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. 2021 Apr 5;16(4):e0249645. doi: 10.1371/journal.pone.0249645

Could prokinetic agents protect long-term nasogastric tube-dependent patients from being hospitalized for pneumonia? A nationwide population-based case-crossover study

Kun-Siang Huang 1, Bo-Lin Pan 1, Wei-An Lai 1, Pin-Jie Bin 1, Yao-Hsu Yang 2,3,4, Chia-Pei Chou 1,*
Editor: Alexandru Rogobete5
PMCID: PMC8021154  PMID: 33819293

Abstract

Background

Some studies have indicated that the use of prokinetic agents may reduce pneumonia risk in some populations. Nasogastric tube insertion is known to increase the risk of pneumonia because it disrupts lower esophageal sphincter function. The aim of this study was to evaluate whether prokinetic agents could protect long-term nasogastric tube-dependent patients in Taiwan from being hospitalized for pneumonia.

Methods

A case-crossover study design was applied in this study. Long-term nasogastric tube-dependent patients who had a first-time admission to a hospital due to pneumonia from 1996 to 2013 that was recorded in the Taiwan National Health Insurance Research Database were included. The case period was set to be 30 days before admission, and two control periods were selected for analysis. Prokinetic agent use during those three periods was then assessed for the included patients. Conditional logistic regression was used to calculate the odds ratio (OR) for pneumonia admission with the use of prokinetic agents.

Results

A total of 639 first-time hospitalizations for pneumonia among patients with long-term nasogastric tube dependence were included. After adjusting the confounding factors for pneumonia, no negative association between prokinetic agent use and pneumonia hospitalization was found, and the adjusted OR was 1.342 (95% CI 0.967–1.86). In subgroup analysis, the adjusted ORs were 1.401 (0.982–1.997), 1.256 (0.87–1.814), 0.937 (0.607–1.447) and 2.222 (1.196–4.129) for elderly, stroke, diabetic and parkinsonism patients, respectively.

Conclusion

Prokinetic agent use had no negative association with pneumonia admission among long-term nasogastric tube-dependent patients in Taiwan.

Introduction

Pneumonia was the third leading cause of death in Taiwan in 2018, with the number of deaths from pneumonia increasing by 7.5% over the number in 2017 [1]. There are several known risk factors for pneumonia, including unclear consciousness, dementia, Parkinson’s disease, stroke, chronic obstructive pulmonary disease, gastroesophageal reflux disease, gastroparesis, bowel obstruction and ileus, esophageal motility disorders, the presence of an endotracheal tube and enteral tube feeding [2–7]. Enteral feeding with nasogastric tube use is indicated for patients with impaired swallowing function and malnutrition. In Taiwan, long-term nasogastric tube feeding may be required in patients with stroke, dementia, parkinsonism and old age due to the progression of neurodegenerative diseases or aging-related functional declines. However, enteral feeding with nasogastric tube placement may disrupt the function of the upper and lower esophageal sphincters, increase the frequency of transient lower esophageal sphincter relaxations and desensitize the pharyngoglottal adduction reflex [3]. Relatedly, aspiration pneumonia is one potential consequence of the inhalation of oropharyngeal secretions or gastric contents [8], and nasogastric tube placement may increase the risk of both aspiration and pneumonia [9] due to the aforementioned mechanism. Meanwhile, prokinetic agents such as metoclopramide, cisapride, mosapride and domperidone, which are used for gastroesophageal reflux and gastroparesis, increase gastric motility and facilitate gastric emptying [10–13], and in a prior study, it was found that metoclopramide may decrease the pneumonia risk of acute stroke patients with nasogastric tube feeding [14]. Until now, however, there had been no studies investigating the association between the use of prokinetics and pneumonia in long-term nasogastric tube-fed patients. Therefore, the objective of this study was to examine whether prokinetic use protects long-term nasogastric tube-fed patients from being hospitalized for pneumonia.

Materials and methods

Data source

Begun in 1995, Taiwan’s National Health Insurance (NHI) system currently provides healthcare services and coverage to more than 99% of Taiwan’s residents. The beneficiary data of the people covered by the NHI system is recorded in the National Health Insurance Research Database (NHIRD), which is maintained by the National Health Research Institutes. The present study was conducted using data from the Longitudinal Health Insurance Database 2005 (LHID 2005), a subset of the NHIRD that includes the longitudinal health care data for NHI beneficiaries for the period from 1996 to 2013. More specifically, the LHID 2005 contains data for 1 million representative beneficiaries sampled in 2005 from among the overall total of roughly 25.68 million people registered with the NHI system, with the data in question including the given patient’s sex; age; diagnoses according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes; prescribed medications; medication dosages; durations of prescribed medications; medical interventions and medical expenditures.

Patient selection

The study covered the period from January 1, 1996, to December 31, 2013. The discharge diagnoses of interest in the LHID 2005 consisted of 5 ICD-9-CM diagnoses. In the first step of the patient selection process, patients aged over 20 years old were included if they met either of the following criteria: 1. a primary discharge diagnosis of aspiration pneumonia (ICD-9-CM 507) or pneumonia (ICD-9-CM 480–487) or 2. a primary discharge diagnosis of septicemia (ICD-9-CM 038.0–038.9), respiratory failure (ICD-9-CM 518.81–518.89) or sepsis (ICD-9-CM 995.91–995.92) in combination with a secondary discharge diagnosis of aspiration pneumonia (ICD-9-CM 507) or pneumonia (ICD-9-CM 480–487). In a prior study, the diagnostic codes for pneumonia identification were validated [15], and only one modification was applied in this study (specifically, ICD-9-CM 507 was added as a secondary discharge diagnosis). If a patient had several admissions with discharge diagnoses that met the above criteria, only the first-time admission for pneumonia was included to avoid interference during the control periods. The first-time admission date of each patient was defined as the index date. In Taiwan, a nasogastric tube is usually replaced at least once every month depending on the condition of the nasogastric tube and the patients’ long-term nasogastric tube dependence was presumed to be at least 3 months in this study. Therefore, in the second step of the patient selection process, the patients with long-term nasogastric tube use were selected by screening for the procedure code for nasogastric tube insertion to see if it was noted in the LHID 2005 data at least 1 time per month in the 7 months before the index date to ensure that each included patient was nasogastric tube dependent at least 3 months among the case period and the control periods. Meanwhile, any patients who received a gastrostomy or jejunostomy before the index date were excluded. The study patient selection flow chart is shown in Fig 1.

Fig 1. The flow diagram of the patient selection process.

Fig 1

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*Index date refers to the first date of each patient’s first admission with the primary diagnosis of pneumonia in the LHID 2005.

