DOI: 10.1111/ggi.

13450

ORIGINAL ARTICLE
EPIDEMIOLOGY, CLINICAL PRACTICE AND HEALTH

Use of proton pump inhibitors is associated with increased

mortality due to nosocomial pneumonia in bedridden patients
receiving tube feeding
Kosuke Hamai,1,2,3 Hiroshi Iwamoto,3 Shinichiro Ohshimo,4 Yu Wakabayashi,2,3 Daisuke Ihara,2,5
Kazunori Fujitaka,3 Hironobu Hamada,3 Koichi Ono2 and Noboru Hattori3
1 Aim: To investigate the association between the use of proton pump inhibitors (PPI) and
Department of Respiratory
Medicine, Hiroshima Prefectural nosocomial pneumonia and gastrointestinal bleeding in bedridden patients receiving tube
feeding.
Hospital, Hiroshima, Japan
2
Department of Internal Medicine, Methods: A total of 116 bedridden hospitalized patients receiving tube feeding, of which
Rikita Hospital, Hiroshima, Japan 80 were supported by percutaneous endoscopic gastrostomy and 36 by nasogastric tube, were
3
Department of Molecular and included in the present study. The patients were divided into two groups: 62 patients treated
with PPI (PPI group) and 54 patients without PPI (non-PPI group). Mortality due to nosoco-
Internal Medicine, Graduate
mial pneumonia was evaluated using the Kaplan–Meier approach and the log–rank test.
School of Biomedical and Health
Sciences, Hiroshima University, Results: A total of 36 patients (31%) died of nosocomial pneumonia during the observation
Hiroshima, Japan period; the mortality rate due to nosocomial pneumonia was significantly higher in the PPI
4 group than in the non-PPI group (P = 0.0395). Cox proportional hazard analysis showed that
Department of Emergency and
the use of PPI and lower levels of serum albumin were independent predictors of 2-year mor-
Critical Care Medicine, Graduate
tality due to nosocomial pneumonia. Gastrointestinal bleeding was observed in four patients
School of Biomedical and Health in the non-PPI group (7.7%) and in one patient in the PPI group (1.6%); there was no signifi-
Sciences, Hiroshima University, cant difference between the two groups.
Hiroshima, Japan
5 Conclusion: The use of PPI in bedridden tube-fed patients was independently associated
Department of Respiratory
with mortality due to nosocomial pneumonia, and the PPI group had a non-significant lower
Medicine, Hiroshima City incidence of gastrointestinal bleeding than the non-PPI group. Geriatr Gerontol Int 2018;
Hiroshima Citizens Hospital, ••: ••–••.
Hiroshima, Japan
Keywords: bedridden, mortality, nosocomial pneumonia, proton pump inhibitors, tube
Correspondence feeding.
Hiroshi Iwamoto MD, PhD,
Department of Molecular and
Internal Medicine, Graduate
School of Biomedical Sciences,
Hiroshima University, 1-2-3
Kasumi, Minami-ku, Hiroshima
734-8551, Japan.
Email: iwamotohiroshig@gmail.
com

Revised: 18 April 2018

Accepted: 25 April 2018

Introduction neurodegenerative diseases and obstruction due to cancer. How-

Proton pump inhibitors (PPI) are known to be highly effective in the
treatment of peptic disease and are often used for a long period to
prevent gastrointestinal bleeding, especially in hospitalized
patients.1,2 However, recent observational studies have shown that
the use of acid-suppressive medications, especially PPI, were associ-
ated with an increased risk of nosocomial pneumonia.3–6 Therefore,
risk–benefit considerations might be important to determine the
indication and discontinuation of acid-suppressive medications.
Nasogastric tube (NGT) and gastrostomy tube placement are
useful to maintain enteral access for nutrition, hydration and
medication for patients with dysphagia due to stroke, brain injury,
ever, previous studies reported a poor prognosis in elderly patients
with tube feeding, mainly due to complications of aspiration
pneumonia.7–9 Furthermore, elderly tube-fed patients might have
several risk factors for gastrointestinal bleeding, such as aging, his-
tory of esophagitis and peptic ulcer, antiplatelet and anticoagulant
therapy, and gastrostomy tube placement,10,11 and are often trea-
ted with acid-suppressive medications. Thus, the aim of the pre-
sent study was to investigate the association between the use of
PPI and the incidence and mortality of nosocomial pneumonia in
bedridden patients receiving tube feeding. Additionally, the inci-
dence of gastrointestinal bleeding was compared between elderly
tube-fed patients with and without PPI treatment.

