) 4020 (21.0) 2%
Second 42,479 (22.0) 4161 (21.8) 1%
Third (middle) 38,237 (19.8) 3680 (19.3) 1%
Fourth 35,380 (18.3) 3625 (19.0) 2%
Fifth (highest) 34,069 (17.6) 3560 (18.6) 3%
Rural location, n (%) 26,806 (13.9) 2517 (13.2) 2%
Modified Charlson scorea
0 133,247 (69.0) 12,985 (67.9) 2%
1 21,296 (11.0) 2282 (11.9) 3%
2 18,499 (9.6) 1808 (9.5) 0%
≥3 20,093 (10.4) 2040 (10.7) 1%
Comorbiditiesb, n (%)
Chronic kidney diseasec 9226 (4.8) 1250 (6.5) 7%
Chronic liver disease 7964 (4.1) 736 (3.9) 1%
Chronic obstructive pulmonary disease 9382 (4.9) 958 (5.0) 1%
Coronary artery diseased 71,980 (37.3) 7464 (39.1) 4%
Heart failure 23,420 (12.1) 2688 (14.1) 6%
Stroke/transient ischemic attack 4777 (2.5) 652 (3.4) 6%
Dementiae 12,368 (6.4) 1603 (8.4) 8%
Medicationf, n (%)
Anticonvulsants 8497 (4.4) 884 (4.6) 1%
Antidepressants 22,120 (11.5) 2283 (11.9) 2%
Antipsychotics 5515 (2.9) 565 (3.0) 1%
Barbiturates 234 (0.1) 19 (0.1) 1%
Benzodiazepines 41,397 (21.4) 4070 (21.3) 0%
Diabetic medicationsg 32,475 (16.8) 3304 (17.3) 1%
Dopamine agonists 803 (0.4) 88 (0.5) 1%
Muscle relaxants 1192 (0.6) 103 (0.5) 1%
Opioids 43,636 (22.6) 3716 (19.4) 8%
Overactive bladder medications 5467 (2.8) 580 (3.0) 1%
Prescribing physician, n (%)
General practitioner 138,671 (71.8) 12,924 (67.6) 9%
Internist 2547 (1.3) 334 (1.8) 3%
Neurologist 492 (0.3) 75 (0.4) 2%
Other 18,657 (9.7) 2395 (12.5) 9%
Missing 32,768 (17.0) 3387 (17.7) 2%
ER visits in 1 year prior, mean (SD) 2.1 (2.2) 2.1 (2.6) 0%
Hospitalizations in 1 year prior, mean (SD) 1.8 (1.3) 1.8 (1.4) 0%
Family physician visits in 1 year prior, mean (SD) 14.5 (14.2) 15.1 (15.5) 4%
Unique prescriptions in 1 year prior, mean (SD) 8.9 (5.8) 8.9 (5.7) 1%
a
Assessed with an algorithm using diagnosis codes from hospitalizations in the 5 years prior; patients with no hospitalizations during this period were given a value of zero.
b
Comorbidities were assessed in the 5 years prior to the index date.
c
Assessed with an algorithm validated in our region which used diagnosis codes.
d
Coronary artery disease includes receipt of coronary artery bypass graft surgery, percutaneous coronary intervention and diagnoses of angina.
e
Assessed with an algorithm using diagnosis codes.
f
Medication use was assessed in the 120 days prior to the index date.
g
Diabetic medications include oral anti-hyperglycemics and insulin.