Study design

The association between the use of prokinetics and hospitalization for pneumonia was assessed using a case-crossover study design. Maclure et. al proposed the case-crossover design as a means of providing within-subject comparisons of transient effects for acute events [16]. Because the case-crossover design uses each patient as his or her own control group by considering data from a different time point or time points, the confounding factors are automatically adjusted for [17, 18]. In this study, the case period was defined as a time period before the index date, and the control periods were defined as time periods without any pneumonia admission. Each patient’s exposure to prokinetics during the case period was compared to the patient’s exposure to prokinetics during the control periods. In Taiwan, prokinetics are usually indicated for nausea, vomiting, gastroesophageal reflux and poor digestion, and physicians may prescribe these medicines for a duration of 28 to 30 days in stable patients. As such, the time periods for the case period, control periods and washout period were defined as 30 days in this study. Two control periods (specifically, the periods 91 to 120 days and 121 to 150 days before admission) were selected to compare with a single case period. The study design is shown in Fig 2. In this study, sensitivity analyses were conducted by changing the length of each time period to 14 days and 45 days because patients may not always use a given medicine regularly. The length of the washout period was also changed to 7 days and 15 days to assess the robustness of this study in terms of sensitivity analyses.

Fig 2. The 2:1 case-crossover study design used in the primary analysis.

Fig 2

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Day 0 indicates the first admission date with pneumonia as the discharge diagnosis. The time period and washout periods each lasted 30 days.

Variable assessment and confounding factors

The prescription status for prokinetics during the case period and control periods was examined for each patient. The prokinetics themselves were identified by the Anatomical Therapeutic Chemical (ATC) code A03F (propulsives). The data indicate each patient’s sex, age, comorbidities and medications prescribed were also collected. Aside from clinical characteristics, some medications have been reported to be associated with pneumonia occurrence. To account for the possible impacts of these medications, they were regarded as confounding factors and their prescription statuses were also examined during the case period and control periods. The confounding medications that were included are as follows: 1. Antipsychotic agents (ATC code: N05A): In prior studies, antipsychotic agents were reported to be associated with increased pneumonia risk due to unknown mechanisms [19–21]; 2. Benzodiazepine-receptor agonists (BZRA, ATC codes: A05CD, A05BA, N03AE and N03CF): BZRAs were also reported to increase the risk of aspiration pneumonia by reducing consciousness [22–24]; 3. Histamine H2-blockers (H2B, ATC code: A02BA) and proton pump inhibitors (PPI, ATC code: A02BC): H2Bs and PPIs suppress gastric acid secretion, which may facilitate pathogen colonization in the upper gastrointestinal tract and subsequently cause pneumonia by aspiration. In fact, the aforementioned acid-reducing agents have been proved to increase the risk of pneumonia in several studies [25–29]; 4. Statin (ACT codes: C10AA, C10BA, C10BX): Statins have been reported to reduce the risk of pneumonia due to possible anti-inflammatory and immunomodulatory effects [30–32]; 5. Angiotensin receptor blockers (ARB, ATC codes: C09C, C09D) and angiotensin-converting enzyme inhibitors (ACEi, ATC codes: C09A, C09B): ARBs and ACEis have also been found to be associated with reduced pneumonia risk [33]. The abovementioned medication exposures were regarded as confounding factors in the adjusted analyses.

Statistical analysis

The SAS software version 9.4 was used for all the statistical analyses. Conditional logistic regression was applied for paired data (1 case period matched to 2 control periods), and odds ratios (ORs) and 95% confidence intervals (CIs) for pneumonia hospitalization associated with exposure versus non-exposure to prokinetics were calculated. In addition to crude ORs, ORs adjusted for exposure to antipsychotic agents, BZRAs, H2Bs, PPIs, statins, ARBs and ACEis were also calculated. Subgroup analyses were performed for patients with diabetes, stroke, parkinsonism and old age (age≧65 years old). A p value less than 0.05 was considered to be statistically significant.

Ethics statement

The study was implemented with the approval of the Chang Gung Medical Foundation Institutional Review Board (201801143B0). Proof of informed consent documents was not required by the review board because the NHIRD had de-identified all patient data.

Results

The basic characteristics of the included patients are shown in Table 1. A total of 639 long-term nasogastric tube-dependent patients with pneumonia admission were included in the analysis. The included patients’ mean age was 77.91±12.06 years, 88% were older than 65 years old and 54% were women. Furthermore, 80% had a history of stroke, 61% had a history of diabetes mellitus and 26% had a history of parkinsonism. In total, 124 patients used metoclopramide, 56 used mosapride and 88 used domperidone during the case or control periods.

Table 1. Patient demographic and clinical characteristics, n = 639.

Variables Number (%)
Age
    Age ≥ 65 years old 564 (88)
    Age < 65 years old 75 (12)
Gender
    Female 348 (54)
    Male 291 (46)
Comorbidity
    Diabetes mellitus 391 (61)
    Stroke 510 (80)
    Parkinsonism 166 (26)
Prokinetic agents
    Metoclopramide user 124 (19)
    Mosapride user 56 (9)
    Domperidone user 88 (14)
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Table 2 lists all the analysis results of this study. In the primary analysis, the crude OR (95% CI) of the study population for all prokinetics exposure and pneumonia admission was 1.293 (0.941–1.777). After adjustment for confounding factors, the adjusted OR (95% CI) was 1.342 (0.967–1.86). In the further analysis of individual prokinetic drugs for the study population, the adjusted ORs (95% CI) were 1.03 (0.672–1.578), 1.53 (0.814–2.877) and 1.394 (0.838–2.32) for metoclopramide, mosapride and domperidone use, respectively. In the subgroup analysis, the prokinetics exposure was not significantly associated with reduced hospitalization for pneumonia among the elderly, diabetes mellitus, stroke or parkinsonism patients. The adjusted ORs (95% CI) were 1.673 (1.052–1.661) and 2.222 (1.196–4.129) in females and parkinsonism patients, respectively, which indicated a slight positive association between prokinetics exposure and hospitalization for pneumonia. In the sensitivity analyses (S1–S4 Tables) for different time periods and washout periods, similarly, there was no significant reduction in hospitalization for pneumonia with prokinetics exposure. Therefore, the analyses results are robust.

Table 2. The association between prokinetics exposure and pneumonia admission.

