Eur J Clin Pharmacol (2016) 72:731–736

DOI 10.1007/s00228-016-2026-0

PHARMACOEPIDEMIOLOGY AND PRESCRIPTION

Drug-related mortality among inpatients: a retrospective

observational study
Alfredo José Pardo Cabello 1 & Esperanza Del Pozo Gavilán 2 & Francisco Javier Gómez Jiménez 3 &
Carmen Mota Rodríguez 4 & Juan de Dios Luna Del Castillo 5 & Emilio Puche Cañas 6,7

Received: 29 September 2015 / Accepted: 10 February 2016 / Published online: 20 February 2016
# Springer-Verlag Berlin Heidelberg 2016

Abstract
Purpose Hospital mortality related to adverse drug reactions
(ADRs) is a relevant clinical problem with major health and
economic consequences. We conducted a study to assess hospi-
tal mortality related to ADRs, the drugs most frequently in-
volved, and the possible risk factors associated with fatal ADRs.
Methods A retrospective observational study was conducted,
reviewing the clinical records of 1388 consecutive adult pa-
tients (18–101 years) who died during a 22-month period in a
tertiary hospital in Southern Europe (Granada, Spain). The
main outcome was the prevalence of hospital death suspected
to be related to administered drugs.
Electronic supplementary material The online version of this article
(doi:10.1007/s00228-016-2026-0) contains supplementary material,
which is available to authorized users.
* Alfredo José Pardo Cabello
apardoc05@yahoo.es
Results Out of the 1388 adult deaths studied, 256 (18.4 %)
were suspected of being related to drugs. Drugs were
suspected of causing death in 146 inpatients (10.5 %) and
contributing to death in 110 (7.9 %). Drugs related to death
were administered during the hospital stay in 161 cases
(11.5 %) and before hospital admission in 95 (6.84 %). The
most frequent fatal ADRs were cardiac arrhythmia, gastroin-
testinal bleeding, and respiratory failure. The drugs most fre-
quently involved in fatal ADRs were antithrombotics (antico-
agulants or antiplatelets) (23 %), psychotropic drugs (21.2 %),
and digoxin (11.3 %). Independent risk factors for ADR-
related death were the presence of ≥4 diseases (OR = 1.43)
and the receipt of ≥10 drugs (OR = 3.24), but no significant
association with gender or age was found.
Conclusions A high percentage of hospital deaths were
suspected of being associated with ADRs, especially in patients
with comorbidity and/or polypharmacy. Antithrombotics, psy-
chotropics, and digoxin were the drugs most frequently associ-
ated with in-hospital drug-related deaths.

1
Department of Internal Medicine, San Cecilio University Hospital, Keywords Adverse drug reactions . Hospital mortality .
Avda. Dr. Olóriz n°16, 18012 Granada, Spain Inpatients . Epidemiology
2
Department of Pharmacology, School of Medicine, Biomedical
Research Institute ibs. Granada, University of Granada,
Granada, Spain
3
Department of Medicine, School of Medicine, University of Introduction
Granada, Granada, Spain
4
School of Health Sciences of the University of Granada, Drugs are widely used in the control of disease currently,
Granada, Spain but it is well known that they are not free from risk of
5
Department of Biostatistics, School of Medicine, University of harm, especially in some clinical circumstances. The ad-
Granada, Granada, Spain verse drug reactions associated to pharmacological treat-
6
Clinical Pharmacology Unit of San Cecilio University Hospital, ments remains an unresolved clinical challenge with
Granada, Spain health and economic implications, which affects patients
7
Department of Pharmacology of School of Medicine, University of in hospital and community settings [1–5]. An extensive
Granada, Granada, Spain literature review on drug-related deaths in hospital
732
patients reported a wide range of prevalences (0.30–19 %)
depending on the methodology employed [6–17].
A previous meta-analysis reported that adverse drug reac-
tions (ADRs) affected 13 % of adult patients in Spanish hos-
pitals and were strongly associated with polypharmacy and
advanced age, being the cause of death in 0.1 % of hospital-
ized patients [18]. A pilot observational study of 289 adult
patients dying during their stay in our hospital revealed that
5.9 % of the deaths were related to their pharmacological
treatment according to WHO methodology [19]. Based on
these preliminary results, a wider study was designed to assess
the prevalence of drug-related death and the associated risk
factors in a larger sample of patients dying in the hospital
during a 22-month period.