© 2018 The Authors Geriatrics & Gerontology International | 1

published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
 K Hamai et al.

Methods Table 2 Patient characteristics in the proton pump inhibitor and

the non-proton pump inhibitor groups
The present study included 116 hospitalized, bedridden patients PPI Non-PPI P-value
receiving tube feeding who were admitted to the Rikita Hospital,
Hiroshima, Japan, from January 2011 to December 2015; the (n = 62) (n = 54)
patients were unable to move by themselves or communicate with Age 81.5  9.5 81.7  9.4 0.725
each other. A total of 80 were supported by percutaneous endo- Sex (male/female) 25/37 17/37 0.349
scopic gastrostomy and 36 by NGT. Patients who had continued PEG/NGT 46/16 34/20 0.230
tube feeding without early complications for at least 1 month were Bedsore 7 (11.3%) 5 (9.3%) 0.769
included in the analysis. The diagnosis of pneumonia was based on Tracheotomy 8 (12.9%) 6 (11.1%) 1.000
infiltrative shadows on chest X-ray or computed tomography, Malignancy 3 (4.8%) 4 (7.4%) 0.703
blood examination and clinical symptoms. Causes of death were Peptic ulcers 6 (9.7%) 3 (5.6%) 0.500
determined by reviewing the clinical documents of the attending Laboratory data
physicians. All percutaneous endoscopic gastrostomy placements Hb (g/dL) 11.7  2.0 11.8  1.9 0.676
had been carried out before admission. The patients were catego- TP (g/dL) 6.5  0.6 6.6  0.5 0.308
rized into two groups: patients treated with PPI (PPI group) and Alb (g/dL) 3.5  0.5 3.4  0.5 0.702
those without PPI (non-PPI group). The baseline characteristics of ChE (IU/L) 196.9  69.3 200.6  66.3 0.840
the PPI group and the non-PPI group were compared using the HDL-C (mg/dL) 46.8  13.0 44.5  14.1 0.368
Mann–Whitney U-test or Fisher’s exact test. Durations from hos- LDL-C (mg/dL) 111.6  30.6 108.8  30.2 0.680
pital admission to the onset of or death from nosocomial pneumo- TG (mg/dL) 95.0  38.9 95.3  47.0 0.723
nia were evaluated using the Kaplan–Meier approach and the log– HbA1c >7.0% 4 (6.5%) 4 (7.4%) 1.000
rank test. Patients for whom tube feeding was discontinued and Medications
substituted with total parenteral nutrition or peripheral infusion, or ACEI 7 (11.3%) 2 (3.7%) 0.172
patients who died from other causes were censored. Furthermore, Mosapride 14 (22.6%) 4 (7.4%) 0.038
those who stopped PPI or changed PPI to histamine type-2 recep- Corticosteroids 3 (4.8%) 2 (3.7%) 1.000
tor antagonists in the PPI group and those who started PPI in the NSAIDs 0 (0%) 0 (0%) 1.000
non-PPI group were also censored. Next, the Cox proportional Antiplatelet agents/ 31 (50%) 20 (37%) 0.191
hazards model was used to identify significant predictors of 2-year anticoagulants
mortality due to nosocomial pneumonia. In addition, the fre- Data presented as the mean  SD. Significant differences were evalu-
quency of gastrointestinal bleeding was compared between the two ated using the Mann–Whitney U-test or Fisher’s exact test. ACEI,
groups. All statistical analyses were carried out using the statistical angiotensin-converting enzyme inhibitors; Alb, albumin; ChE, cholin-
software R version 3.2.2 (R Foundation, Vienna, Austria). The log– esterase; Hb, hemoglobin; HDL-C, high-density lipoprotein choles-