Crude OR 95% Cl P value Adjusted ORa 95% Cl P value
General population All prokinetics 1.29 (0.94 1.78) 0.1133 1.34 (0.97 1.86) 0.0782
n = 639 Metoclopramide 1.03 (0.68 1.56) 0.8868 1.03 (0.67 1.58) 0.8924
Mosapride 1.48 (0.80 2.72) 0.2081 1.53 (0.81 2.88) 0.1865
Domperidone 1.30 (0.79 2.14) 0.3010 1.39 (0.84 2.32) 0.2013
Age ≧ 65 years old All prokinetics 1.35 (0.96 1.90) 0.0872 1.40 (0.98 2.00) 0.0627
n = 564 Metoclopramide 1.07 (0.69 1.68) 0.7582 1.06 (0.67 1.68) 0.8122
Mosapride 1.43 (0.76 2.72) 0.2714 1.47 (0.76 2.86) 0.2556
Domperidone 1.42 (0.83 2.43) 0.1955 1.54 (0.89 2.67) 0.1225
Male All prokinetics 1.02 (0.64 1.62) 0.9369 1.04 (0.65 1.67) 0.8643
n = 291 Metoclopramide 0.88 (0.47 1.63) 0.6768 0.85 (0.45 1.61) 0.6268
Mosapride 1.15 (0.48 2.76) 0.7632 1.19 (0.47 3.00) 0.7145
Domperidone 0.78 (0.36 1.68) 0.5262 0.84 (0.38 1.83) 0.6581
Female All prokinetics 1.61 (1.03 2.50) 0.0350* 1.67 (1.05 2.66) 0.0296*
n = 348 Metoclopramide 1.18 (0.67 2.08) 0.5604 1.17 (0.65 2.12) 0.5968
Mosapride 1.89 (0.80 4.45) 0.1456 1.98 (0.82 4.78) 0.1275
Domperidone 1.98 (1.00 3.89) 0.0487* 2.11 (1.05 4.24) 0.0352*
Diabetes Mellitus All prokinetics 0.91 (0.60 1.39) 0.6696 0.94 (0.61 1.45) 0.7707
n = 391 Metoclopramide 0.71 (0.41 1.24) 0.2330 0.73 (0.41 1.28) 0.2677
Mosapride 0.90 (0.41 1.98) 0.7905 0.82 (0.36 1.87) 0.6412
Domperidone 0.93 (0.50 1.75) 0.8321 1.03 (0.54 1.96) 0.9347
Stroke All prokinetics 1.19 (0.84 1.70) 0.3306 1.26 (0.87 1.81) 0.2233
n = 510 Metoclopramide 1.04 (0.66 1.64) 0.8756 1.07 (0.67 1.71) 0.7878
Mosapride 1.41 (0.73 2.72) 0.3099 1.44 (0.72 2.86) 0.3009
Domperidone 0.97 (0.55 1.73) 0.9221 1.06 (0.59 1.92) 0.8421
Parkinsonism All prokinetics 2.41 (1.32 4.40) 0.0043* 2.22 (1.20 4.13) 0.0115*
n = 166 Metoclopramide 1.91 (0.87 4.18) 0.1073 1.79 (0.78 4.10) 0.1695
Mosapride 2.73 (0.79 9.50) 0.1138 2.80 (0.66 11.94) 0.1644
Domperidone 2.00 (0.82 4.89) 0.1289 1.90 (0.77 4.67) 0.1639
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CI = Confidence Interval, OR = Odds Ratio.

* p value < 0.05.

a Odds ratios adjusted for antipsychotic agents, benzodiazepine-receptor agonists, histamine H2-blockers, proton pump inhibitors, statins, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors exposure.

Discussion

According to the analyses of this nationwide population-based study, there was no significant negative association between prokinetics exposure and hospitalization for pneumonia among the investigated long-term nasogastric tube-dependent population in Taiwan. In the subgroup analyses, there was also no significant negative association between hospitalization for pneumonia and prokinetics exposure among the elderly patients or patients with diabetes mellitus, stroke and parkinsonism.

In Taiwan, 198,393 people used nasogastric tubes in 2018, and of these people, 61.3% were older than 65 years old and 56.6% were males [34]. In this study, elderly patients accounted for 88% of the long-term nasogastric tube-dependent patients, and male patients accounted for 46% of the long-term nasogastric tube-dependent patients. The patients included in this study were nasogastric tube-dependent for at least 7 months before the occurrence of hospitalization due to pneumonia. Therefore, the patients included in this analysis, 80% of whom were stroke patients, 60% of whom were diabetes mellitus patients and 88% of whom were elderly patients, were at substantially high risk for pneumonia [35].

Hiyama et al. indicated that prokinetic agents may reduce the risk of aspiration pneumonia in tube-fed patients via the direct effects of their motility stimulation properties [36]. Warusevitane et al. found that among tube-fed acute stroke patients, a placebo group had a higher rate of pneumonia than a metoclopramide group (rate ratio 5.24, p<0.001), which indicated that metoclopramide use may prevent pneumonia from occurring. Pareek et al. indicated that among tube-fed patients with severe developmental disabilities, prokinetic therapy (cisapride) could reduce the rate of hospitalization for aspiration pneumonia, with the relative risk being reduced by 4.5 times [37]. However, in our analysis, there was no significant negative association between prokinetics use and hospitalization for pneumonia. Even among the stroke patients, the adjusted OR for all prokinetics was 1.265 (p = 0.2233), while that for metoclopramide was 1.067 (p = 0.7878). Because all the patients included in this case-crossover design study had relatively long-term nasogastric tube dependence, their general health conditions may have been quite different from those of post-acute stroke patients. Because the drug license for cisapride was withdrawn in Taiwan in 2004 due to the adverse effect of lethal QT prolonged syndrome, the number of cisapride users included in the primary analysis was small. Therefore, cisapride users were not included in this case-crossover study. A prokinetic agent with similar pharmacologic action as cisapride, mosapride, was more widely used among this Taiwanese cohort. However, there was still no significant negative association between mosapride use and pneumonia admission in this analysis.

Nassaji et al. indicated that metoclopramide appeared to have no effect on the occurrence of nosocomial pneumonia among patients with nasogastric feeding [38]. In another randomized control trial, Yavagal et al. also found that metoclopramide use did not decrease the rate of nosocomial pneumonia in critically ill patients undergoing nasogastric tube feeding [39]. Two meta-analysis studies also revealed no obvious protective effect of metoclopramide in critically ill tube-fed patients. In their meta-analysis, Lewis et al. indicated that the risk ratio of metoclopramide use compared with placebo for intensive care unit (ICU)-acquired pneumonia was 1.00 (95% CI: 0.76–1.32) [40]. Meanwhile, in a pooled meta-analysis, Liu et al. also reported that metoclopramide use showed no reduction in pneumonia risk compared with placebo in critically ill tube-fed patients, with the risk ratio being 0.79 (95% CI: 0.45–1.38) [41]. The abovementioned studies showed results similar to those of our study, that is, that prokinetics use does not reduce the occurrence of pneumonia. The patients included in our study were mostly elderly and were nasogastric tube-dependent for at least 7 months. The findings of our study thus provide further evidence that prokinetics agent use among elderly and chronic nasogastric tube-fed patients does not prevent pneumonia from occurring, despite the gastric-emptying properties of such agents.