to 0.36%], number needed to harm 417 (95% CI 278 to 910), relative
risk 1.33 [95% CI 1.12 to 1.58]). Adjusting for 16 potential confounders
had no appreciable impact on the observed association (Table 3).
The association was no different in patients with or without chronic
kidney disease (when the presence of this condition was assessed
with diagnosis codes; Fig. 2; interaction P value = 0.71). In the subpop-
ulation with available baseline laboratory values, the association
remained evident in those with preserved renal function (Appendix D;
eGFR ≥ 60 mL/min per 1.73 m2; n = 26,508 standard dose, n = 2618
low dose).
3.2. 30-Day all-cause mortality
Standard vs. low H2RA dose was also associated with a higher
30-day risk of all-cause mortality (Table 3; 2074/193,135 [1.07%] vs.
141/19,115 [0.74%], absolute risk difference 0.34% [95% CI 0.20% to
0.46%], number needed to harm 295 (95% CI 218 to 500), relative risk
1.46 [95% CI 1.23 to 1.73]). Adjusting for the 16 potential confounders
had no appreciable impact on the observed association (Table 3).
The association was no different in patients with and without chron-
ic kidney disease (when the presence of this condition was assessed

Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx 5

Table 3
Association between oral histamine2-receptor antagonist dose and 30-day outcomes.

Number of events (%) Absolute risk difference (%) Number needed to harm Relative risk (unadjusted) Relative risk (adjusted)
(95% CI) (95% CI) (95% CI) (95% CI)a
Standard dose Low dose
N = 193,135 N = 19,115

Hospital admission with head CT scan 1895 (0.98) 141 (0.74) 0.24% (0.11 to 0.36) 417 (278 to 910) 1.33 (1.12–1.58) 1.39 (1.17–1.65)
All-cause mortality 2074 (1.07) 141 (0.74) 0.34% (0.20 to 0.46) 295 (218 to 500) 1.46 (1.23–1.73) 1.38 (1.16–1.64)

A standard daily dose was 300 mg of ranitidine or 40 mg/day of famotidine. A low daily dose was 150 mg of ranitidine or 20 mg of famotidine. Patients prescribed the low H2RA dose
served as the referent group.
Abbreviations: CI, confidence interval, CT computed tomography.
a
Adjusted for 16 covariates, see Methods section.

with diagnosis codes; Fig. 2; interaction P value = 0.13). In the sub-
population with available baseline laboratory values, the association
remained evident in those with preserved renal function (Appendix D;
eGFR ≥ 60 mL/min per 1.73 m2).
3.3. Additional analyses
We excluded individuals with evidence of a hospital discharge in the
5 days prior to an H2RA prescription (vs. within 2 days). The results did
not differ from the primary analysis (Appendix E; 1841/191,614 [0.96%]
vs. 141/18,989 [0.74%], absolute risk difference 0.22% [95% CI 0.08% to
0.34%], number needed to harm 459 (95% CI 295 to 1260), adjusted
relative risk 1.35 [95% CI 1.13 to 1.60]). When defining the primary
outcome by a head CT scans performed in the emergency department
preceding hospital admission or within the first 2 days of a hospital
admission (vs. within 5 days), the results did not differ from our pri-
mary analysis (Appendix F; 1765/193,135 [0.91%] vs. 132/19,115
[0.69%], absolute risk difference 0.22% [95% CI 0.09% to 0.34%], num-
ber needed to harm 448 (95% CI 295 to 1120), relative risk 1.38 [95%
CI 1.15 to 1.65]). Furthermore, the association between H2RA dosing
(standard vs. low) and our primary outcome was not statistically dif-
ferent in subgroups of patients defined by age (Appendix G; interac-
tion P value = 0.35).
4. Interpretation
We conducted this study to compare the 30-day risk of altered
mental status using neuroimaging as a proxy in older adults initiated
on either a standard dose or a low dose of oral H2RA in routine outpa-
tient care. Compared to a lower H2RA dose, receipt of a standard dose
was associated with an increased 30-day risk of hospitalization with
urgent neuroimaging and all-cause mortality, possibly late and extreme
outcomes in the spectrum of altered mental status.
The magnitude of the increase in the likelihood of altered mental
status and death, in absolute terms, was small. However, there are
two important considerations that give significance to this small but
increased risk. First, H2RA use is very common [1]. At a population
level it is possible that hundreds of hospital admissions with altered
mental status and potentially many deaths may be prevented by initiat-
ing patients on a low versus standard dose of H2RA for the symptoms of
gastroesophageal reflux disease. Given the associated health care costs
of caring for a patient with altered mental status (ranges from $16,303
to $64,421 US), it is also possible that several million dollars may be
saved each year as well [36]. Second, the absolute increase in the risk
of delirium is likely greater than we could estimate as some older adults
with altered mental status did not present to hospital and therefore
were not investigated with neuroimaging.
We hypothesized that the presence of chronic kidney disease would
make older adults particularly vulnerable to H2RA toxicity due to re-
duced elimination of the drug. However, in this study we noted similar
risks of adverse events from standard H2RA doses in patients with and
without chronic kidney disease. In light of this finding, we suspect
that older adults in general may have increased sensitivity to H2RA
effects independent of their renal function. Reasons for toxicity may in-
clude reduced first-pass liver metabolism, changes in receptor function
and post-receptor signaling, as well as impaired homeostatic compen-
satory mechanisms such as increased fat content and decreased body
water resulting in a decreased volume of distribution (H2RAs are hydro-
philic) [6,7]. We suspect that some of these mechanisms may contribute
to increased plasma concentrations and drug sensitivity to H2RAs which
ultimately leads to adverse drug events such as delirium. However, we
recognize that this assumption is limited by the fact that the general
pathophysiology of delirium is not well understood [26].

