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Effect of hypoalbuminemia on short-term outcomes after colorectal cancer surgery: A propensity score matching analysis

Purpose The purpose of our study was to investigate the effect of pre-operative hypoalbuminemia on the short-term outcomes after primary colorectal cancer (CRC) surgery. Materials and methods The retrospective study enrolled CRC patients who underwent primary surgery from January 2011 to December 2021 in a single teaching hospital. The short-term outcomes were compared between the hypoalbuminemia group and the normal group using propensity score matching (PSM). Univariate and multivariate logistic regression analyses were used for analyzing independent predictors of overall complications and major complications. Results A total of 7,072 patients from a single center were enrolled in this study. There were 1,078 (15.2%) patients in the pre-operative hypoalbuminemia group and 5,994 (84.8%) patients in the normal pre-operative albumin group. After 1:1 PSM, there were 1,028 patients in the hypoalbuminemia group and 1,028 patients in the normal group. No significant differences were found in baseline information between the two groups after PSM. In terms of short-term outcomes, the hypoalbuminemia group had a longer operation time (p = 0.003), greater volume of blood loss (p = 0.036), longer hospital stays (p < 0.01), higher proportion of overall complications (p = 0.003), major complications (p = 0.016), higher incidence of pneumonia and abdominal infection (p = 0.001) than the normal group after PSM. Furthermore, hypoalbuminemia was an independent predictor for overall complications (p = 0.008) and major complications (p = 0.016). Conclusion Pre-operative hypoalbuminemia increased overall complications and major complications after primary CRC surgery. Furthermore, hypoalbuminemia was an independent predictor for overall complications and major complications.


Introduction
Colorectal cancer (CRC) is the third most commonly occurring cancer and the second leading cause of cancerrelated mortality worldwide (1)(2)(3). It is estimated that approximately 147,950 new CRC cases would be diagnosed, and 53,200 individuals would die of this disease in 2020 (4,5). Although there have been many treatment methods for CRC including endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), surgery, cytotoxic chemotherapy, radiotherapy, and biologic therapy such as antibodies to cellular growth factors, immunotherapy, and combinations of methods (6)(7)(8), surgical resection remains the main curative option for both colon and rectal cancer (9)(10)(11).
Previous studies have shown that the rates of malnutrition in CRC patients ranged from 20 to 37%, depending on the tool used to assess nutritional status (12,13). Pre-operative malnutrition is associated with higher post-operative morbidity, mortality, and length of hospital stay (14). Albumin has been used as a nutritional and inflammatory indicator (15) and preoperative hypoalbuminemia was associated with post-operative complications, mortality, overall survival (OS), and cancerspecific survival (CSS) (16-18).
Hu et al. (19) previously reported an effect of pre-operative mild hypoalbuminemia on post-operative complications in CRC patients using propensity score matching (PSM), however, it depended on the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database which lacks some important data such as tumor stage, operative time, the volume of blood loss, and length of hospital stay which are crucial in analyzing the effect of hypoalbuminemia on prognosis. Therefore, the purpose of our study was to investigate the effect of pre-operative hypoalbuminemia on short-term outcomes after primary CRC surgery using PSM.

Setting
We retrospectively enrolled patients who underwent primary CRC surgery from January 2011 to December 2021 in a single teaching hospital. The study was approved by the ethics committee of the First Affiliated Hospital of Chongqing Medical University (2022-K205), and informed consent was obtained from all participants.

Study population selection
All enrolled patients underwent radical CRC resection (total mesorectal excision or complete mesocolic excision) by experienced surgeons according to the clinical guidelines, and the pathologic examination confirmed R0 resection. The exclusion criteria were as follows: (1) recurrent CRC surgery; (2) non-R0 CRC surgery, which was confirmed according to the pathologic examination; (3) incomplete baseline information; (4) incomplete information on albumin, hemoglobin, and lymphocyte levels.