In addition to the lack of a negative association between prokinetics exposure and pneumonia admission, this study found, in the subgroup analysis, that the adjusted ORs in female patients and patients with parkinsonism were 1.673 (95% CI: 1.052–2.661) and 2.222 (95% CI:1.196–4.129), respectively. There were also increased trends of positive association between prokinetics exposure and pneumonia admission in the overall population, elderly patients and stroke patients. Among possible reasons for these results, first, receptor hyperstimulation and automatic downregulation or upregulation mechanisms of synaptic receptors [42] may have played some role. Perhaps the downregulation of serotonin 5HT4 receptors after long-term mosapride exposure or the upregulation of dopamine receptors after long-term metoclopramide or domperidone exposure resulted in the lack of a negative association between prokinetics exposure and pneumonia admission, although there is no relevant basic research in this field to date. Second, indication bias may also have played an important role in this data analysis. Indication bias occurs when results may be influenced by the reason for a prescription being related to the measured outcome [43, 44]. Even though the case-crossover design eliminated confounding factors, such as the comorbidities of the included patients, through within-subject comparison, indication bias may still have been present and could have interfered with the outcomes. In addition to fever, chills and productive cough, up to 20% of pneumonia patients have gastrointestinal symptoms such as nausea and vomiting, while some patients also have malaise and fatigue [45, 46]. What’s more, patients with parkinsonism also have high rates of gastroparesis symptoms such as nausea, vomiting, early satiety and postprandial fullness [47–50]. Therefore, such patients may initially receive prescribed prokinetic agents for gastrointestinal symptoms in an outpatient department before being hospitalized due to pneumonia, a phenomenon which may have contributed an indication bias in this analysis.

Limitations

Although this was the first nationwide database study to investigate the association between prokinetic agent exposure and pneumonia admission among long-term nasogastric tube-dependent patients, there were several limitations in the study design. First, the number of included patients was relatively small even though the large nationwide health insurance database analyzed in this study contained 1 million representative samples. Only slightly fewer than 700 patients were included, and this low number may have affected the statistical power and validity of the study. Second, this was a retrospective study using NHIRD data; therefore, the prescription adherence of each patient could not be assessed. That is, while the prescriptions of the patients could be identified through the health insurance database, the true drug dosage consumed by each patient could not be assessed. Third, it could not be fully guaranteed that the included patients used a nasogastric tube at each time point during the whole seven-month period because this retrospective study could only select patients based on the procedure code recorded in the NHIRD. Fourth, the indication bias discussed above may also have played an important role in the analysis of the results.

Conclusion

According to the results of this study, there was no significant negative association between prokinetic agent use and pneumonia admission among the long-term nasogastric tube-dependent patients. There is no evidence supporting the prescription of prokinetic agents for pneumonia prevention in long-term nasogastric tube-dependent patients. Further prospective randomized controlled trials may be needed to examine the effects of prokinetic agents on pneumonia prevention among the long-term nasogastric tube-dependent patients.

Supporting information

S1 Table. The association between prokinetics exposure and pneumonia admission (time period changed to 14 days).

(DOCX)

Click here for additional data file. (20.8KB, docx)
S2 Table. The association between prokinetics exposure and pneumonia admission (time period changed to 45 days).

(DOCX)

Click here for additional data file. (22.5KB, docx)
S3 Table. The association between prokinetics exposure and pneumonia admission (washout period changed to 7 days).

(DOCX)

Click here for additional data file. (22.5KB, docx)
S4 Table. The association between prokinetics exposure and pneumonia admission (washout period changed to 15 days).

(DOCX)

Click here for additional data file. (22.8KB, docx)

Acknowledgments

The authors appreciate the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital, for their statistical work. The authors also wish to thank the Health Information and Epidemiology Laboratory at Chiayi Chang Gung Memorial Hospital for comments and assistance in performing the data analysis.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This work was supported by grants from Chang Gung Memorial Hospital (CFRPG8H0321).