rank test and Cox proportional hazards model were carried out terol; LDL-C, low-density lipoprotein cholesterol; NGT, nasogastric
tube; NSAIDs, non-steroidal anti-inflammatory drugs; PEG, percuta-
using the “survival” package of the R software.
neous endoscopic gastrostomy; PPI, proton pump inhibitors; TC, total
cholesterol; TG, triglyceride; TP, total protein.
Results
(P = 0.0394; Fig. 1a). Furthermore, 58 patients died during the
The mean observation period of 116 patients was 251 days (95%
observation period, of which 36 patients died of pneumonia.
confidence interval 205–296 days). A total of 73 patients (62.9%)
There was no significant difference in the all-cause mortality rate
had cerebrovascular diseases, and 27 patients (23.3%) had cere-
between the two groups (P = 0.5040; Fig. 1b). However, the mor-
bral degenerative disorders (Table 1). PPI were prescribed in
tality rate due to nosocomial pneumonia within 2 years in the PPI
62 patients (53.4%; Table 2). A total of 31 patients in the PPI
group was significantly higher than that in the non-PPI group
group and 20 patients in the non-PPI group received anticoagu-
(39% vs 22%, P = 0.0395; Fig. 1c). Cox proportional hazard analy-
lant and/or antiplatelet therapy. Histamine type-2 receptor antago-
sis showed that the use of PPI and the lower levels of serum albu-
nists were prescribed to 19 patients in the non-PPI group.
min were independent predictors of 2-year mortality due to
Mosapride was prescribed more frequently in the PPI group than
nosocomial pneumonia (Table 3). The use of mosapride or
in the non-PPI group.
angiotensin-converting enzyme inhibitors (ACEI) was not associ-
A total of 73 patients suffered from nosocomial pneumonia,
ated with lower mortality due to pneumonia.
and the incidence of the nosocomial pneumonia in the PPI group
Clinically significant gastrointestinal bleeding was observed in
was significantly higher than that in the non-PPI group
four of 52 patients in the non-PPI group (7.7%) and in one of
62 patients in the PPI group (1.6%), and there was no significant
Table 1 Primary diagnosis of inpatients enrolled in this study difference between the two groups (P = 0.182). Among those with
anticoagulant and/or antiplatelet therapy, two of the 20 patients
Cerebrovascular diseases
(10%) in the non-PPI group developed upper gastrointestinal
Cerebral stroke 45 (38.8%) bleeding, and none of the 32 patients in the PPI group
Cerebral hemorrhage 19 (16.3%) (P = 0.143).
Subdural hematoma 5 (4.3%)
Traumatic brain injury 3 (2.6%)
Subarachnoid hemorrhage 1 (0.9%)
Discussion
Cerebral degenerative disorders
Alzheimer’s disease 23 (19.8%)
In the present study, we have investigated the risks and benefits of
Parkinson’s disease 2 (1.7%)
PPI in elderly patients receiving tube feeding with special focus on
Progressive supranuclear palsy 1 (0.9%)
pneumonia and gastrointestinal bleeding. During the observation
Multiple system atrophy 1 (0.9%)
period, 31% of the patients died of nosocomial pneumonia, and
Disuse atrophy 11 (9.5%)
the use of PPI was an independent risk factor for mortality due to
Hypoxic brain damage 3 (2.6%)
pneumonia. Additionally, 53% of the patients used PPI, and the
Brain tumor 2 (1.7%)
incidence of gastrointestinal bleeding was non-significantly lower
Total 116
in the PPI group than in the non-PPI group.

