Is Percutaneous Endoscopic Gastrostomy (PEG) tube feeding Benecial for Improving Survival in Patients with Dementia? A systematic review and meta- analysis of current evidences

Background Dementia is a progressive disabling neurogenic disease resulted in serious nutritional deciencies included dysphagia, malnutrition and weight loss. The Percutaneous Endoscopic Gastrostomy (PEG) which is a long-term enteral feeding method that routinely use in demented patients with poor food intake as a standard protocol. However, most of the evidences have not shown benecial effects of PEG feeding on complications or survival rates in these patients. Some studies have even reported an increase in mortality. The current systematic review and meta-analysis aimed to evaluate the mortality rate and survival in primary demented patients with PEG.Methods A systemically search conducted on Pubmed and Scopus databases up to Aug 2019 without language restriction. The data were reviewed according to Cochrane handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA) and meta-analysis of observational studies in epidemiology (MOOSE). Based on random-effects model, mortality rate and median survival were expressed as risk ratio and weighted mean difference (WMD) and 95% CI respectively.Results Among 13 included studies, PEG insertion in patients with primary dementia has no signicant effect on 30-day, 90-day, 180-day, 1-year and 2- year mortality rate or median survival (WMD: 9.77; 95% CI: -22.43 to 41.98; P= 0.55). It seems that naso-gastric tube (NGT) feeding in compared to PEG in this population is more effective.Conclusion Further prospective studies are needed to comprehensive evaluation of mortality or survival regarding to comorbidities, underlying disease, cognitive and physical performance and nutritional problems in demented patients.


Background
Dementia is a progressive disabling neurogenic disease, derived from neurons damage in the brain (1). The patients with dementia often need hospitalization care which exert a lot of costs on the medical system (2). Dementia often lead to serious nutritional de ciencies because the patients with dementia are progressively losing their ability to chewing, swallowing or in advanced stage, even they cannot recognize food or eating components (3,4) resulted in dehydration, malnutrition and weight loss (5).
In dementia patients with nutritional problem, percutaneous endoscopic gastrostomy (PEG) usually is inserted although its bene cial effects are unclear (6). On the basis of evidences, the PEG which is a long-term enteral feeding method of administration, can improve nutritional status in patients with inadequate intake in neurogenic disorders (7). In papulation with dementia, while the PEG feeding tube placement is accepted as a standard care method in many health professionals, the evidences which evaluating the outcome of PEG feeding in dementia patients with poor food intake, malnutrition and who with nutritional di culties reported no positive effects on survival rate (8). In the other hand, the most existing observation had revealed no harmful outcomes from PEG method usage in patients with dementia compared to in non-dementia patients (9).
In view of the contradictory effects of PEG insertion on survival as a routine method in dementia patients and regarding to limit data from previous evidences, the present study for the rst time amid to perform a systematic review and meta-analysis of all relevant published studies to clarify the effects of PEG tube feeding on mortality rate and median survival in primary dementia patients.

Literature screening and systematic search strategy
The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) (10) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) (11) instruction was used in present systematic review and meta-analysis. A systematically computerized search was performed on PubMed and SCOPUS up to Aug 2019 publications in English language. The Medical subject headings (MeSH) and non-MeSH key words used for search process were included Mental Disorders [ The references section of all eligible articles as well as reviews or systematic reviews was checked manually to avoiding miss any related data. In next step, after importing relevant publication to the EndNote document management software (Clarivate Analytics), the duplicate data were detected and removed. We excluded laboratory studies (in vitro, in vivo or ex-vivo studies), animal studies, conference papers and review articles based on eligibility and exclusion criteria. The eligible studies were enrolled to this meta-analysis after review their abstract or full-text.

Eligibility and Exclusion criteria
At the present meta-analysis, we included the articles which met following eligibility criteria: I) The studies with full-text in English language II) Intervention with PEG as enteral tube feeding and III) The publications which reported su cient information in the case of mortality rate and median survival at the intervention in PEG and control groups.
The studies with any following de ned exclusion criteria were excluded from our meta-analysis: I) laboratory research (in vitro, in vivo or ex-vivo) or animals studies, II) studies which not performed on elderly patients III) studies with no enough data about mortality rate and survival in demented patients with PEG or control group IV) Studies on effect of any other supplemental feeding method along with PEG in intervention group but not in control group and VI) Studies which had no control group.

Data selection and extraction
At the current systematic review and meta-analysis, the data from de ned included studies, were extracted indecently by two reviewers (M.S. and M.A.). Any possible disagreement was solved after discussing or based on third reviewer (R.H.) consensus. In continue, following data extracted from all included studies: the rst author name, the publication year, the country of study, the sample size, the design of studies, the gender of participants, mean age, the population type, the intervention feeding type, complications, risk ratio of 30day, 90-day, 180-day, 1-year and 2-year mortality as well as mean ± standard deviation (SD) of median survival.