References

  • 1.Welfare MoHa. 2018 Cause of Death Statistics [updated 2020/03/02; cited 2020 08/16]. Available from: https://www.mohw.gov.tw/cp-16-48057-1.html.
  • 2.Masiero S, Pierobon R, Previato C, Gomiero E. Pneumonia in stroke patients with oropharyngeal dysphagia: a six-month follow-up study. Neurol Sci. 2008;29(3):139–45. Epub 2008/07/10. 10.1007/s10072-008-0925-2 . [DOI] [PubMed] [Google Scholar]
  • 3.Gomes GF, Pisani JC, Macedo ED, Campos AC. The nasogastric feeding tube as a risk factor for aspiration and aspiration pneumonia. Curr Opin Clin Nutr Metab Care. 2003;6(3):327–33. Epub 2003/04/12. 10.1097/01.mco.0000068970.34812.8b . [DOI] [PubMed] [Google Scholar]
  • 4.Cabre M, Serra-Prat M, Palomera E, Almirall J, Pallares R, Clave P. Prevalence and prognostic implications of dysphagia in elderly patients with pneumonia. Age Ageing. 2010;39(1):39–45. Epub 2009/06/30. 10.1093/ageing/afp100 . [DOI] [PubMed] [Google Scholar]
  • 5.Luk JK, Chan DK. Preventing aspiration pneumonia in older people: do we have the ’know-how’? Hong Kong Med J. 2014;20(5):421–7. Epub 2014/07/06. 10.12809/hkmj144251 . [DOI] [PubMed] [Google Scholar]
  • 6.Langmore SE, Skarupski KA, Park PS, Fries BE. Predictors of aspiration pneumonia in nursing home residents. Dysphagia. 2002;17(4):298–307. Epub 2002/10/02. 10.1007/s00455-002-0072-5 . [DOI] [PubMed] [Google Scholar]
  • 7.van der Maarel-Wierink CD, Vanobbergen JN, Bronkhorst EM, Schols JM, de Baat C. Risk factors for aspiration pneumonia in frail older people: a systematic literature review. J Am Med Dir Assoc. 2011;12(5):344–54. Epub 2011/04/01. 10.1016/j.jamda.2010.12.099 . [DOI] [PubMed] [Google Scholar]
  • 8.Janda M, Scheeren TW, Noldge-Schomburg GF. Management of pulmonary aspiration. Best Pract Res Clin Anaesthesiol. 2006;20(3):409–27. Epub 2006/11/04. 10.1016/j.bpa.2006.02.006 . [DOI] [PubMed] [Google Scholar]
  • 9.Blumenstein I, Shastri YM, Stein J. Gastroenteric tube feeding: techniques, problems and solutions. World J Gastroenterol. 2014;20(26):8505–24. Epub 2014/07/16. 10.3748/wjg.v20.i26.8505 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Curran MP, Robinson DM. Mosapride in gastrointestinal disorders. Drugs. 2008;68(7):981–91. Epub 2008/05/07. 10.2165/00003495-200868070-00007 . [DOI] [PubMed] [Google Scholar]
  • 11.Barone JA. Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother. 1999;33(4):429–40. Epub 1999/05/20. 10.1345/aph.18003 . [DOI] [PubMed] [Google Scholar]
  • 12.DiPalma JR. Metoclopramide: a dopamine receptor antagonist. Am Fam Physician. 1990;41(3):919–24. Epub 1990/03/01. . [PubMed] [Google Scholar]
  • 13.Wiseman LR, Faulds D. Cisapride. An updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders. Drugs. 1994;47(1):116–52. Epub 1994/01/01. 10.2165/00003495-199447010-00008 . [DOI] [PubMed] [Google Scholar]
  • 14.Warusevitane A, Karunatilake D, Sim J, Lally F, Roffe C. Safety and effect of metoclopramide to prevent pneumonia in patients with stroke fed via nasogastric tubes trial. Stroke. 2015;46(2):454–60. Epub 2014/12/18. 10.1161/STROKEAHA.114.006639 . [DOI] [PubMed] [Google Scholar]
  • 15.Aronsky D, Haug PJ, Lagor C, Dean NC. Accuracy of administrative data for identifying patients with pneumonia. Am J Med Qual. 2005;20(6):319–28. Epub 2005/11/11. 10.1177/1062860605280358 . [DOI] [PubMed] [Google Scholar]
  • 16.Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991;133(2):144–53. Epub 1991/01/15. 10.1093/oxfordjournals.aje.a115853 . [DOI] [PubMed] [Google Scholar]
  • 17.Delaney JA, Suissa S. The case-crossover study design in pharmacoepidemiology. Stat Methods Med Res. 2009;18(1):53–65. Epub 2008/09/04. 10.1177/0962280208092346 . [DOI] [PubMed] [Google Scholar]
  • 18.Maclure M, Mittleman MA. Should we use a case-crossover design? Annu Rev Public Health. 2000;21:193–221. Epub 2000/07/08. 10.1146/annurev.publhealth.21.1.193 . [DOI] [PubMed] [Google Scholar]
  • 19.Knol W, van Marum RJ, Jansen PA, Souverein PC, Schobben AF, Egberts AC. Antipsychotic drug use and risk of pneumonia in elderly people. J Am Geriatr Soc. 2008;56(4):661–6. Epub 2008/02/13. 10.1111/j.1532-5415.2007.01625.x . [DOI] [PubMed] [Google Scholar]
  • 20.Tolppanen AM, Koponen M, Tanskanen A, Lavikainen P, Sund R, Tiihonen J, et al. Antipsychotic Use and Risk of Hospitalization or Death Due to Pneumonia in Persons With and Those Without Alzheimer Disease. Chest. 2016;150(6):1233–41. Epub 2016/06/15. 10.1016/j.chest.2016.06.004 . [DOI] [PubMed] [Google Scholar]
  • 21.Trifiro G, Gambassi G, Sen EF, Caputi AP, Bagnardi V, Brea J, et al. Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-control study. Ann Intern Med. 2010;152(7):418–25, W139-40. Epub 2010/04/07. 10.7326/0003-4819-152-7-201004060-00006 . [DOI] [PubMed] [Google Scholar]
  • 22.Chen TY, Winkelman JW, Mao WC, Liu CL, Hsu CY, Wu CS. The Use of Benzodiazepine Receptor Agonists and the Risk of Hospitalization for Pneumonia: A Nationwide Population-Based Nested Case-Control Study. Chest. 2018;153(1):161–71. Epub 2017/08/08. 10.1016/j.chest.2017.07.030 . [DOI] [PubMed] [Google Scholar]
  • 23.Lin SM, Yang SH, Liang CC, Huang HK, Loh CH. Association between benzodiazepine use and risks of chronic-onset poststroke pneumonia: a population-based cohort study. BMJ Open. 2019;9(1):e024180. Epub 2019/02/21. 10.1136/bmjopen-2018-024180 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Wang MT, Wang YH, Chang HA, Tsai CL, Yang YS, Lin CW, et al. Benzodiazepine and Z-drug use and risk of pneumonia in patients with chronic kidney disease: A population-based nested case-control study. PLoS One. 2017;12(7):e0179472. Epub 2017/07/12. 10.1371/journal.pone.0179472 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Arai N, Nakamizo T, Ihara H, Koide T, Nakamura A, Tabuse M, et al. Histamine H2-Blocker and Proton Pump Inhibitor Use and the Risk of Pneumonia in Acute Stroke: A Retrospective Analysis on Susceptible Patients. PLoS One. 2017;12(1):e0169300. Epub 2017/01/14. 10.1371/journal.pone.0169300 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ. 2011;183(3):310–9. Epub 2010/12/22. 10.1503/cmaj.092129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Jaynes M, Kumar AB. The risks of long-term use of proton pump inhibitors: a critical review. Ther Adv Drug Saf. 2019;10:2042098618809927. Epub 2019/04/26. 10.1177/2042098618809927 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS One. 2015;10(6):e0128004. Epub 2015/06/05. 10.1371/journal.pone.0128004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Wang CH, Li CH, Hsieh R, Fan CY, Hsu TC, Chang WC, et al. Proton pump inhibitors therapy and the risk of pneumonia: a systematic review and meta-analysis of randomized controlled trials and observational studies. Expert Opin Drug Saf. 2019;18(3):163–72. Epub 2019/02/02. 10.1080/14740338.2019.1577820 . [DOI] [PubMed] [Google Scholar]
  • 30.Novack V, MacFadyen J, Malhotra A, Almog Y, Glynn RJ, Ridker PM. The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial. CMAJ. 2012;184(7):E367–72. Epub 2012/03/21. 10.1503/cmaj.111017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.van de Garde EM, Hak E, Souverein PC, Hoes AW, van den Bosch JM, Leufkens HG. Statin treatment and reduced risk of pneumonia in patients with diabetes. Thorax. 2006;61(11):957–61. Epub 2006/07/01. 10.1136/thx.2006.062885 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Vinogradova Y, Coupland C, Hippisley-Cox J. Risk of pneumonia in patients taking statins: population-based nested case-control study. Br J Gen Pract. 2011;61(592):e742–8. Epub 2011/11/08. 10.3399/bjgp11X606654 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Caldeira D, Alarcao J, Vaz-Carneiro A, Costa J. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis. BMJ. 2012;345:e4260. Epub 2012/07/13. 10.1136/bmj.e4260 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Welfare MoHa. [updated 2019/09/202020/07/12]. Available from: https://dep.mohw.gov.tw/DOS/lp-1720-113-xCat-8.html.
  • 35.Jackson ML, Nelson JC, Jackson LA. Risk factors for community-acquired pneumonia in immunocompetent seniors. J Am Geriatr Soc. 2009;57(5):882–8. Epub 2009/05/21. 10.1111/j.1532-5415.2009.02223.x . [DOI] [PubMed] [Google Scholar]
  • 36.Hiyama T, Yoshihara M, Tanaka S, Haruma K, Chayama K. Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract. J Gastroenterol Hepatol. 2009;24(4):537–46. Epub 2009/02/18. 10.1111/j.1440-1746.2009.05780.x . [DOI] [PubMed] [Google Scholar]
  • 37.Pareek N, Williams J, Hanna D, Johnson WD, Minocha A, Abell TL. Prokinetic therapy reduces aspiration pneumonia in tube-fed patients with severe developmental disabilities. Am J Ment Retard. 2007;112(6):467–71. Epub 2007/10/30. 10.1352/0895-8017(2007)112[467:PTRAPI]2.0.CO;2 . [DOI] [PubMed] [Google Scholar]
  • 38.Nassaji M, Ghorbani R, Frozeshfard M, Mesbahian F. Effect of metoclopramide on nosocomial pneumonia in patients with nasogastric feeding in the intensive care unit. East Mediterr Health J. 2010;16(4):371–4. Epub 2010/08/28. . [PubMed] [Google Scholar]
  • 39.Yavagal DR, Karnad DR, Oak JL. Metoclopramide for preventing pneumonia in critically ill patients receiving enteral tube feeding: a randomized controlled trial. Crit Care Med. 2000;28(5):1408–11. Epub 2000/06/02. 10.1097/00003246-200005000-00025 . [DOI] [PubMed] [Google Scholar]
  • 40.Lewis K, Alqahtani Z, McIntyre L, Almenawer S, Alshamsi F, Rhodes A, et al. The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials. Crit Care. 2016;20(1):259. Epub 2016/08/17. 10.1186/s13054-016-1441-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Liu Y, Dong X, Yang S, Wang A, Wang M. Metoclopramide for preventing nosocomial pneumonia in patients fed via nasogastric tubes: a systematic review and meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr. 2017;26(5):820–8. Epub 2017/08/15. 10.6133/apjcn.102016.01 . [DOI] [PubMed] [Google Scholar]
  • 42.Hall JE. Guyton and Hall Textbook of Medical Physiology. 14 ed: Elsevier; 2020. 587–98 p. [Google Scholar]
  • 43.Faillie JL. Indication bias or protopathic bias? Br J Clin Pharmacol. 2015;80(4):779–80. Epub 2015/06/30. 10.1111/bcp.12705 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Kyriacou DN, Lewis RJ. Confounding by Indication in Clinical Research. JAMA. 2016;316(17):1818–9. Epub 2016/11/02. 10.1001/jama.2016.16435 . [DOI] [PubMed] [Google Scholar]
  • 45.Grief SN, Loza JK. Guidelines for the Evaluation and Treatment of Pneumonia. Prim Care. 2018;45(3):485–503. Epub 2018/08/18. 10.1016/j.pop.2018.04.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Mandell LA, Wunderink R. Pneumonia. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine, 20e. New York, NY: McGraw-Hill Education; 2018. [Google Scholar]
  • 47.Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson’s disease. Mov Disord. 2014;29(1):23–32. Epub 2013/10/24. 10.1002/mds.25708 . [DOI] [PubMed] [Google Scholar]
  • 48.Tanaka Y, Kato T, Nishida H, Yamada M, Koumura A, Sakurai T, et al. Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson’s disease? An analysis using the 13C-acetate breath test. J Neurol. 2011;258(3):421–6. Epub 2010/10/13. 10.1007/s00415-010-5769-z . [DOI] [PubMed] [Google Scholar]
  • 49.Heetun ZS, Quigley EM. Gastroparesis and Parkinson’s disease: a systematic review. Parkinsonism Relat Disord. 2012;18(5):433–40. Epub 2012/01/03. 10.1016/j.parkreldis.2011.12.004 . [DOI] [PubMed] [Google Scholar]
  • 50.Mukherjee A, Biswas A, Das SK. Gut dysfunction in Parkinson’s disease. World J Gastroenterol. 2016;22(25):5742–52. Epub 2016/07/20. 10.3748/wjg.v22.i25.5742 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Alexandru Rogobete