Fig. 2. Interaction of CKD status and H2RA dosing on study outcomes.

Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
6 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

Considering our findings, the impetus exists to consider initiating
older adults on low H2RA doses for control of symptomatic gastro-
esophageal reflux symptoms. In a randomized, double-blind, parallel
group, multicenter dose-ranging study, Pappa et al. (1999) found that
ranitidine 75 mg compared to placebo provided clinically significant
prompt relief of symptoms of gastroesophageal reflux that lasted for
up to 12 hours (P value ≤ 0.002; 16 percentage points) [37]. While pa-
tients were permitted to use up to four ranitidine 75 mg tablets per day,
most (92%) only needed one or two tablets a day [37]. These findings are
supported in a biologic study where a single oral dose of 75 mg of ranit-
idine or 10 mg of famotidine resulted in lower gastric acid level which
lasted approximately 9 hours after dosing [38]. Therefore, high H2RA
dosing may simply be unnecessary as initial therapy.
In light of our findings and the best available evidence, we recom-
mend that clinicians initiate older adults on a low dose of H2RA for con-
trol of gastroesophageal reflux symptoms, irrespective of their kidney
function. Dosing can be titrated as needed to achieve gastrointestinal
symptom control. To optimize the risks and benefits of H2RAs, we pro-
pose an initial maximum daily dose of 150 mg of ranitidine or 20 mg of
famotidine. However, information from future prospective research
studies and clinical trials would be best suited to alter clinical practice
guidelines.
Our study has many strengths. To our knowledge it is the first
population-based study of adverse clinical events from H2RA use in
the outpatient setting. The use of Ontario's broadly inclusive healthcare
databases provided us with a large representative sample and allowed
us to estimate the risk of an uncommon but serious adverse drug reac-
tion with good precision and external validity. The data was complete,
drug dose and outcomes were accurately recorded, and patient loss
to follow-up was minimal (emigration in our region is less than 1%
per year) [39].
Our study has some limitations. As in any observational study the
possibility of confounding can never be completely eliminated. Howev-
er, the similarity of the 27 patient baseline characteristics in both H2RA
dosing groups helped reduce concerns about the influence of residual
confounding. Further, while we observed no change in associations fol-
lowing adjustment for multiple potential confounders, we were limited
by the lack of information on pertinent confounders such as sensory im-
pairment, sleep deprivation and immobilization. Additionally, we did
not have access to information on drug compliance, dosing regimens,
or over-the-counter H2RA use. Our primary outcome was assessed
retrospectively using existing healthcare database records and relied
on urgent neuroimaging as a proxy for the diagnosis of altered mental
status. A well-designed prospective study with independent outcome
adjudication would more precisely capture cases of altered mental
status. Specific causes of mortality were not explored, as the reliability
of such data in our region is questionable.
In conclusion, older adults can be initiated on a low H2RA dose in
light of the small but increased risk of urgent neuroimaging (proxy
for altered mental status), with dosing titrated to best achieve symp-
tom control. This recommendation can feature in quality improve-
ment initiatives, drug prescribing references, and the packaging
of over-the-counter H2RA preparations. Prospective research studies
and clinical trials are needed to better characterize the risk of H2RA-
induced delirium, and validate neuroimaging as a proxy measure for
delirium.
Conflict of interests
The authors declare that they have no relevant financial interests. Dr.
Garg received an investigator-initiated grant from Astellas and Roche to
support a Canadian Institutes of Health Research study in living kidney
donors, and his institution received unrestricted funding from Pfizer for
research unrelated to the current project. The Institute for Clinical Eval-
uative Sciences (ICES) is a non-profit research corporation funded by an
annual grant from the Ontario Ministry of Health and Long-Term Care
(MOHLTC). The research was conducted at the ICES Western facility,
which receives financial support from the Academic Medical Organiza-
tion of Southwestern Ontario, the Schulich School of Medicine and Den-
tistry at Western University and the Lawson Health Research Institute.
The opinions, results and conclusions are those of the authors and are
independent from the funding sources. No endorsement by ICES or
the Ontario MOHLTC is intended or should be inferred.
Acknowledgements
We thank Brogan Inc., Ottawa, for use of its Drug Product and
Therapeutic Class Database, Gamma Dynacare for use of the outpatient
laboratory database and the team at London Health Sciences Centre,
St. Joseph's Health Care, and the Thames Valley Hospitals for providing
access to the Cerner laboratory database.
Support
Mr. Tawadrous was supported by a Medical Student Schulich
Research Training Program award from the Schulich School of Medicine
and Dentistry. Dr. Garg was supported by a Clinician Scientist Award
from the Canadian Institutes of Health Research, and his institution re-
ceived an unrestricted grant from Pfzier to conduct research unrelated
to this study.