Quality assessment
The quality of observational studies was assessed according to the Newcastle-Ottawa Quality Assessment Scale included fallowing factors: I) Patient selection, II) comparability of the study groups, and III) assessment of outcome. Each study had a score of 0-9 and the studies that achieved six score or more stars considered as high quality (12) ( Table 1).

Statistical analysis
At the current work, Review Manager 5.3.5 (The Nordic Cochrane Center, The Cochrane Collaboration) software was applied to data statistical analysis. The mortality rate (30-days, 90-days, 180-days, one-year and two-years mortality) as well as median survival days were considered as continuous variables and in continue, according random-effects model, mortality rate and median survival were expressed as risk ratio and weighted mean difference (WMD) and 95% CI respectively. The heterogeneity or homogeneity among included studies were identi ed based on Cochrane's Q test and I 2 statistical test; If P < 0.1 and I 2 > 50%, the study de ned heterogeneous and If P> 0.1 and I 2 ≤ 50%, the data accounted homogenous. In addition, the potential heterogeneity sources was detected by subgroup analyses (13) consist of disease, feeding method and age. It is necessary to mention, in the studies that the mortality rate was not available, we calculated mortality rates in groups using Kaplan-Meier graph and WebPlotDigitizer online software as well as the studies which median survival and range were not clari ed (13,14). Then, the median and rang were converted to mean and standard deviation according to method devised by Hozo et al (15). The P<0.05 accounted as statistically signi cant in analysis.

Literature search
The ow diagram of publications in Figure 1, is illustrated according to the Quality of Reporting of Meta-analyses statements. Overall, 13 study were included at present systematic review and meta-analysis. Two articles reported mortality in dementia patients who had PEG feeding tube (16, 17), 10 studies reported survival rate (18-27) and one reported both of mortality rate and survival in this papulation (28).
At the primary databases searching, 11377 related data were identi ed (762 in PubMed and 10610 in Scopus). In continue, fallowing manual search of related articles, 5 additional studies were enrolled in the present systematic review and meta-analysis. In next step, the duplicated studies were determined and removed using Endnote software (n=742).
The title and abstract of remained publications (10635) were reviewed to determine included studies. The fallowing studies were excluded from this work (totally 10574): Unrelated studies (n=7891), the disorder other than dementia (872), the Data from patients with dementia were combined with other diseases (n=166), animal or in vitro studies (n=1053), case reports (261) and review articles (n=249). Sixty-one articles selected and their eligibility were evaluated exactly trough review their full-text. Finally, 13 articles included to meta-analysis after studies with the following characteristics were excluded (totally n=48): Full text not found (n=5), non-english full-texts (n=12), without expected outcomes (n=15), PEG was administered in combination with naso-gastric tube (NGT) or other alternative nutrition (n=8) and the data from patients with dementia were combined with other diseases (n=8).