Covariates
Data were collected through the inpatient system, outpatient system, and telephone review. The baseline information included serum albumin level, age, sex, body mass index (BMI), smoking, drinking, hypertension, type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), chronic kidney disease (CKD), chronic liver disease (CLD), surgical history, laparoscopy, serum hemoglobin and lymphocyte levels, tumor size, tumor location, and tumor stage. Blood for testing was collected in the morning after 8 h of fasting in the supine position on the first day after admission.
The short-term outcomes studies were operation time, the volume of blood loss, hospital stay, blood transfusion, and overall complications (including anastomotic leakage, pneumonia, wound infection, lymphatic fistula, intestinal obstruction, venous thrombosis, abdominal infection, 30-day death, and other complications), major complications. The tumor stage was diagnosed according to the AJCC 8th Edition (20). Pre-operative serum albumin < 35 g/L was considered hypoalbuminemia. The severity of post-operative complications was defined according to the Clavien-Dindo classification (21), and ≥III classification, including requiring surgical, Frontiers in Nutrition 02 frontiersin.org Flow chart of patient selection.
endoscopic, or radiological intervention; life-threatening complications (central nervous system complications: brain hemorrhage, ischemic stroke, and subarachnoid bleeding, but excluding transient ischemic attacks); requiring intermediate care (IC)/intensive care unit (ICU) management and death were considered major complications (21,22).

Statistical analysis
Propensity score matching was conducted between the hypoalbuminemia group and the normal group to minimize the bias of baseline information. Nearest neighbor matching was performed without replacement at a 1:1 ratio and a caliper width with a.01 standard deviation was specified. The baseline information was matched including age, sex, BMI, smoking, drinking, hypertension, T2DM, CHD, CKD, CLD, surgical history, laparoscopy, serum hemoglobin and lymphocyte levels, tumor size, tumor location, and tumor stage.
For statistical analysis, SPSS 22 analysis software was used. Continuous variables are expressed as the mean ± standard deviation (SD) and an independent-sample t-test was used to compare the difference between the hypoalbuminemia group and the normal group. Categorical variables are expressed as absolute values and percentages, and the Chi-square test or Fisher's exact test was used to compare the differences between the hypoalbuminemia group and the normal group. Univariate and multivariate logistic regression analyses were performed to identify independent predictive factors for overall complications and major complications. A bilateral p-value < 0.05 was considered statistically significant.

Results
According to the inclusion and exclusion criteria, a total of 7,072 patients with CRC from a single center were enrolled. There were 1,078 (15.2%) patients in the pre-operative hypoalbuminemia group and 5,994 (84.8%) patients in the normal pre-operative albumin level group. After 1:1 PSM, 1028 patients with pre-operative hypoalbuminemia and 1,028 without pre-operative hypoalbuminemia were included in this study. The flow chart of patient selection is shown in Figure 1.  Variables are expressed as the mean ± SD, n (%), *P-value < 0.05. T2DM, type 2 diabetes mellitus; BMI, body mass index; PSM, propensity score matching; CHD, coronary heart disease; CKD, chronic kidney disease; CLD, chronic liver disease.

Baseline information
Baseline information was compared between the hypoalbuminemia group and the normal group. The hypoalbuminemia group had an older age (p < 0.01), lower BMI (p < 0.01), lower proportion of CHD (p < 0.01), lower proportion of laparoscopic CRC surgery (p < 0.01), lower serum hemoglobin level (p < 0.01), fewer serum lymphocyte (p < 0.01), larger tumor size (p < 0.01), and higher portion of colon cancer (p < 0.01) than the normal group before PSM. However, there were no significant differences in age, CHD, laparoscopy, hemoglobin, lymphocytes, tumor size, tumor location, or tumor stage between the two groups after PSM (p > 0.05) ( Table 1). Table 2 shows the differences in short-term outcomes, including operation time, the volume of blood loss, hospital stay, blood transfusion, overall complications, major complications, 30-day death, and different types of post-operative complications between the hypoalbuminemia group and the normal group before and after PSM. The hypoalbuminemia group had a longer operation time (p = 0.015), greater volume of blood loss (p < 0.01), longer hospital stays (p < 0.01), higher proportion of blood transfusion (p < 0.01), overall complications (p < 0.01), major complications (p < 0.01), and 30-day death (p < 0.01) than the normal group before PSM. In terms of post-operative complications, the hypoalbuminemia group had more pneumonia (p < 0.01), wound infection       Table 3).  Table 4).