Appendix A. Checklist of recommendations for reporting of observational studies using the STROBE guidelines

Item no Recommendation Reported

Title and abstract 1 (a) Indicate the study's design with a commonly used term in the title Abstract
or the abstract
(b) Provide in the abstract an informative and balanced summary of Abstract
what was done and what was found

Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation Introduction
being reported
Objectives 3 State specific objectives, including any prespecified hypotheses Introduction

Methods
Study design 4 Present key elements of study design early in the paper Methods — Setting and study design
Setting 5 Describe the setting, locations, and relevant dates, including periods of Methods — Setting and study design
recruitment, exposure, follow-up, and data collection
Participants 6 (a) Give the eligibility criteria, and the sources and methods of Methods — Participants
selection of participants. Describe methods of follow-up
(b) For matched studies, give matching criteria and number of exposed Not applicable
and unexposed

Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx 7

Appendix
(continued)
A (continued)
Item no Recommendation Reported

Variables 7 Clearly define all outcomes, exposures, predictors, potential Methods — H2RA dosing; outcomes
confounders, and effect modifiers. Give diagnostic criteria, if applicable
Data sources/ measurement 8 For each variable of interest, give sources of data and details of methods Methods — Data sources
of assessment (measurement). Describe comparability of assessment
methods if there is more than one group
Bias 9 Describe any efforts to address potential sources of bias Methods — Statistical analysis; Discussion
Study size 10 Explain how the study size was arrived at not applicable; use of existing health records
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If Not applicable
applicable, describe which groupings were chosen and why
Statistical methods 12 (a) Describe all statistical methods, including those used to control for Methods — Statistical analysis
confounding
(b) Describe any methods used to examine subgroups and interactions Methods — Participants; statistical analysis
(c) Explain how missing data were addressed Not applicable
(d) If applicable, explain how loss to follow-up was addressed Not applicable
(e) Describe any sensitivity analyses Results — Subpopulation with eGFR N 60

