Association Between Serum Albumin and Mortality in Older People With Dysphagia: a Retrospective Cohort Study

Gaigai Li The Second A liated Hospital of Guizhou University of Traditional Chinese Medicine Tongtao Fan (  gyfyfantongtao@163.com ) A liated Hospital of Guizhou Medical University Xun Zhou The Second A liated Hospital of Guizhou University of Traditional Chinese Medicine Xunrui Hou A liated Hospital of Guizhou Medical University Yuheng Luo A liated Hospital of Guizhou Medical University Danmao Li A liated Hospital of Guizhou Medical University


Introduction
Dysphagia, or disordered oropharyngeal swallowing, is a common nding in elderly persons [1] whether institutionalized or living in the community [2,3], caused by age-related physiological changes in swallowing, including a decline of swallowing function and decreased digestive tract motility due to decreases in muscle mass and connective tissue elasticity [4,5]. Cicheroet[6]reported a 25-30% prevalence among acute inpatients who underwent clinical screening for dysphagia. Dysphagia may lead to malnutrition, dehydration [5]. It is a risk factor for pneumonia, and a risk factor for mortality from pneumonia [7,8] and stroke [9].
Serum albumin is a widely used routine clinical test and serves as a biomarker of in ammatory and nutritional status [10][11][12], which is a reliable index of malnutrition. The effect of in ammation on albumin levels is responsible for much of the morbidity and mortality associated with hypoalbuminemia [10]. Some of the prior studies reported serum albumin is association with chronic kidney disease and cardiovascular [13][14][15],also a risk factor for dysphagia in elderly hip fracture surgery patients [16]. Hypoalbuminemia is strongly associated with mortality [12], and were an independent determinant of poor outcome following acute ischemic stroke [17].
Although some studies have shown that serum albumin is associated with many diseases, but no studies have revealed the association between serum albumin and mortality in elderly swallowing patients. A previous propensity-matched cohort study shows PEG (percutaneous endoscopic gastrostomy) was associated with a signi cantly longer survival time in older persons with dysphagia[18]. We perform a secondary analysis of the cohort study data to evaluate whether there is a link between serum albumin and mortality among participants in Japan.

Patients And Methods
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Study population and design
This study was a single-center, retrospective cohort study. Consecutive older patients with dysphagia who received PEG or TPN ( total parenteral nutrition) [19] between January 2014 and January 2017 in Japan. People who had advanced cancer or required a PEG for gastric decompression were excluded. Patients who had a PEG inserted before January 2014 were also excluded.
Because of the anonymous nature of the data, the requirement for informed consent was waived. All methods were performed in accordance with the relevant guidelines and regulations. The present study was approved by the Ethical Review Board of Miyanomori Memorial Hospital and was exempted from informed consent requirements owing to its retrospective design.

Procedures
The decision to select PEG feeding or TPN was made after su cient discussion, including patients or their family and clinicians. Appropriate nutrition was administered based on clinical evaluation by clinicians. Clinical details were obtained from patients' medical records including age, gender, height, weight, underlying diseases, and blood test results.

Laboratory assays
The blood test results were performed within 7 days before the start of PEG feeding or TPN. Body mass index (BMI) was calculated using the height and weight measured on admission. Daily calorie was investigated on the seventh day after the procedure in both groups.

Outcomes
The primary outcome was de ned as mortality after the start of the procedure during the follow-up period.

Statistical analysis
All normally distributed and skewed continuous variables were described as mean (SD) or median (interquartile range [IQR]). Categorical variables were expressed as frequencies (%). Baseline characteristics are presented according to the serum albumin by 3g/dl. Multivariable Cox regression analyses were adopted to assess the independent association between serum albumin and mortality. An extended Cox model approach was used for different covariates adjusted models. Survival curves were plotted by Kaplan-Meier analyses. These potential confounders were chosen on the basis of previous scienti c literature, or a more than 10% change in effect estimates.All the analyses were performed with the statistical software packages R (http://www.R-project.org, The R Foundation) and Free Statistics software versions 1.2.

Study participants and baseline characteristics
A total of 253 patients were included in the analysis, of whom the number of serum albumin below 3g/dl was 93. 180 underwent PEG feeding and 73 peoples underwent TPN. The median length of follow-up for censored cases was 601 days (range, 404-823 days). The mean age was 84.8 years old (SD 7.1) in low serum albumin group. The mean hemoglobin value was 9.8g/dl (SD 1.9) in low serum albumin group. The median of survival time was 306 days. Baseline clinical and biochemical characteristics of participants were strati ed by serum albumin(3g/dl) in Table 1.