27 Jan 2021

PONE-D-20-36433

Could prokinetic agents protect long-term nasogastric tube-dependent patients from being hospitalized for pneumonia? A nationwide population-based case-crossover study

PLOS ONE

Dear Dr. Chou,

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Please consider all the suggestions of the reviewers.

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: N/A

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: The subject of the article is extremely important and actual.

I have the following comments and questions for the authors. There are many awkward phrases that I do not point out here; I only point out those where the meaning cannot be interpreted:

The table 1 is extremely hard to read! Try to make more readable.

The paragraph "Variable assessment" is not clear can be rewrite in more clear format.

The conclusion need to clear and specific.

My recommendation is to focus on 3 short conclusion!

Please recheck the References order.

Please double check the article by a native English reader.

Reviewer #2: In my opinion, this manuscript is clearly written and well structured. It does explain appropriately the rationale for the evaluation of the presented outcome: the need for hospitalisation for pneumonia considering, however, no other secondary outcomes, which I will refer further.

1. The authors defined 7- month period for nasogastric tube placement as being long-term period? Why was considered this time interval fur studying this issue?

2. A modern approach of the patients with neurodegenerative diseases, which implies deglutition problems is considered to be, nowadays, the percutaneous or laparoscopic gastrostomy with or without fundoplication. Considering that, the importance of the issue discussed here (the patients with long-term nasogastric tube-placement) is reduced even more. Additionally, it would be appropriate to analyse the PEG-patients (subsequently excluded for this study) vs. naso-gastric-tube dependent patients in terms of aspiration pneumonia.

3. Regarding lines 114-116, in my opinion, it would be valuable to reconsider the study design strategy in order to introduce as secondary outcome the number of pneumonia recurrences in this patients and not to eliminate completely this relevant clinical fact. Maybe prokinetics could reduce the incidence of the aspiration pneumonia episodes. A statistical analysis of this issue should be considered.

4. In accordance with table 1, mosapride was used in 56 patients only. Were there any statistical power tests conducted in order to evaluate the patients number needed for an accurate statistical analysis? If yes, it should be specified.

5. In accordance with FDA recommendation from 2017, metoclopramide should be used with caution in patients with Parkinson. What was the rationale to consider this subgroup of patients receiving this drug?