Study characteristics
The included studies characteristics are presented in Table 2. Based on search strategy in this mete-analysis, the relevant data were enrolled up to Aug 2019. A total of 1020 dementia patients who had PEG feeding tube, and 1296 patients in control group (408 demented patients with oral nutrition (ON) or NGT nutrition support, 678 patients with secondary dementia as a result of stroke with PEG and 210 patients with other disease and PEG nutrition support) participated in current meta-analysis. The mean age of participants were 78.5 years old. Among included studies, 3 studies were performed in United States (16, 19,21), 3 studies in Japan (24,26,27), 2 studies in Israel (18, 22), 1 study in United Kingdom (17), 1 study in France (20), 1 study in Sweden (23), 1 study in Colombia (25) and 1 study in Italy (28). Across the eligible articles, eight studies reported survival or mortality rate in dementia patients with PEG feeding as illustrated in Kaplan-Meier graph or table, one reported only 180-day mortality and in 7 articles median survival days was extractable from the study text or Kaplan-Meier graph (16-28). All of studies were performed on both of male and female except one (21). The feeding method, underling disorder, complications and predictors of poor survival of participants are presented in Table 2. In the 4 studies the complications were not mentioned (19,23,26,28). In 8 articles age has been evaluated as a survival predictor (17, 18, 20, 22, 23, 26- Table 2).
The 30-day mortality in demented patients with PEG As presented in gure 2, the risk ratio preformed on 8 studies, showed PEG intervention had no statistically signi cant effect on 30-day mortality (RR: 1.16; 95% CI: 0.59 to 2.28; P= 0.66). In addition, a signi cant heterogeneity was observed among studies (I 2 =81%, P<0.001).
To identify the between study heterogeneity sources, subgroup analysis was conducted on control group intervention (oral, NGT or PEG), diseases, and age ( Table 3). The subgroup analysis found that in 30-day mortality, the PEG method intervention in control group, as well as disease (dementia or other disorder), and 80> age was detected as the potential sources of heterogeneity. However, among these subgroups, no signi cant reduction in 30-day mortality was found after subgroup analysis based on feeding method, disease and age (Table 3).
The 90-day mortality in demented patients with PEG The overall RR from 8 studies showed that PEG intervention exerts no signi cant reduction in 90-year mortality (RR: 1.13; 95% CI: 0.60 to 2.16; P = 0.70), with a considerable between studies heterogeneity (I 2 =93%, P<0.001) ( Figure 3). Subgroup analysis showed that PEG intervention in control group, disease (dementia or other diseases) and age (80> or 80≤) are considered as heterogeneity sources. Fallowing subgroup analysis based on feeding rout in control participants, a signi cant reduction in 90-day mortality was found in NGT group (RR: 0.51; 95% CI: 0.31 to 0.82; P=0.005) and increasing in 90-day mortality in oral feeding in (RR: 1.70; 95% CI: 1.06 to 2.74; P=0.03) comparison with PEG receiving patients with dementia.
In addition, no signi cant differences in 90-day mortality was observed after subgroup analysis based on other diseases or age ( Table 3).
The 180-day mortality in demented patients with PEG According to gure 4 illustrated RR of PEG feeding on 180-day mortality rate in patients with dementia preformed on 9 studies (505 cases and 857 controls), PEG intervention exerts no statistically signi cant reduction on 180-day mortality rate (RR: 1.07; 95% CI: 0.75 to 1.53; P=0.70). There was a signi cant heterogeneity among included studies (I 2 =88%, P<0.001). Fallowing subgroup analysis based on feeding rout, disease and age as identi ed heterogeneity sources, a signi cant reduction in 180-day mortality was observed in NGT receiving group (RR: 0.59; 95% CI: 0.43 to 0.81; P=0.001) comparison with PEG intervention in patients with dementia. also, no signi cant differences in 180-day mortality was found after subgroup analysis based on other diseases or age ( Table 3).
The 1-year mortality in demented patients with PEG At the present meta-analysis, based on overall effect sizes of 8 included data, the PEG intervention had no signi cant effect on 1-year mortality reduction (RR: 1.01; 95% CI: 0.77 to 1.33; P = 0.94), with a considerable heterogeneity across enrolled studies (I 2 =92%, P<0.001) ( Figure 5). After subgroup analysis, a signi cant reduction in 1-year mortality rate was detected in NGT receiving group (RR: 0.67; 95% CI: 0.46 to 0.97; P=0.04) comparison with PEG intervention in dementia patients ( Table 3).
The median survival days in demented patients with PEG The gure 7 illustrated the WMD of median survival days in demented patients with PEG method. The overall effect from the randomeffect model that preformed on 7 studies showed PEG intervention had no statistically signi cant effect on patient's median survival (WMD: 9.77; 95% CI: -22.43 to 41.98; P= 0.55) (Figure 7). In addition, no signi cant between studies heterogeneity was identi ed among included studies (I 2 =0%, P= 0.48) ( Table 4).

Discussion
The current systematic review and meta-analysis included 13 studies and a total of 1020 participants in PEG group with dementia and 1296 participants in control group. The PEG intervention has no statistically signi cant effect on 30-day, 90-day, 180-day, 1-year and 2year mortality rate or median survival days in patients with dementia. In addition, in order to clarify the effect of PEG feeding method on mortality rate and survival in dementia patients, subgroup analyzes was performed based on age as 80> or 80≤, control group disorders as dementia or other disease and feeding method in control group as oral, NGT or PEG. However, after subgroup analysis it is found that NGT intervention in compared to PEG in dementia patients can signi cantly reduce 90-day, 180-day, 1-year and 2-year mortality rate while oral intake signi cantly increased 90-day and 2-year mortality rate. Also, 2-yaer mortality signi cantly increased in patients 80≤ years old.
The PEG has been considered as a long-term enteral feeding since the 1980s (29) which can reduce aspiration rate in compare to NGT can be used in patients who are expected to require antral feeding for more than 2-3 weeks (30,31). On the basis of evidences PEG insertion can increases serum albu min that it accounts a biomarker of nutritional status evaluation (32). The PEG method is well accepted in patients with neurological disease who have nutritional di culty such as dysphagia (33). But PEG placement in dementia patients is con icting. Dementia is usually associated with major nutritional problems such as eating, chewing, swallowing, etc., especially with progression of the disease which lead to inadequate intake, weight loss and serious malnutrition (2). So, these patients often need support nutrition. Despite contradictory evidences, at the moment, PEG insertion is prescribed by physicians in the majority of dementia cases since they can't intake adequate energy and proteins which may affects dementia progression (34).
In the current systematic review and meta-analysis, in dementia patients, PEG intervention could not affect mortality rate at any time and even increased mortality risk ratio, although it was not statistically signi cant. These nding are parallel with the results of several trials which reported that mortality rate signi cantly increase in PEG receiving patients with dementia (16, 28). In this context, Sanders et al demonstrated that dementia patients with PEG had a lower prognosis, with a 54% mortality at 30-day,78% at 90-day, 81% at 180-day, and 90% at one-year (17). Also, similar to mortality results, the PEG insertion in dementia patients had exert no signi cant positive differences on median survival. The most of previous studies in the context of PEG intervention and survival con rm the present results (26,27). Some studies found no association between PEG insertion and survival in dementia patients (19,21)