Methods
Study design and setting
A retrospective observational study was performed in consec-
utive adults (age ≥18 years) of either sex who died between
January 1 2009 and October 31 2010 during their stay in a
502-bed tertiary hospital, which serves a population of 428,
000 inhabitants in Southern Spain and admits around 22,000
patients per year. The study inclusion criteria were as follows:
death in the hospital after a stay of at least 24 h in any depart-
ment (except the emergency room); and the availability of
clinical records containing all data required for the study.
Exclusion criteria were as follows: age <18 years, hospital
stay <24 h, drug consumption in a suicide attempt or an in-
complete clinical record. The study was undertaken jointly by
the Clinical Pharmacology Unit of the hospital and the
Department of Medicine of the University of Granada (Spain).
Data collection
The clinical records of the eligible patients were reviewed,
gathering data on their sex, admission diagnosis, personal his-
tory, clinical evolution, cause of death, length of stay, depart-
ment in which the death took place, laboratory data, imaging
results, and pharmacological treatment. All records were on
paper (the study ended on October 31 2010 because a com-
puterized records system was established in the hospital from
the next day). Five researchers (A.P.C., E.P.G., F.G.J., C.M.R.,
and E.P.C) independently reviewed all clinical records, includ-
ing nursing reports, evaluating the association of drugs with
the death of patients and possible causal relationships. The
researchers then met twice a month to decide on the degree
of association of drugs with death after an exhaustive case-by-
case discussion. The level of agreement (kappa index) among
the researchers in their individual evaluation of the cases, be-
fore group discussions, was measured for the first 100 deaths
Eur J Clin Pharmacol (2016) 72:731–736
out of the 1388 studied. When the researchers could not reach
a unanimous agreement after the discussion, the association of
drug(s) with the death in question was rejected. The final
decision was entered in a database with the aforementioned
study variables. The anonymity of the patients and the confi-
dentiality of their data were preserved at all times, in accor-
dance with Spanish data protection legislation. The committee
comprised two internal medicine specialists (F.G.J. and
A.P.C.), two clinical pharmacologists (E.P.G. and E.P.C.),
and a nurse (C.M.R.), all with wide experience in the clinical
setting and in the detection of ADR in inpatients. The data
obtained were previously checked and then entered into a
SPSS 20.0 database for statistical analysis.
Identification of fatal ADRs and causality assessment
ADRs were defined as proposed by the WHO as Ba response to
a drug that is noxious and unintended and that occurs at doses
normally used in humans for the prophylaxis, diagnosis or ther-
apy of disease^. Evaluation of the relationship between death
and drug consumption was based on causality as described by
Henrik Wulff [20], employing the criteria applied by Ebbesen et
al. [9]. Following these criteria, the likelihood that death was
caused by an ADR was categorized as BADR suspected of caus-
ing the death^ or BADR suspected of contributing to the death^.
Variables
The main outcome variable was the prevalence of mortality
suspected to be associated with pharmacological treatment;
secondary variables were the drugs associated with fatal
ADRs and the diseases that caused the deaths. Predictive var-
iables included patient age, sex, number of drugs adminis-
tered, number of diseases, length of stay, and hospital depart-
ment. Diagnoses were encoded using the 10th revision of the
International Classification of Diseases (ICD-10) [21], and
drugs were reported according to the Anatomical
Therapeutic Chemistry (ATC) classification [22]. A standard
form was used for the data collection.
Statistical analysis
A descriptive statistical analysis was performed. The asso-
ciation of the presence/absence of ADR-related death with
study variables was examined by using the chi-square test
for categorical variables and the Student’s t test for numer-
ical variables. The independent effects of the different co-
variates on the presence/absence of ADR-related death
were studied by fitting a logistic regression model and
estimating the odds ratio for each study variable. Median
values were compared by means of the Mann-Whitney-
Wilcoxon test. STATA 13.0 was used for the statistical
analysis. P < 0.05 was considered significant.
Eur J Clin Pharmacol (2016) 72:731–736
Ethics
This study was approved by the Clinical Research Ethics
Committee of San Cecilio University Hospital, Granada
(Spain).