6. I would consider, as well, the timespan between the nasogastric tube insertion and the first aspiration pneumonia episode. It could be relevant as secondary outcome.

7. Another major concern is the inability of the study to identify the patient prescription adherence. It is indeed very difficult to consider this, but this is, in fact, the main purpose of this study: to determine if the prokinetic therapy influences the appearance of pneumonia episodes, who need hospitalisation.

**********

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Reviewer #2: No

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PLoS One. 2021 Apr 5;16(4):e0249645. doi: 10.1371/journal.pone.0249645.r002

Author response to Decision Letter 0

9 Mar 2021

Reply to reviewer #1

We appreciated a lot for your useful recommendation about our article. We apologized for poor English grammar and expression since English is not our native language. We have had our manuscript revised by native English reader. We would explain the revisions according to your precious suggestions as followings:

1. The table 1 is extremely hard to read! Try to make more readable.

Response:

Thank for your suggestion. We had modified the table 1 content to make it more readable. Please see the modified table 1 for details (line 211).

2. The paragraph "Variable assessment" is not clear can be rewrite in more clear format.

Response:

We appreciated your recommendation. We had revised our manuscript in variable assessment section to make it more fluent and readable. We also add confounding factors in the subtitle because in that paragraph, we also focused on explaining the confounding medications. Please refer to the Variable assessment and confounding factors section for more details (line 159-184).

3. The conclusion need to clear and specific. My recommendation is to focus on 3 short conclusion!

Response:

Thank you for your useful recommendation. We tried to make our conclusion objective and evidence-based according to results. Although the findings in our analyses revealed no significant results, there are still some implications for clinical practice. We had revised the conclusion section to make it clearer and more specific. Please refer to the conclusion section for details (line 333-340).

4. Please recheck the References order.

Response:

Thank for your carefully reminder. We have rechecked our reference order and found that in the original manuscript line 72, the reference 3 appeared after the reference 7 (in line 64). This is because reference 3 was also cited in line 64 which was expressed by “the presence of an endotracheal tube and enteral tube feeding[2-7].” We also revised the reference citation format to meet the PLOS one requirement. Please refer to the line 64 and 72 for further information and inform us if there were other mistakes that we don’t find. Thank you very much.

5. Please double check the article by a native English reader.

Response:

We appreciated your recommendation. We have invited a professional native English reader to recheck and revise English expressions in our manuscript for more clarity and fluency. The English revision certification would also attached in our uploaded files.

Reply to reviewer #2

We are so grateful for your precious comments and suggestions for our manuscript which were really clinically practical. We would reply to your suggestions as followings:

1. The authors defined 7- month period for nasogastric tube placement as being long-term period? Why was considered this time interval fur studying this issue?

Response:

Thank for your opinion and question. In this study, we used case-crossover design to do the within-object evaluation of prokinetic agent exposure and pneumonia admission in long-term nasogastric tube (NG tube) dependent patients. In fact, we presumed the long-term period as 3-month in our study design. The reason for selecting patients with NG tube placement for 7-month period before pneumonia admission was to confirm all the patients included were NG tube dependent at least 3 months among case period and control periods. Please refer to the Fig 2 in our manuscript (or below this paragraph). In Fig 2, the second control period (Control Period 2) was defined as the period between day -121 to day -150 and if we did not select patients had NG tube dependence 210 days before the index date, then the patient may not have NG tube dependence for 3 months in the second control period. For example, if a patient was NG tube dependent only 180 days before the index date, then at the second control period time point (the -121 day), the patient would only had used NG tube for 60 days before that control period date and which did not meet the long-term NG tube dependent presumption (3-month period) in our study. We had added the long-term NG tube dependent presumption in the Patient Selection section (line 117-125).

2. A modern approach of the patients with neurodegenerative diseases, which implies deglutition problems is considered to be, nowadays, the percutaneous or laparoscopic gastrostomy with or without fundoplication. Considering that, the importance of the issue discussed here (the patients with long-term nasogastric tube-placement) is reduced even more. Additionally, it would be appropriate to analyse the PEG-patients (subsequently excluded for this study) vs. naso-gastric-tube dependent patients in terms of aspiration pneumonia.

Response:

We are very appreciated for your opinion and useful suggestion. Indeed, the percutaneous or laparoscopic gastrostomy is getting more and more important in the neurodegenerative disease patients. However, in Taiwan, despite that PEG had been introduced in since 1995, the use rate of PEG was still low, and it may be explained by the traditional Chinese cultural value. Nasogastric tubes were used for a year or more in over half of the patients requiring enteral feeding in Taiwan(Yeh, Lo, Fetzer, & Chen, 2010). Under such social value in Taiwan, our article was aimed to evaluate the current clinical condition. Therefore, we still selected all the long-term NG tube dependent patients for analysis. What’s more, because the NG tube may be a risk factor of pneumonia occurrence by gastric organism migration along the tube to the pharynx(Gomes, Pisani, Macedo, & Campos, 2003). It may be more valuable and interesting to evaluation the prokinetic agent’s pharmacologic effect in pneumonia occurrence in these NG tube feeding patients rather than PEG dependent patients. However, it is still important in comparing the pneumonia risk between NG tube feeding patients and PEG dependent patients. Nevertheless, under our case crossover study design, the gastrostomy or PEG users were only 11 (in our manuscript Fig1, patient selection flow diagram). Hence, it was difficulty in analyzing the difference between NG tube users and PEG users in our study. It may be a very good and important implication in the future.

3. Regarding lines 114-116, in my opinion, it would be valuable to reconsider the study design strategy in order to introduce as secondary outcome the number of pneumonia recurrences in this patients and not to eliminate completely this relevant clinical fact. Maybe prokinetics could reduce the incidence of the aspiration pneumonia episodes. A statistical analysis of this issue should be considered.

Response:

We appreciated for your precious suggestion very much. Indeed, in cohort study design, it is important to consider the pneumonia occurrence episode in the data analysis between the exposure group and control group. However, in our manuscript, the case crossover study design was quite different from the cohort study design. The case crossover design was introduced by Maclure et. al(Maclure, 1991) and it is the case-only study design. This case crossover study design included all the participants with events (such as pneumonia admission in our study) and provided within subject comparison at different time points (case periods and control periods) for short-term effect of medicines or environmental exposure. Therefore, all included patients had pneumonia admission and we set the index date as the day of pneumonia admission. We included the first-time pneumonia admission patients in the database only to prevent from interfering of control periods and case period. To say, it is unable to analyze the pneumonia episodes as outcome evaluation under our case crossover study design in this nationwide database study because of the case crossover study designation nature and method. However, you still give us a very important and useful suggestion for future study design direction. We thank you very much.