while Ticinesi et al (2016) and
Atencio et al (2015) reported a signi cantly shorter survival in the PEG group with dementia (25,28). In contrast, a signi cant positive effects of PEG insertion on increasing survival in dementia patients have been demonstrated (18). However, the most of the prospective studies the PEG enteral nutrition is not associated with an improvement in nutritional status, course of disease or survival (6). In this context, Teno et al., in their large prospective cohort study in patients with dementia found no correlation between PEG and survival (35). Even, PEG method may be associated with higher risk of pressure ulcers as secondary adverse effects (36). Also, in other disorder with nutritional problems such as Amyotrophic lateral sclerosis no signi cant improvement in mortality or survival were observed (37).
In the current meta-analysis, we observed that NGT in compared to PEG in dementia patients can signi cantly reduce mortality rate.
Although the results of studies in this area are con icting, the majority of evidences did not observe signi cant effects on mortality or survival (18). A meta-analysis by Elke et al (2016) reported that in critically ill patients, the NGT had no effect on mortality rate but could decreases comorbidities (such as infectious complications or mechanical ventilation (38). Another study also, reported that the PEG insertion is more effective and safer compared to NGT, but no signi cant difference in mortality rates or adverse outcomes were observed (39). It seems that mortality or survival may depend more on nature and stage of disease, comorbidities and performance status which still poorly have been investigated (40).
In addition, our subgroup analysis found 80≤ age as a strong predictor of 2-years mortality which is contrary to Ticinesi et al. results (28).
Parallel with this, it has been observed that PEG insertion in patients before the age of 80 had signi cantly longer survival than others (41, 42). However, Further studies are needed to reach a de nitive conclusion in this case. In this regard, to evaluate the effect of PEG feeding on mortality and survival and make a correct decision to apply in patients with dementia, further comprehensive evaluation of comorbidities, underlying disease, life style, cognitive and physical performance as well as nutritional problems should be conducted in older patients with advanced or not-advanced dementia.
The main limitation of the present study was that the control group was not homogeneous in terms of underlying diseases and the feeding method adjusted by subgrouping analysis. Another limitation was the limit number of studies in primary dementia condition. The majority of studies were performed in patients with secondary dementia derived from stroke or other disease. In addition, the stage of dementia was not mentioned in many studies which exert a considerable effect on prognosis of disease.

Conclusions
In conclusion, present systematic review and meta-analysis showed that PEG insertion in patients with primary dementia has no signi cant effect on mortality rate or median survival. It seems that NGT feeding in compared to PEG in this population is more effective in the context of reduction of mortality rate. Larger human studies with considering clinical, paraclinical and nutritional status as well as disease stage, etc., should be performed in primary dementia patients to clarify whether PEG feeding method can be effective in reducing mortality and increasing survival.

Availability of data and materials
The data that support the ndings of this study are available from Mina Abdolahi but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Mina Abdolahi (m-abdolahi@razi.tums.ac.ir)

Competing interests
The authors declare that they have no competing interests.   a The study quality was assessed according to the Newcastle Ottawa Quality assessment scale for cohort studies. This scale awards a maximum of 9 points to each study: 4 for selection, 2 for comparability, and 3 for assessment of outcomes (for cohort study). 1 = "Yes", 0 = "No", "Unable to determine" or "Not available      30-day mortality rate in demented patients with PEG feeding Figure 3 90-day mortality rate in demented patients with PEG feeding Figure 4 180-day mortality rate in demented patients with PEG feeding Page 16/16 Figure 5 1-year mortality rate in demented patients with PEG feeding Figure 6 2-yaer mortality rate in demented patients with PEG feeding Figure 7 Median survival in demented patients with PEG feeding

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