Results
Out of the 1400 adult patients who died after a hospital stay of
≥24 h during the 22-month study period, 12 were excluded
because data were missing from their clinical records, leaving
a final study sample of 1388 patients. Their mean age was
74.9 years (range, 18–101 years), 44 % were female, the mean
length of hospital stay was 8.9 days (range, 1–82 days), and
the mean number of drugs per patient was 8.8 (range, 1–15).
The median values and interquartile ranges for these variables
are reported in Table 1. There were no significant differences
(P ≥ 0.05) in these variables between the cases of death in
which drug(s) were considered to be Bcausal^ or
Bcontributory.^ The main causes of hospital death were as
follows: septic shock, ICD 785.59 (18.8 %); multiple organ
failure, ICD 5724 (16.7 %); cancer, ICD 140 (15.3 %); respi-
ratory failure, ICD 786.09 (13.7 %); heart failure, ICD 428
(13.6 %); acute renal failure, ICD 584 (8.2 %); and acute
cerebrovascular disease, ICD 436 (6.2 %).
There was no significant difference between male and fe-
male patients in the number of diseases, number of drugs, or
length of hospital stay, but the mean age was higher in females
than in males (76.9 ± 12.9 vs. 73.3 ± 13.4 years; P < 0.001).
The level of agreement among the researchers, measured in
the first 100 cases, was acceptable (kappa = 0.78). A unani-
mous consensus on ADR-related death was not reached in 13
cases. A total of 282 suspected fatal ADRs were detected,
corresponding to 256 deaths (18.4 %, 95 % CI, 16.4–20.6);
146 (57 %) of these deaths were suspected of being caused by
drugs (Table 1). The interaction of two or more drugs (range,
2–4) was recorded in 30 % of ADR-related deaths. The drugs
most frequently associated with a fatal ADR were
Table 1 Characteristics of the
patients who died in the hospital Variables/groups
during the study period
Number of deaths
Agea
Females, n (%)
Comorbiditiesa
Length of stay in daysa
Number of drugsa
a
Data expressed as median (interquartile range). No significant differences were found between cases in which
drugs were suspected of Bcausing^ or Bcontributing to^ the death (Mann-Whitney-Wilcoxon test)
733
antithrombotics, including anticoagulants (heparins
[BO1AB] or coumarins [BO1AA]) and antiplatelets
[BO1AC], in 23 % of cases; psychotropics (antidepressants
[NO6AD], antipsychotics [NO5AD, NO5AH, NO5AL,
NO5AX] and benzodiazepines [NO5BA]) in 21.2 %; digoxin
(CO1A) in 11.3 %; opiates (N02A) in 10.6 %; NSAIDs
(M01A) in 7.4 %; and antineoplastic (L01A, L05B, L05C,
L05X), or immunosuppressive (L04A) agents in 6 %.
Heparins implicated in fatal ADRs were administered at pro-
phylactic doses in 97 % of cases. For their part, digoxin-
related fatal cardiac arrhythmias were associated with high
serum digoxin concentrations in all cases, with a mean
(±SEM) digoxinaemia value of 2.82 ± 0.23 ng x ml−1. As
shown in Supplementary Material 1, the most frequent causes
of death of patients with fatal ADRs were cardiac arrhythmia
(13.4 %), gastrointestinal bleeding (13.12 %), respiratory fail-
ure (10.3 %), aspiration pneumonia (7.4 %), acute renal failure
(7.4 %), electrolyte and acid-base disorders (7.4 %), and other
hemorrhages (5.32 %). Among the 256 ADR-related deaths,
63 % were related to drugs prescribed during the hospital stay
and 37 % to drugs prescribed before admission.
Bivariate logistic regression analysis showed a significant-
ly higher prevalence of ADR-related death in the elderly, pa-
tients with comorbidity, polymedicated patients, and those
admitted to a surgery department (Table 2). Multivariate lo-
gistic regression analysis revealed that the number of diseases
(≥4 diseases) and number of drugs (≥10 drugs) were the sole
independent risk factors for ADR-related death in the study
population (Table 2). The odds ratios for other variables (age
and admission in surgery department) were markedly reduced,
and their statistical significance was lost when the regression
analysis was adjusted for the remaining variables.