4. In accordance with table 1, mosapride was used in 56 patients only. Were there any statistical power tests conducted in order to evaluate the patients number needed for an accurate statistical analysis? If yes, it should be specified.

Response:

Thank you for your opinion and suggestion. Indeed, the mosapride users were only 56 patients and statistical power test should be conducted in cohort study to verify the statistical validity. However, in case crossover study, which is a retrospective case only study design comparing the same subject at different time point exposures, it is unusual to calculate the statistical power or the patient number needed to reach the statistical power.

Regardless of that, we still conducted the statistical power test for the mosapride user group and the statistical power test for mosapride user group was only 43.50% which was far below 80%. We also conducted the statistical power test for all prokinetic agent, and the patient number needed to reach statistical power of 80% was 3,049. However, in our study, only 639 patients were included in this large scale nationwide longitudinal database consisted of 1 million people under the rigorous inclusion criteria for this case crossover design. To say, we have tried our best to extract all the patients we needed in this large database, but it was still difficult to reach the number needed for statistical power of 80%. It was almost impossible to increase included patient number in current large database and study design. We thought that It represented that we have interpret our results with caution, but the results of our study were still valuable for applying in the long-term NG tube dependent patients. Therefore, we have mentioned the small sample size in the manuscript “Limitation” section and revised the text to explain this problem (line 319-322). Again, we really appreciate your suggestion for the statistically problem.

5. In accordance with FDA recommendation from 2017, metoclopramide should be used with caution in patients with Parkinson. What was the rationale to consider this subgroup of patients receiving this drug?

Response:

Thank you for careful clinical suggestion and opinion. Certainly, according to the FDA recommendation, it was not suggested to use metoclopramide in patients with parkinsonism in case of extrapyramidal symptoms exacerbating the parkinsonism. However, in clinical practice, there may still some parkinsonism patients may have severe gastrointestinal tract symptoms like delayed emptying despite of other prokinetic agent use. Under such circumstances, metoclopramide may still be used with caution for symptom relief. What’s more, this study included patients’ data among 1997 and 2013 when the 2017 FDA recommendation not applied yet. Therefore, clinicians may still use metoclopramide in these parkinsonism patients after weighing the benefits and harms during that period of time.

6. I would consider, as well, the timespan between the nasogastric tube insertion and the first aspiration pneumonia episode. It could be relevant as secondary outcome.

Response:

We appreciated for your suggestion and opinion very much. It is really important and needed to consider the timespan between the NG tube insertion and the first pneumonia episode in cohort study design and it should provide some clinical useful information for data analysis or clinical implication. However, we have to apologize for inability to do such analysis. The main reason was somewhat like question 3, the study design method. We would like to restate that we used case crossover design as the basic foundation in our study. In this study design, we included all the patients with pneumonia admission and long-term NG tube dependence. We used conditional logistic regression to compare the drug exposures among case period and control periods WITHIN the same subjects at DIFFERENT time points. It is somewhat not that meaningful to compare the timespan between the nasogastric tube insertion and the first pneumonia episode because the case period and control periods are already set by study designer. For example, the NG tube insertion timespan would certainly be more at the case period (the time when pneumonia admission) than the first control period (day -61) by 60 days. The timespan between NG tube insertion and admission could not be analyzed in the case crossover design. Therefore, this is why the reason we set the 7-month NG tube dependence period as inclusion criteria to make sure that all the participants in control periods were NG tube dependence at least for 3-month period which was presumed to be the long-term NG tube dependence in this study.

We hope our explanation would be clear enough, but we still really appreciated your professional suggestion to include the timespan as secondary outcome. We would take that in mind and may analyze the timespan in another future cohort study design. Thank you very much!

7. Another major concern is the inability of the study to identify the patient prescription adherence. It is indeed very difficult to consider this, but this is, in fact, the main purpose of this study: to determine if the prokinetic therapy influences the appearance of pneumonia episodes, who need hospitalisation.

Response:

We appreciated for your comment on this important limitation of our study. In such kind of nationwide database study, the prescription adherence was somewhat an inherent limitation. Because we could only collect data or prescription status from the national health insurance database record, it is really difficulty to evaluate the realistic medicine consumption status. However, the advantage of large-scale database study is its large case number which may offset the bias of prescription adherence. A prior meta-analysis study included around 60 to 300 participants to explore the association of prokinetic agent and pneumonia in NG tube dependent patients(Liu, Dong, Yang, Wang, & Wang, 2017). Our study included more than 600 participants which was the most participants in this kind of studies evaluating the association of pneumonia and prokinetics in NG tube dependent patients. Therefore, we thought the results of our study was still valuable by its large case number despite the prescription adherence problem. We also mentioned the prescription adherence problem in our limitation section (line 322-326).

References:

Gomes, G. F., Pisani, J. C., Macedo, E. D., & Campos, A. C. (2003). The nasogastric feeding tube as a risk factor for aspiration and aspiration pneumonia. Curr Opin Clin Nutr Metab Care, 6(3), 327-333. doi:10.1097/01.mco.0000068970.34812.8b

Liu, Y., Dong, X., Yang, S., Wang, A., & Wang, M. (2017). Metoclopramide for preventing nosocomial pneumonia in patients fed via nasogastric tubes: a systematic review and meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr, 26(5), 820-828. doi:10.6133/apjcn.102016.01

Maclure, M. (1991). The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol, 133(2), 144-153. doi:10.1093/oxfordjournals.aje.a115853

Yeh, L., Lo, L. H., Fetzer, S., & Chen, C. H. (2010). Limited PEG tube use: the experience of long-term care directions. J Clin Nurs, 19(19-20), 2897-2906. doi:10.1111/j.1365-2702.2009.03157.x

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Decision Letter 1

Alexandru Rogobete

23 Mar 2021

Could prokinetic agents protect long-term nasogastric tube-dependent patients from being hospitalized for pneumonia? A nationwide population-based case-crossover study

PONE-D-20-36433R1

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Acceptance letter

Alexandru Rogobete

25 Mar 2021

PONE-D-20-36433R1

Could prokinetic agents protect long-term nasogastric tube-dependent patients from being hospitalized for pneumonia? A nationwide population-based case-crossover study

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. The association between prokinetics exposure and pneumonia admission (time period changed to 14 days).

    (DOCX)

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    S2 Table. The association between prokinetics exposure and pneumonia admission (time period changed to 45 days).

    (DOCX)

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    S3 Table. The association between prokinetics exposure and pneumonia admission (washout period changed to 7 days).

    (DOCX)

    Click here for additional data file. (22.5KB, docx)
    S4 Table. The association between prokinetics exposure and pneumonia admission (washout period changed to 15 days).

    (DOCX)

    Click here for additional data file. (22.8KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (195.6KB, docx)

    Data Availability Statement

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