Kaplan-Meier curve
The Kaplan-Meier curve is illustrated in Figure 1. The log-rank test showed a signi cantly longer mortality in the high group(serum albumin >=3g/dl) compared with the low group (median, 382 vs 176 days, P < 0.0001).

Association between serum albumin and mortality in different models
Cox regression analysis showed that unadjusted HR for the high group relative to the low group was 0.40 (95% CI: 0.29-0.57; P <0.001). After adjustment in multivariable analyses, serum albumin was signi cantly associated with mortality, so that survival time was longer in Alb≥3 compared with Alb<3 group. Furthermore, additional adjustment for age, sex, PEG, cerebrovascular diseases, severe dementia, neuromuscular diseases, aspiration pneumonia, chronic heart failure, total lymphocyte count (mm3), and c-reactive protein (mg/dl) did not substantially change the results. The adjusted HRs (95% CI) for total mortality rates were 0.46 (0.33~0.65), 0.66 (0.44~0.99) and 0.64 (0.42~0.97), from model 2 to model 4.

Discussion
In this retrospective study, we found that lower levels of serum albumin (<3g/dl) were associated with an increased risk of mortality. The association persisted after adjusting for different models.
The elderly people are more likely to suffer malnutrition due to a comprehensive factors, from physiological changes, such as appetite loss, changes in taste, depressive symptoms, to social and economic factors such as income, living circumstances and lifestyle [20][21][22]. Malnutrition in elderly was associated with higher mortality risk [23] and poor Quality of life [24] .
Serum albumin, a protein which is synthesized in the liver [25], is a marker of nutritional status of older people [26,27]. Serum albumin has antioxidative properties[28] and low serum concentrations have been suggested to be an indicator of in ammation, hypercoagulable states and liver disease [29,30]. The levels of serum albumin are associated with various diseases, although some studies do not provide direct evidence [31], other studies report that a lower concentration of serum albumin is associated with cardiovascular mortality, acute respiratory distress syndrome, acute stroke, chronic kidney disease and other complications [13-15, 32, 33]. Indeed, a meta-analysis showed that hypoalbuminemia was an independent predictor of poor outcome [34], which appeared to be independent of both nutritional status and in ammation. A study showed that low admission serum albumin was a prognostic determinant of 30-day case fatality and adverse functional outcome following acute ischemic stroke [35].Meanwhile, high serum albumin has a protective effect in healthy older persons who do not have evidence of cytokine-mediated in ammation [33] .
On one hand, serum albumin may refelect the the nutritional state of the human body. On the other hand, we can use proserum to supplement the serum albumin when below 3 g/dl. Protein powders and a high protein diet was needed when the serum albumin was 3-4 g/dl. Albumin administration may improve organ function and in hypoalbuminemic critically ill patients [36]. However, results of the SOAP study [37] showed ICU and hospital mortality rates were higher in patients who received albumin than those not. Other two studies revealed the similar results, albumin using showed no bene t in outcome [38,39]. Further studies are needed to clarify the role of albumin in ICU patients.
The subgroup of PEG shows no differences in two groups(Supplementary material Tbble1). Previous studies have shown that enteral nutrition was associated with lower mortality rates [40,41]. Also there is no signi cant superiority of TPN feeding compared with PEG [42,43]. The FOOD study didn't support a policy of early initiation of PEG feeding in dysphagic stroke patients [44]. There is strong evidence for not using enteral nutrition (EN) in the rst week in dysphagic, and not using volitional nutrition support (VNS) in nondysphagic stroke patients [45].
There are some limitations to our study. First, subjects in this study were older people with dysphagia, thus limiting the generalizability of our ndings. Second, there is a possibility of a selection bias because we only had one measurement of serum albumin within 7 days of hospitalization, without follow-up measurements. We were unable to assess the effect of serum albumin levels at different time periods on outcomes. Third, this was single-center study, and the sample size is small, so a larger multicenter sample is needed to con rm this result.
Fourth, this was a retrospective observational study ,therefore, assignment to each group may have been biased. Information bias and unmeasured confounding could have in uenced our results.

Conclusions
Our results suggest that there is negative association between serum albumin and mortality in older people with dysphagia, implying we should pay more attention to the serum albumin and nutritional status of elderly people.

Data Availability
The data are available at http://www.Datadryad.org/. which allows researchers to freely download the original data.

Con ict of interest
The authors have declared that no competing interests exist. Kaplan Meier curve of time to death during follow-up. The log-rank test showed a signi cantly longer mortality in the high group(serum albumin >=3g/dl) compared with the low group (median, 382 vs 176 days, P < 0.0001).

Supplementary Files
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