Discussion
Few reliable data are available on the detection of fatal ADRs
in hospitalized patients, and reported estimates have varied
widely. Besides the difficulty in identifying ADRs, imputation
All deaths Deaths suspected to be Deaths suspected to be
Bcaused^ by drugs Bcontributed^ by drugs
1388 146 110
78 (68–84) 79 (69–84) 81 (75–86)
609 (44) 67 (45.9) 52 (47.3)
4 (3–6) 5 (4–7) 5 (4–7)
5 (2–12) 6 (3–11) 9 (5–15)
9 (5–12) 11 (8–13) 12 (9.7–14)
734 Eur J Clin Pharmacol (2016) 72:731–736

Table 2 Logistic regression analysis of risk factors associated with In the present study, the drugs most frequently suspected to
ADRs-related deaths in the hospital
be associated to death were antithrombotics, psychotropics,
Non-adjusted model Adjusted model and digoxin, in line with previous reports [10, 19]. Fatal
ADR-related suspected cases in our study included the follow-
Variable OR (95 % CI) OR (95 % CI) ing: sudden death [26] and bronchoaspiration [27] associated
Sex with consumption of single or multiple psychotropic drugs
Male 1.00 1.00 [28]; heart failure due to digitalis toxicity, mainly in females,
Female 1.14 (0.87–1.49) 1.12 (0.84–1.49) as also observed in a study by the digitalis investigation group
Age (DIG) [29]; acute respiratory failure in patients with a history
18–68 1.00 1.00 of respiratory insufficiency after taking opiates alone or in
69–78 1.36 (0.91–2.04) 1.19 (0.77–1.85) association with sedatives [30]; severe gastrointestinal and
79–84 1.94 (1.3–2.9) 1.45 (0.92–2.3) cerebral hemorrhages in patients receiving single or multiple
>84 1.61 (1.07–2.41) 1.29 (0.81–2.06) antithrombotics alone or associated with NSAIDs or corti-
Number of diseases coids [10, 16, 19]; and hip fractures or traumatic brain injuries
≤4 1.00 1.00 from falls at home in elderly patients receiving psychotropic
>4 1.82 (1.38–2.4) 1.43 (1.04–1.95) or antihypertensive drugs [31], causing their admission to the
Number of drugs emergency department (Supplementary Material 1). Most of
0–5 1.00 1.00 the drugs associated with fatal ADRs are commonly used to
6–9 1.53 (0.95–2.45) 1.46 (0.9–2.39) treat pain and cardiovascular, respiratory, or psychiatric disor-
10–12 3.53 (2.29–5.45) 3.24 (2.05–5.12) ders, the most prevalent diseases among inpatients.
>12 4.94 (3.17–7.7) 4.44 (2.77–7.11) It appears that a high proportion of these cases might po-
Department tentially be prevented, underlining the need to prescribe these
Oncology 1.00 1.00 drugs with special care in elderly patients with multiple dis-
Intensive Care 1.48 (0.83–2.64) 0.71 (0.38–1.35) eases; however, the preventability of fatal ADRs is a difficult
Internal Medicinea 1.81 (1.13–2.9) 0.79 (0.45–1.4) issue, especially in retrospective studies [32]. We also found
Surgeryb 2.75 (1.61–4.7) 1.32 (0.71–2.44) that a third of drug-related deaths were associated with drug-
Length of stay 1.02 (1–1.03) 1.01 (0.99–1.02) drug interactions, largely pharmacodynamic, consistent with
the high prevalence (28 %) of interactions reported for all
ADRs adverse drug reactions, OR odds ratio, CI confidence Interval medical prescriptions in inpatients [33].
a
And other medical specialties The number of drugs received by patients and the number
b
And other surgical specialties of their diseases emerged as independent risk factors for
ADR-related death in our study, as indicated by the multilevel
adjusted regression analysis. The risk of fatal ADR has previ-
of the drugs responsible is more challenging in dead patients. ously been associated with polypharmacy [9, 14, 34], but not
Our study showed an elevated prevalence (18.4 %) of hospital all studies have found an association with the number of as-
deaths suspected of being caused by or contributed to by sociated diseases [9, 14, 19]. Age and admission in a surgery
drugs. This prevalence is very similar to the percentage report- department did not behave as independent risk factors for
ed by Ebbesen et al. [9] in a Norwegian Internal Medicine drug-related death, with the odds ratio for these variables be-
Department (18.2 %) using the present methodology. These ing markedly reduced and losing statistical significance when
prevalences are markedly higher than those of 5–6.4 % report- the analysis was adjusted for the number of drugs and
ed by other researchers using a different approach [16, 19], diseases.
