Postoperative Hypoalbuminemia: Prevalence, Risk Factors, Association with Postoperative Pneumonia in Brain Tumors Patients Undergoing Craniotomy

Purpose Hypoalbuminemia is associatied with to poor outcome in patients undergoing surgery intervention. The main aim for this study was to investigate the incidence and the risk factors of postoperative hypoalbuminemia and assessed the impact of postoperative hypoalbuminemia on postoperative complications in patients undergoing brain tumor surgery. Methods This retrospective study included 372 consecutive patients who underwent craniotomy for brain tumors from January 2017 to December 2019. The demographic data, pre- and post-operative laboratory tests and postoperative complications were collected. The patients were divided into two groups based on the postoperative serum albumin levels; hypoalbuminemia group (< 35 g/L) and non-hypoalbuminemia group ( ≥ 35 g/L). Univariate and multivariate logistic regression analyses were used to determine risk factors of postoperative hypoalbuminemia and complications. incision failure, renal failure, hydrocephalus, thrombosis) The pre- and rst post-operative (within 6 hours after surgery) laboratory tests included white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count, brinogen (FIB), prothrombin time (PT), prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), thrombin time (TT), D-dimers, potassium (K), sodium (Na), chloride (Cl), blood glucose, calcium (Ca), phosphorus (P), magnesium (Mg), serum prealbumin, total protein, albumin and albumin/globulin (A/G) ratio.


Introduction
Hypoalbuminemia is associated with poor postoperative outcomes and complications in patients underwent surgical intervention, such as cardiac [1,2], hand [3], colorectal cancer surgery [4] and orthopedic surgery [5,6]. In central nervous system, hypoalbuminemia is also associated with increased odds of mortality and a nonroutine hospital discharge [7,8], and is a risk factor for postoperative acute kidney injury in patients who underwent craniotomy for tumor [9]. In addition, hypoalbuminemia is independent predictor of extended hospital stay following brain tumor surgery [10].
Postoperative hypoalbuminemia has a considerable incidence in patients underwent craniotomy due to brain tumor in our institution. However, little is known about the association between preoperative clinical parameters and postoperative hypoalbuminemia in patients undergoing brain tumor surgery. Thus, the aim of our study was to investigate the incidence and the risk factors of postoperative albuminemia in patients underwent brain tumor surgery. Furthermore, we assessed the impact of postoperative hypoalbuminemia on postoperative complications after brain tumor surgery. University has approved this study. For retrospective study, formal consent is not required and the requirement for the informed consent of patients was waived prior to the collection of their medical data in this study.

Inclusion and exclusion criteria
In this study, 372 adult patients with normal preoperative total (≥ 60 g/L) and albumin (≥ 35 g/L), who underwent craniotomy due to intracranial solid tumors, such as gliomas, meningiomas, acoustic neuromas, and metastatic tumors, were included. Patients who underwent craniotomy due to non-solid tumors, such as aneurysm, vascular malformation, intracerebral hemorrhage, hydrocephalus, cranioplasty or skull lesion, had been excluded. Patients younger than 18 years old, who had hypoalbuminemia (< 35 g/L) before operation were also excluded. Patients with abnormal proteinuria that may lead to protein loss were also excluded. For the purpose of this study, patients with postoperative serum albumin of < 35 g/L were de ned as hypoalbuminemia group, while those with postoperative serum albumin of ≥ 35 g/L were de ned as non-hypoalbuminemia group. The postoperative albumin level was checked on the rst blood samples taken upon after craniotomy.

Clinical data collection
For each patients, demographic data [age, sex, body mass index (BMI), histories of smoking and drinking], comorbidities (hypertension, diabetes mellitus, coronary heart disease, viral hepatitis, and history of stroke etc.), as well as pre-and post-operaotive laboratory test were collected. Operation time, intraoperative blood loss, intraoperative total input and intraoperative total urine output composed the operative-related medical data. Pathological classi cation were documented according to Central Nervous System Tumor Classi cation by the World Health Organization in 2016. The durations of postoperative neurological intensive care unit (NICU) and hospitalization and postoperative complications (pneumonia, epilepsy, incision infection, respiratory failure, renal failure, hydrocephalus, deep vein thrombosis) were also collected.