Results
Participants 13 (a) Report numbers of individuals at each stage of study—e.g. numbers Results; Fig. 1
potentially eligible, examined for eligibility, confirmed eligible,
included in the study, completing follow-up, and analysed
(b) Give reasons for non-participation at each stage Fig. 1
(c) Consider use of a flow diagram Fig. 1
Descriptive data 14 (a) Give characteristics of study participants (e.g. demographic, clinical, Methods — Participants; Results, Table 2
social) and information on exposures and potential confounders
(b) Indicate number of participants with missing data for each variable Complete with exception of specialty of prescribing
of interest physician (missing data described in Table 2)
(c) Summarise follow-up time (e.g. average and total amount) Not applicable
Outcome data 15 Report numbers of outcome events or summary measures over time Results; Table 3; Appendix B
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted Results; Table 3; Appendix B
estimates and their precision (e.g. 95% confidence interval). Make clear
which confounders were adjusted for and why they were included
(b) Report category boundaries when continuous variables were Not applicable
categorized
(c) If relevant, consider translating estimates of relative risk into Results; Table 3; Appendix B
absolute risk for a meaningful time period
Other analyses 17 Report other analyses done—e.g. analyses of subgroups and Results; Fig. 1; Appendix B-F
interactions, and sensitivity analyses

Discussion
Key results 18 Summarise key results with reference to study objectives Discussion
Limitations 19 Discuss limitations of the study, taking into account sources of potential Discussion
bias or imprecision. Discuss both direction and magnitude of any
potential bias
Interpretation 20 Give a cautious overall interpretation of results considering objectives, Discussion
limitations, multiplicity of analyses, results from similar studies, and
other relevant evidence
Generalisability 21 Discuss the generalisability (external validity) of the study results Discussion

Other information
Funding 22 Give the source of funding and the role of the funders for the present
study and, if applicable, for the original study on which the present
article is based

Appendix B. Algorithm of OHIP, CIHI, and OMHRS diagnostic codes for dementia

Code Description

ICD9
2900 Senile dementia uncomp
2901 Presenile dementia/delusion/delirium
2903 Senile delirium
2904 Arterioscle delirium/delusion
2908 Senile psychosis nec
2909 Senile psychot cond nos
2948 Organic brain synd nec
2949 Organic brain synd nos
3310 Alzheimer's
3311 Pick's disease
3312 Senile degenerat brain
2941 Dementia in other diseases
797 Senility w/o psychosis

ICD10
F065 Organic dissociative disorder
F066 Organic emotionally labile disorder
(continued on next page)

Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
8 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

Appendix
(continued)
B (continued)
Code Description

F068 Other specified mental disorder due to brain damage or physical disease
F069 Unspecified mental disorder due to brain damage or physical disease
F09 Unspecified organic or symptomatic mental disorder
F00 Dementia in Alzheimer's disease
F01 Vascular dementia
F02 Dementia in other diseases classified elsewhere
F03 Unspecified dementia
F051 Delirium superimposed on dementia
G30 Alzheimer's disease
G31 Other degenerative diseases of nervous system, not elsewhere classified
R54 Senility

OHIP
290 Senile dementia, presenile dementia
331 Other cerebral degenerations
797 Senility, senescence

DSM-IV (OMHRS)
29040 Vascular dementia, uncomplicated
29041 Vascular dementia, with delirium
29042 Vascular dementia, with delusions
29043 Vascular dementia, with depressed mood
29120 Alcohol-induced persisting dementia
29282 Substance-induced persisting dementia
29410 Dementia due to general medical condition, without behavioural disturbance
29411 Dementia due to general medical condition, with behavioural disturbance
29480 Dementia & amnestic disorder nos
78090 Age-related cognitive decline

Appendix C. Stability of dosing among standard and low-dosing groups during follow-up prescriptions

Drug Dosing N Index prescription Follow-up prescription

Mean STD Median Lower IQR Upper IQR Mean STD Median Lower IQR Upper IQR

Famotidine Low 1179 20 0.17 20 20 20 21.58 6.46 20 20 20

Standard 6157 40 1.25 40 40 40 39.52 10.14 40 40 40
Ranitidine Low 8524 150 1.04 150 150 150 174.13 73.25 150 150 150.00
Standard 75,994 300 6.14 300 300 300 295.01 145.52 300 300 300