Discussion
In this study, we found that the hypoalbuminemia group had a longer operation time and hospital stay, a greater volume of blood loss, a higher proportion of overall complications and major complications, and a greater incidence of pneumonia and abdominal infection than the normal group after 1:1 PSM. Hypoalbuminemia was an independent predictor for overall complications and major complications.
Regarding short-term outcomes, some studies reported that pre-operative hypoalbuminemia was associated with postoperative outcomes following CRC surgery including prolonged length of hospital stay (16,17,26,31), more complications (15, 17-19, 24, 26, 28, 29), and higher incidence of mortality (15,19,27,29). However, most of these studies had small sample sizes, and all of them lacked the matching of confounding factors in basic data which may interfere with the results. Hu et al. (19) previously reported that pre-operative mild hypoalbuminemia affected post-operative complications for CRC patients using PSM, however, it depended on the ACS-NSQIP database which lacked some important data such as tumor stage, operative time, the volume of blood loss, and length of hospital stay which were crucial in analyzing the effect of hypoalbuminemia on prognosis. Interestingly, the study of Sofić et al. (30) showed that pre-operatively measured levels of serum albumin cannot serve as predictors for post-operative complications. Therefore, whether pre-operative hypoalbuminemia can affect short-term outcomes or be an independent predictor for overall complications and major complications after primary radical CRC surgery should be analyzed in a large sample size with less confounding baseline information.
In this study, we analyzed the effect of pre-operative hypoalbuminemia on the short-term outcomes of CRC surgery, furthermore, PSM was conducted to minimize the bias of baseline information. To avoid affecting pre-operative serum albumin levels, commodities, including CKD and CLD were analyzed by PSM between the two groups. We found that pre-operative hypoalbuminemia prolonged the operation time and hospital stays and increased blood loss and the incidence of major complications and pneumonia. Albumin is the most abundant protein in human blood and increasing capillary permeability during inflammation promotes albumin transfer to the interstitial space (32,33). Hypoalbuminemia was associated with inflammation (32,34,35), indicating that in patients with pre-operative inflammation (36), the inflammation might induce more blood loss, increase the difficulty of the operation and prolong the operation time. Furthermore, hypoalbuminemia affects tissue damage and wound healing post-operatively, impairing gastrointestinal function and mobility, and slowing recovery (35,36), which might lead to a longer hospital stay.
After 1:1 PSM, we found that the hypoalbuminemia group had more overall complications than the normal group. In one study that enrolled 75 patients in the hypoalbuminemia group and 32 patients in the normal group pre-operatively measured levels of serum albumin could not serve as predictors for post-operative complications (30). The sample size of this German study was small, and some bias might exist. In the present study, hypoalbuminemia was found to be an independent predictive factor of overall complications, which was consistent with a previous study (17). A decrease in pre-operative albumin might be associated with inflammation which increases tissue catabolism (37), and patients with colorectal cancer might have accelerated loss of albumin from the gastrointestinal tract (32,37,38). Therefore, hypoalbuminemia might increase the incidence of post-operative overall complications.
Regarding major complications, the hypoalbuminemia group had more major complications than the normal group after PSM in this study. Many factors might affect major complications after primary CRC surgery, such as age, preoperative morbidities, surgical methods, and tumor stage (39). A previous study showed that hypoalbuminemia was an independent risk factor for post-operative high-grade morbidity (28), and Montomoli et al. (27) found that pre-operative hypoalbuminemia increased 30-day mortality following CRC surgery. Our study was consistent with these studies, and we also found that hypoalbuminemia was an independent predictive factor of major complications. Large samples and randomized controlled trials are needed to clarify the mechanisms of this correlation.
The current study analyzed the effect of hypoalbuminemia on short-term outcomes after CRC surgery in relatively big data using PSM. To our knowledge, this was the first study to analyze the effect of pre-operative hypoalbuminemia on short-term outcomes after primary radical CRC surgery in southwestern China.
There are some limitations of our study. First, this was a retrospective single-center study that inevitably had some selection bias. Second, the important inflammation parameter C-reactive protein (CRP) was not a routine test in our patients; we did not include CRP in this study and did not judge the degree of inflammation. Third, we defined hypoalbuminemia according to the lower limit of reference values and did not consider it a continuous variable or classify it into multiple categories, which might affect the results. Multicenter and multigroup (according to different serum albumin levels) trials with long-term prognosis could be conducted further.
In conclusion, pre-operative hypoalbuminemia increases overall complications and major complications after primary CRC surgery. Furthermore, hypoalbuminemia is an independent predictor for overall complications and major complications.

Data availability statement
The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethics statement
The studies involving human participants were reviewed and approved by The First Affiliated Hospital of Chongqing Medical University, 2022-K205. The patients/participants provided their written informed consent to participate in this study.

Author contributions
BK, X-YL, and DP contributed to the conception and design of the study. Y-XC and WT organized the database. DP finished the statistical analysis. BK and X-YL wrote the first draft of the manuscript. All authors contributed to revising the manuscript, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.