Statistical analysis
All statistical analysis was performed using the SPSS software for Windows (version 25.0, IBM SPSS Inc., Chicago, IL) software. Descriptive statistical analysis of the data (e.g., means, medians, frequencies, and percentages) was performed. Normally distributed quantitative variables are presented as the mean ± standard deviation (SD) and were compared using independent unpaired two-tailed Student's t test. Nonnormally distributed quantitative variables are presented as the median [interquartile range (IQR)] and were compared using independent-sample nonparametric test. Categorical variables were expressed as counts with percentages and compared using the chi-squared test or continuity correction test. Logistics reression analysis was used to investigate the risk factors of postoperative hypoalbuminemia and pneumonia. The variables were analyzed by univariate binary logistic regression analysis. Multicolinearity was assessed using the Pearson correlation coe cient statistic and by checking the Variance In ation Factor multiple regression model with the same dependent and independent variables. Multivariate logistic regression model was performed on variables with signi cant differences (P < 0.05) determined in the univariate analysis to investigate the relationship between variables and postoperative hypoalbuminemia/pneumonia. All statistical tests of hypothesis performed at the 0.05 level of signi cance.

Characteristics of Patients Underwent Craniotomy for Tumor
A total of 372 patients who underwent craniotomy for solid tumors [161 male (43.3%), 211 female (56.7%)] with a mean age of 48 ± 13 years (range 20-86 years) were enrolled. Of these, 333 (89.5%) patients developed hypoalbuminemia, whereas 39 (10.5%) patients remained normal albumin levels after craniotomy. There were signi cant statistical differences in BMI (P < 0.05) between with and without hypoalbuminemia patients. The patients with hypoalbuminemia had signi cant greater intraoperative blood loss, intraoperative total input, intraoperative total urine output, operation time and incidence of postoperative pneumonia than those without hypoalbuminemia after craniotomy (all P < 0.05). There were no signi cant differences in age, sex, previous diseases, lifestyle factors, pathological classi cation and other complications (all P > 0.05) between the two groups. The baseline characteristics of the two groups patients are shown in Table 1. There were signi cant statistical differences in preoperative laboratory tests, including red blood cells, PT, albumin, globulin, A/G ratio (P < 0.05) between with and without postoperative hypoalbuminemia patients (Table 2).

Predictors Associated with Postoperative Hypoalbuminemia
In univariate analysis, BMI, intraoperative blood loss, intraoperative total input, intraoperative total urine output, operation time, red blood cells, PT, albumin, globulin and A/G ratio were signi cantly associated with postoperative hypoalbuminemia (  (Table 4).

Predictors Associated with Postoperative Pneumonia
The overall incidence rate of postoperative pneumonia was 39.2% in total of 372 patients underwent craniotomy for brain tumor resection. Table 1 shows that the incidence of postoperative pneumonia in patients with hypoalbuminemia (41.1%) signi cantly higher than that in patients without hypoalbuminemia (23.1%) (P = 0.029). So we compared the baseline characteristics and postoperative laboratory test data of patients with and without postoperative pneumonia (Supplementary table 1 (Table 5).