Appendix D. Association between oral histamine-2receptor antagonist dose and 30-day outcomes in patients with evidence of a baseline
estimated glomerular filtration rate (eGFR) ≥ 60 mL/min per 1.73 m2

Number of events (%) Absolute risk difference (%) Number needed to harm Relative risk (unadjusted) Relative risk (adjusted)
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) a

Standard dose Low dose

N = 26,508 N = 2618

Hospital admission with head CT scan 225 (0.85) 9 (0.34) 0.51 (0.18 to 0.71) 197 (141 to 556) 2.48 (1.27–4.84) 2.53 (1.30–4.95)
All-cause mortality 179 (0.68) 7 (0.27) 0.41 (0.11 to 0.58) 244 (173 to 910) 2.54 (1.19–5.40) 2.19 (1.01–4.71)

A standard daily dose was 300 mg of ranitidine or 40 mg of famotidine. A low daily dose was 150 mg of ranitidine or 20 mg of famotidine. Patients prescribed the low H2RA dose served as
the referent group.
Abbreviations: CI, confidence interval, CT computed tomography.
a
Adjusted for 16 covariates, see ‘Methods’ section for description (no adjustment for chronic kidney disease was required).

Appendix E. Sensitivity Analysis: no evidence of hospitalization in 5 days prior to index prescription date

Number of events (%) Absolute risk difference (%) Number needed to harm Relative risk (unadjusted) Relative risk (adjusted)a
(95% CI) (95% CI) (95% CI)
Standard dose Low dose
N = 191,614 N = 18,989

Hospital admission with head CT scan 1,841 (0.96) 141 (0.74) 0.22 (0.08 to 0.34) 459 (295 to 1260) 1.30 (1.09–1.54) 1.35 (1.13–1.60)

Abbreviations: CI, confidence interval, CT computed tomography.

a
Adjusted for 16 covariates, see ‘Methods’ section for description.

Please cite this article as: Tawadrous D, et al, Altered mental status in older adults with histamine2-receptor antagonists: A population-based
study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021
 D. Tawadrous et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx 9

Appendix F. Sensitivity analysis: head CT scans performed in the emergency department preceding hospital admission or within two days of
hospital admission (vs. five days)

Number of events (%) Absolute risk difference (%) Number needed to harm Relative risk (unadjusted) Relative risk (adjusted)a
(95% CI) (95% CI) (95% CI) (95% CI)
Standard Dose Low Dose
N = 193,135 N = 19,115

Hospital admission with head CT scan 1,765 (0.91) 132 (0.69) 0.22 (0.09 to 0.34) 448 (295 to 1120) 1.33 (1.11–1.58) 1.38 (1.15–1.65)

Abbreviations: CI, confidence interval, CT computed tomography.

a
Adjusted for 16 covariates, see ‘Methods’ section for description.

Appendix G. Subgroup analysis: association between H2RA dosing and primary outcome in patients defined by age

Median age stratified Dosing (per day) # patients Inpatient Proportion of patients Unadjusted OR (95% CI) Interaction Adjusted OR (95% CI)a Interaction
CT head with events P-value P-value
Odds ratio LCL UCL Odds ratio LCL UCL

Age b 74 Low dose 8522 42 0.49% 1.00 REF REF 0.2512 1.00 REF REF 0.3546
Standard dose 94771 734 0.77% 1.58 1.15 2.15 1.53 1.12 2.09
Age N= 74 Low dose 10593 99 0.93% 1.00 REF REF 1.00 REF REF
Standard dose 98364 1161 1.18% 1.27 1.03 1.56 1.28 1.05 1.59

Abbreviations: CI, confidence interval, CT computed tomography.

a
Adjusted for 16 covariates, see ‘Methods’ section for description.

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study, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.06.021