2 | © 2018 The Authors Geriatrics & Gerontology International

published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society
 PPI increase mortality from pneumonia

Figure 1 Kaplan–Meier analysis showing (a) the probability of 2-year incidence of nosocomial pneumonia, (b) the 2-year
mortality for all causes, and (c) due to nosocomial pneumonia between patients treated with proton pump inhibitors and those
without proton pump inhibitors.

This is the first study to show that the use of PPI is an inde- contents.13 In vitro studies suggested an alternative mechanism of
pendent predictor of mortality due to nosocomial pneumonia in diminished neutrophil bactericidal activity by omeprazole.14,15
elderly bedridden patients receiving tube feeding. Recent meta- Elderly bedridden patients receiving tube feeding were shown to
analysis of observational studies and randomized controlled trials have high mortality due to pneumonia,8,9 and the present study
reported that the use of acid-suppressive medications, especially shows that PPI can increase the risk of and mortality due to pneu-
PPI, is associated with increased incidence of both community- monia in this high-risk patient population.
and hospital-acquired pneumonia.12 Herzig et al. reported that In the present study, the use of PPI was associated with a non-
acid-suppressive medications were used in 52% of 63 878 hospi- significant lower incidence of gastrointestinal bleeding within the
talized patients, and the incidence of hospital-acquired pneumonia mean observation period of 251 days. PPI might be used to pre-
was significantly higher in those treated with acid-suppressive vent gastrointestinal bleeding in critically ill patients.16 They were
medications than in those without (4.9% vs 2.0%, respectively).3 also shown to be effective in non-critically ill patients who had risk
Increased risk of pneumonia due to the use of PPI can be factors, such as age >60 years, male sex, liver disease, acute renal
explained by gastric alkalization and bacterial overgrowth in gastric failure, sepsis, using an internal medicine service, and using anti-
coagulants and antiplatelets.17–19 Furthermore, patients with per-
Table 3 Cox proportional hazards model to predict the 2-year cutaneous endoscopic gastrostomy tube might have a relatively
mortality due to nosocomial pneumonia high risk of esophagitis, duodenal ulcers, gastric erosions and gas-
tritis.11 Therefore, elderly patients receiving tube feeding often
Hazard 95% Confidence have several risks of gastrointestinal bleeding, which makes it diffi-
ratio interval P-value cult to discontinue antacid medications. However, when consider-
Univariate analysis ing the increased pneumonia mortality in the PPI group observed
Age 1.006 0.972–1.041 0.7348 in the present study, discontinuation of PPI might be considered
Sex (male) 1.950 0.987–3.851 0.0546 after thorough evaluation of the risk for gastrointestinal bleeding.
PEG (vs NGT) 1.068 0.512–2.224 0.8614 Future prospective studies might be warranted to evaluate the
PPI 2.082 1.019–4.253 0.0441 benefit and harm by discontinuation of PPI in this patient
Bedsore 0.743 0.227–2.430 0.6233 population.
Tracheotomy 0.684 0.209–2.234 0.5290 In the present study, the use of ACEI or mosapride citrate
Malignancy 0.681 0.093–4.980 0.7049 was not associated with a reduced risk of pneumonia. Mosapride
Hb 0.870 0.740–1.023 0.0925 citrate is a prokinetic drug that promotes upper gastrointestinal
Alb 0.301 0.169–0.535 <0.0001 motility and prevents gastroesophageal reflux, and was also
ChE 0.991 0.986–0.996 0.0009 shown to reduce the incidence of aspiration pneumonia.20,21
HDL-C 0.963 0.937–0.989 0.0054 ACEI also have been shown to be effective in reducing the risk of
LDL-C 0.992 0.981–1.003 0.1691 aspiration.22 However, just nine patients were treated with ACEI,
TG 0.996 0.988–1.004 0.3654 and 18 patients were using mosapride citrate. Therefore, it is
HbA1c >7.0% 0.982 0.235–4.102 0.9799 possible that the present study could not detect a significant
ACEI 1.678 0.592–4.761 0.3305 effect of these medications because of the small sample size of
Mosapride 1.769 0.828–3.777 0.1407 each subgroup.
Corticosteroids 2.325 0.552–9.796 0.2501 The present study had several limitations. First, it was a retro-
Multivariate analysis† spective review from one long-term care hospital. Second, a rou-
Sex (male) 1.795 0.840–3.835 0.1312 tine checkup of the gastrointestinal fiberscope was not usually
PPI 2.377 1.130–5.003 0.0226 carried out. The enrolled patients could not communicate; thus,
Hb 1.134 0.900–1.429 0.2867 asymptomatic gastrointestinal diseases, gastroesophageal reflux or
Alb 0.308 0.113–0.841 0.0216 complications from hiatal hernias were not evaluated. Third,
ChE 0.996 0.989–1.003 0.2956 mosapride and ACEI, which were shown to be effective in reduc-
HDL-C 0.981 0.948–1.014 0.2590 ing the risk of aspiration pneumonia, were not found to be effec-
tive in the present study.
†
Multivariate Cox analysis was adjusted for age. ACEI,
angiotensin-converting enzyme inhibitors; Alb, albumin; ChE, Cholin-
esterase; Hb, hemoglobin; HDL-C, high-density lipoprotein choles-
terol; LDL-C, low-density lipoprotein cholesterol; NGT, nasogastric
Disclosure statement
tube; PEG, percutaneous endoscopic gastrostomy; PPIs, proton pump
inhibitors; TC, total cholesterol; TG, triglyceride; TP, total protein. The authors declare no conflict of interest.

© 2018 The Authors Geriatrics & Gerontology International | 3

published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society
 K Hamai et al.
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How to cite this article: Hamai K, Iwamoto H,
Ohshimo S, et al. Use of proton pump inhibitors is associ-
ated with increased mortality due to nosocomial pneumo-
nia in bedridden patients receiving tube feeding. Geriatr.
Gerontol. Int.. 2018;1–4. https://doi.org/10.1111/ggi.13450
© 2018 The Authors Geriatrics & Gerontology International