Discussion
In this study, the overall incidence of postoperative hypoalbuminemia was 89.5% in brain tumor patients after craniotomy surgery. Patients with hypoalbuminemia had a higher intraoperative blood loss, intraoperative total input, intraoperative total urine output, operation time and incidence of postoperative pneumonia compared to the patients without hypoalbuminemia. Logistic regression analysis showed that operation time, preoperative albumin and peroperative globulin were independent risk factors of postoperative hypoalbuminemia in brain tumor postoperative patients. To our knowledge, there are few reports about the incidence and risk factors of postoperative hypoalbuminemia in patients after brain tumor surgery. In addition, the hypoalbuminemic patients showed a higher rate of pneumonia. Increasing age, extending operation time and decreasing postoperative albumin were risk factors of postoperative pneumonia.
For the mechanism of hypoalbuminemia, decreased intestinal absorption of protein due to poor oral intake, decreased synthesis of albumin due to hepatic dysfunction, increased catabolism of protein, albuminuria, and extensive vascular leakage of serum protein due to increased capillary permeability have been postulated [11]. In this study, the preoperative albumin of the patients were in the normal levels, and there was no signi cant differences between with and without postoperative hypoalbuminemia in the related diseases that may affect protein metabolism and loss, such as hepatitis and diabetes. In our institution, we performed a uniform preoperative fasting time for patients who prepared surgery for brain tumor. Therefore, we speculate that the early decrease of albumin may be related to the intraoperative blood loss and hemodilution caused by positive volume infusion [12]. While patients with hypoalbuminemia had lower levels in red blood cells, hemoglobin, hematocrit, platelets, total protein and A/G ratio (data not shown), which also proved that hemodilution may be responsible for dilution hypoalbuminemia. The extended operation time aggravates the occurrence of this process. The results proved that increasing operation time was an independent risk factor for postoperative hypoalbuminemia, which suggest that surgeons should shorten operation time as much as possible to avoid the risk of postoperative hypoalbuminemia and its related poor outcome.
Hypoalbuminemia is associated with poor outcomes in patients undergoing surgical intervention. In central nervous system, preoperative hypoalbuminemia affected the prognoses of patients with glioblastomas [13,14]. Hypoalbuminemia is also associated with increased odds of mortality and a nonroutine hospital discharge [7,8], and is a risk factor for postoperative acute kidney injury in patients who underwent craniotomy for tumor [9]. In addition, hypoalbuminemia is independent predictor of extended hospital stay following brain tumor surgery [10].
Postoperative pulmonary complications were signi cantly associated with poor outcome, including higher reoperation, readmission, mortality, and extended hospital stay in patients that surgical resection of brain tumors [15,16]. Previous study identi ed increasing operative time, increasing age, and increasing estimated blood loss, diabetes, chronic obstructive pulmonary disease, preoperative leukocytosis, American Society of Anesthesiologists classi cation ≥ 3, and infratentorial lesions as risk factors for postoperative pneumonia in postcraniotomy patients [15][16][17]. However, in infratentorial craniotomy with high risk for the development of postoperative pulmonary complications, the predictors for the occurrence of postoperative pulmonary complications were postoperative blood transfusion, lower cranial nerve palsy, prolonged ICU stay and tracheostomy [18]. Our result showed that pneumonia was more frequently incident in patients with hypoalbuminemia than in patients without hypoalbuminemia. Increasing age, extending operative time as risk factors for postoperative pneumonia were consistent with previous studies [15][16][17]. Postoperative albumin as a novel factors warrant further investigation.
We believe the results from our analysis can provide several bene ts to neurosurgeons and neuroanesthesiologists alike. Most evident is the identi cation of brain tumor patients at risk for postoperative hypoalbuminemia and pneumonia, but perhaps more meaningful is the quanti cation of independent predictors. In addition, the results can provide several suggestions. Surgeons should shorten the operation time as much as possible, while neuroanesthesiologists should re ne the management of intraoperative blood volume and respiratory tract.
Nevertheless, our present study also had several limitations. Firstly, this was a single-center retrospective case control study, which has obvious limitations. Secondly, whether preoperative albumin is normal or not as the inclusion criteria may lead to greater heterogeneity of patients. Thirdly, whether albumin supply can change the incidence of pneumonia still needs to be veri ed by prospective randomized trials.

Conclusions
The incidence of hypoalbuminemia after craniotomy for brain tumors was high, and the incidence of postoperative pneumonia was higher in patients with hypoalbuminemia. The operation time was common independent risk factors for postoperative hypoalbuminemia and pneumonia. Moreover, our results demonstrate that older age and hypoproteinemia have great potential as predictors of postoperative pneumonia and suggests that clinicians need to provide early management of postoperative hypoproteinemia for the prevention of pneumonia. However, a prospective study is needed to determine whether albumin supply can change the incidence of pneumonia in patients underwent craniotomy due to brain tumor.

Declarations
Funding: Not applicable Con icts of interest: The authors declare that they have no con ict of interest.
Data Availability Statement: The datasets used and analysed to support the ndings of current study are available from the corresponding author upon reasonable request.