which may explain the discrepancy [23, 24]. Our findings may Study strengths include the wide sample, which was repre-
reflect the greater sensitivity of the present method to detect sentative of all hospitalized patients in our setting, and the
treatment-related deaths in comparison to techniques based on application of a previously validated methodology. A further
algorithms and continuous scales like Naranjo’s one. This is strength of our approach was the case-by-case classification of
because of the lack of information on the response of the deaths as based on the unanimous decision of a multidisciplin-
individual to the withdrawal and re-administration of the sus- ary committee after an exhaustive and independent review of
pect drug, which are both considered crucial for the definite all cases of death. This procedure contrasts with studies based
imputation of a drug using these methods [25]. Though solely on administrative data, which are considered to sub-
Naranjo’s algorithm is the most frequently used, a previous stantially underestimate the percentage of ADRs in admitted
study by our group [19] found that this scale had a lower patients, whether fatal or not [24, 35, 36].
sensitivity to detect fatal ADR in deceased patients with re- This study has some limitations: (i) the retrospective nature
spect to the method [9, 20] used in the present study. of the study may underestimate the occurrence of ADRs if
Eur J Clin Pharmacol (2016) 72:731–736
these have not been documented or adequately recorded; (ii)
the compliance of patients with their pre-admission drug reg-
imen could not be confirmed, generating some uncertainty
about the causality; and (iii) the true rate of fatal ADRs might
be influenced by the failure to reach unanimous agreement,
although this only occurred in 13 cases.
A minimum hospital stay of 24 h was established to ensure
that data were only gathered from inpatients and that all treat-
ments given during the hospital stay were collected, given our
aim of analyzing deaths related to in-hospital treatments.
Some cases of fatal ADRs might have been missed through
the exclusion of patients dying in the Emergency Department,
producing an underestimation of drug-related deaths; howev-
er, the adoption of rigorous exclusion criteria ensured that the
reported deaths were only those attributable to drugs admin-
istered in the hospital. Although deaths in the Emergency
Department might have been due to extrahospital drug admin-
istration, it was not always possible to identify the name or
dosage of the drug(s) that might have been implicated in the
Emergency admission of severely ill, comatose, or dead
patients.
In conclusion, this study provides evidence of the high
prevalence of suspected ADR-related deaths in hospitalized
patients. The independent risk factors for death from ADR
were the number of diseases and number of drugs. The drugs
most frequently involved were antithrombotics, psychotropic
drugs, and digoxin. Greater research efforts should be focused
on drug-related deaths in hospitalized patients due to the mag-
nitude of this relevant clinical problem.
Acknowledgments The authors are grateful to Eloísa Casado
Fernández MD and Carmen Laraño Díaz MD of the Clinical
Documentation Department of San Cecilio University Hospital of
Granada (Spain) and to Ana García Velasco and María Soriano Segura,
research fellows of the School of Medicine of the University of Granada
(Spain), for their participation in the gathering and coding of the data. The
authors thank Richard Davies for improving the English style.
Authors contributions Dr. AJ Pardo Cabello performed research, an-
alyzed data and wrote the paper. Dr. E Del Pozo Gavilán performed
research, analyzed data and wrote the paper. Dr. FJ Gómez Jiménez per-
formed research, analyzed data and wrote the paper. Dr. C Mota
Rodríguez performed research. Dr. JD Luna del Castillo analyzed data.
Dr. E Puche Cañas conceived and designed study, performed research,
analyzed data and wrote the paper.
Compliance with ethical standards
Ethical approval All procedures performed in this study were in ac-
cordance with the ethical standards of the institutional research commit-
tee. Formal consent is not required for this retrospective study.
Funding This study was funded by Department of Pharmacology (CP-
2), University of Granada (Spain) in manuscript preparation.
Conflict of interest The authors declare that they have no conflict of
interest.
735
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